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S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao Bai, a Alexander M. Kluwer b and and Joost N. H. Reek *a,b a Homogeneous, Supramolecular and Bio-inspired Catalysis, Van ‘t Hoff Institute for Molecular Sciences (HIMS), University of Amsterdam (UvA), Science Park 904, 1098 XH Amsterdam, The Netherlands. Email: [email protected] b InCatT B.V. Science Park 904, 1098 XH Amsterdam, The Netherlands. Electronic Supplementary Material (ESI) for Chemical Communications. This journal is © The Royal Society of Chemistry 2019
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Page 1: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S1

Supporting Information

Effector enhanced enantioselective hydroformylation

Shao-Tao Baia Alexander M Kluwerb and and Joost N H Reekab

a Homogeneous Supramolecular and Bio-inspired Catalysis Van lsquot Hoff Institute for

Molecular Sciences (HIMS) University of Amsterdam (UvA) Science Park 904 1098 XH

Amsterdam The Netherlands Email jnhreekuvanl

b InCatT BV Science Park 904 1098 XH Amsterdam The Netherlands

Electronic Supplementary Material (ESI) for Chemical CommunicationsThis journal is copy The Royal Society of Chemistry 2019

S2

Table of Contents

General Information S3

Synthesis of DIM-ligands L1-3 S3

The effectors used in this study S12

General procedures for the hydroformylation reaction S18

Hydroformylation results S19

S3

General Information

All reactions involving air- or moisture sensitive materials were carried out under nitrogen

atmosphere using standard Schlenk techniques or in Glove-box THF pentane hexane and

toluene were distilled from sodium-benzophenone under nitrogen atmosphere

dichloromethane methanol were distilled from CaH2 under nitrogen atmosphere triethylamine

was distilled from KOH pellets under nitrogen Toluene-d8 CD2Cl2 and NN-

diisopropylethylamine were dried over molecular sieves (3Aring) and degassed by three freeze-

pump-thaw cycles 1H NMR 13C NMR 31P NMR 1H31P NMR experiments were performed

on Bruker AMX 300 MHz Bruker AMX 400 MHz or Bruker AMX 500 MHz 1H NMR

chemical shifts are given in ppm and were calibrated by using the residual solvent as internal

reference (CHCl3 726 ppm CH2Cl2 532 ppm) 13C NMR chemical shifts were reported in ppm

with the solvent peaks used as internal reference (CHCl3 7716 ppm CH2Cl2 5384 ppm) Mass

spectra were collected on an AccuTOF GC v 4g JMS-T100GCV Mass spectrometer (JEOL

Japan) If not stated otherwise syngas referred to a 11 mixture of H2 and CO and the pressure

refers to a sum pressure of both All reagents were purchased from commercial suppliers and

used without further purification unless otherwise noted

Synthesis of DIM-ligands L1-3

Scheme S1 Synthesis of Ligand L11) C2H5CHO CH3CO2H reflux 2 hours 2) C2H5CHO

conc HCl reflux 2 hours 3) 1 bar H2 PdC THFMeOH RT 4) 4-

(Diphenylphosphino)benzoic acid 4-pyrrolidinopyridine 4-Dimethylaminopyridine NNrsquo-

diisopropylcarbodiimide DCM RT

S4

11-Bis-(3-methyl-7-nitro-1H-indol-2-yl)-propane (L1-1)

The compound was prepared as follow based on reported procedure1 A mixture of 2-

nitrophenylhydrazine moistened with 30 water as received from Sigma Aldrich (60 g 038

mol 10 eq) propionaldehyde (50 mL 070 mol 18 eq) acetic acid (20 mL 003 mol 009

eq) and ethanol (05 L) was refluxed for 2 hours After completion (monitored by TLC) the

volatiles were removed under vacuum The yellow solid residue was carefully suspended in

concentrated aqueous HCl (35-37 06 L) by sonication for 1 hour (in the fume hood) After

adding 100 mL ethanol into the mixture the suspension was carefully () warmed up to 100 oC

while vigorously stirring Propionaldehyde (45 mL 063 mol 17 eq) was added dropwise via

a syringe controlled by an injection pump while the heating was continued for 1 hour After

cooling down the reaction mixture was poured into a beaker containing water (1 L) and CHCl3

(300 mL) The reaction mixture was carefully neutralized with Na2CO3 until pH 7 (careful)

After phase separation the water phase was extracted with CHCl3 (2x800 mL) The combined

organic phase was dried over MgSO4 filtrated and evaporated The oil like black residue was

dissolved in hot 12-dichloroethane (50 mL) and slowly cooled down The solid was filtered

off washed thoroughly with hexane until almost all the black impurities were removed (be

patient) and then with a small amount DCM or cold methanol yielding 50 of the desired

compound L1-1 as orange crystals identical to the literature1

1H NMR (400 MHz CDCl3) δ 962 (s 2H indole-NH) 809 (d J = 81 Hz 2H) 784 (d J =

77 Hz 2H) 718 (t J = 79 Hz 2H) 452 (t J = 80 Hz 1H CHCH2CH3) 240 ndash 249 (m 8H

ArCH3 and CHCH2CH3) 107 (t J = 73 Hz 3H CHCH2CH3)

1-Bis-(4-(diphenylphosphino)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-

propane (ParaDIMPhos (L1))

The compound was prepared as follow based on reported procedure2 11-Bis-(3-methyl-7-

nitro-1H-indol-2-yl)-propane (L1-1) (121 g 308 mmol 10 eq) was suspended in

methanolTHF (11 50 mL) and 10 palladium on charcoal was added (039 g) The reaction

S5

mixture was vigorously stirred under 1 bar of H2 atmosphere with a balloon The progress of

the reaction was monitored by TLC and after completion (about 2 hours) the catalyst was

filtered off The solvent was evaporated and the crude diamine was immediately used in the

subsequent reaction without further purification To a solution of the crude diamine (3000 mg

11 mmol 1 eq) 4-(Diphenylphospino)benzoic acid (7660 mg 24 mmol 22 eq) 4-

Dimethylaminopyridine (690 mg 06 mmol 05 eq) and 4-pyrrolidinopyridine (688 mg 05

mmol 04 eq) in dichloromethane (20 ml) NNrsquo-diisopropylcarbodiimide (14 ml 88 mmol

80 eq) was added slowly while stirring at 0 oC under N2 and the mixture was then stirred

overnight The precipitate was filtered off the solvent was evaporated and the solid residue

was purified by column chromatography on silica gel (100 g) with a hexanedichloromethane

(13) mixture to pure dichloromethane as an eluent Then dissolve the product with a minimum

amount of dichloromethane and add pentanehexane slowly until precipitation appears

followed by crystallization under -20 oC overnight After quickly filtration pure compound

was obtained Yield 91 yellow powder Identical to the literature2

1H NMR (400 MHz CD2Cl2) δ 942 (s 2H indole-NH) 821 (s 2H amide-NH) 762 (d J

= 79 Hz 4H) 743 ndash 726 (m 22H) 722 (t J = 74 Hz 4H) 702 (t J = 76 Hz 2H) 694 (d

J = 76 Hz 2H) 448 (t J = 82 Hz 1H CHCH2CH3) 230 (s 6H aryl-Me) 216 (t J = 76

Hz 2H CHCH2CH3) 099 (t J = 73 Hz 3H CHCH2CH3)

13C NMR (126 MHz CD2Cl2) δ 16594 13632 13443 13437 13427 13422 13378

13364 13210 12978 12920 12915 12804 12771 12766 12238 11930 11615

11406 10820 3688 2794 1260 886

31P NMR (162 MHz CD2Cl2) δ -562

S6

Scheme S2 Synthesis of the DIMphosphite L2 and L3 a 1 bar H2 PdC THFMeOH

b 3-benzyloxybenzoyl chloride TEA DCM RT c 1 bar H2 PdC THFMeOH d (S)-

binol-PCl or Diphenyl-PCl THF -78 oC to RT

Bis-(3-(benzyloxy)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-

propane (L2a)

S7

The compound was prepared as follow based on reported procedure3 11-Bis-(-3-methyl-7-

nitro-1H-indol-2-yl)propane (10 g 25 mmol) was suspended in

methanoltetrahydrofuran (11 15 ml) and 10 palladium on charcoal was added (02

g) The reaction mixture was flushed with hydrogen and then vigorously stirred under

1 bar of hydrogen with a balloon The progress of the reaction was monitored by TLC

(DCMMethanol 101) and after completion (~2 hours) the catalyst was filtered off

over Celite The solvent was evaporated and the crude diamine was immediately used

in the subsequent reaction without further purification

To the solution of the crude diamine (25 mmol) and triethylamine (50 mmol) in

dichloromethane (10 ml) a solution of 3-(benzyloxy)benzoyl chloride (16 g 65 mmol)

in dichloromethane (10 ml) was slowly added while stirring and the mixture was

allowed to continue stirring overnight After completion (TLC pentane ethyl acetate

21) the solvent was evaporated and the crude mixture was purified by chromatography

with pentaneethyl acetate (31) to dichloromethanemethanol (201) as the eluent The

product was then dissolved in a minimum amount of chloromethanemethanol and

followed by the addition of hexane to precipitate the compounds which was filtrated

through filter and washed with hexane to obtain pure compound L2a Identical to the

literature3

1H NMR (400 MHz CDCl3) δ 951 (s 2H indole-NH) 815 (s 2H amide-NH) 740

ndash 731 (m 16H) 724 ndash 714 (m 1H) 703 (t J = 68 Hz 5H) 694 (d J = 74 Hz 2H)

503 ndash 489 (m 4H Bn-CH2) 450 ndash 442 (m 1H CHCH2CH3) 231 (s 6H aryl-CH3)

223 ndash 214 (m 2H CHCH2CH3) 099 (t J = 76 Hz 3H CHCH2CH3)

S8

1-Bis-(3-(hydroxyl)benzoamide of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-

propane (L2b)

The compound was prepared as follow based on reported procedure3 Bis-(3-

(benzyloxy)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane (L2a)

(123 g 16 mmol) was suspended in methanol (30 ml) and 10 palladium on charcoal

was added (03 g) The reaction mixture was flushed with hydrogen and then vigorously

stirred under 1 bar hydrogen with a balloon The progress of the reaction was monitored

by TLC (DCMMethanol 101) and after overnight reaction the catalyst was filtered

off over Celite The solvent was evaporated and the pure product was obtained by

crystallization with dichloromethane and hexane Identical to the literature3

1H NMR (500 MHz Methanol-d4) δ 743 ndash 732 (m 6H) 730 ndash 721 (m 4H) 700 (q

J = 80 Hz 4H) 453 (t J = 80 Hz 1H CHCH2CH3) 235 ndash 217 (m 8H aryl-CH3 amp

CHCH2CH3) 099 (t J = 73 Hz 3H CHCH2CH3)

48-Di-tert-butyl-6-chloro-210-dimethoxydibenzo[df][132]dioxaphosphepine

(Diphenyl-PCl)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with 33-di-tert-

butyl-55-dimethoxy-[11-biphenyl]-22-diol (1 eq 1878 mg 052 mmol) followed

by co-evaporation with dry toluene three times Then 5 ml dried and degassed THF was

added into the flask To this solution under -78 oC PCl3 (15 eq 691 uL 078 mmol)

and triethylamine (30 eq 221 uL 156 mmol) was added dropwise After stirring under

-78 oC for 15 min the reaction mixture was slowly warmed up to room temperature and

stirred for another 45 min After completion (monitored by 31P NMR) the volatiles were

evaporated under vacuum and further co-evaporated with dry toluene three times The

product was formed quantitatively and used directly

S9

(Bis-3-((48-Di-tert-butyl-210-dimethoxydibenzo[df][132]dioxaphosphepin-6-

yl)oxyl)benzoamide of 11-bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L2)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 1500 mg 026 mmol) followed by co-evaporation with dry toluene three times

Then 5 ml dried and degassed THF was added into the flask To this solution under -78

oC Diphenyl-PCl (20 eq 052 mmol) and triethylamine (30 eq 221 uL 156 mmol)

in THF was added dropwise After stirring under -78 oC for 15 min the reaction mixture

was slowly warmed up to room temperature and stirred for another 45 min After

completion (monitored by 31P NMR) the volatiles were evaporated under vacuum and

further co-evaporated with dry toluene three times The reaction mixture was evaporated

and to the solid residue THF (5 ml) was added The suspension was filtered through a

plug of celite which was subsequently washed with THF (10 ml) The combined organic

fractions were concentrated hexane (10 ml) was added followed by evaporation of all

volatiles to dryness The product was formed quantitatively without further purification

1H NMR (500 MHz CD2Cl2) δ 982 (s 2H indole-NH) 834 (s 2H amide-NH) 760

ndash 750 (m 2H) 735 (dd J = 65 23 Hz 2H) 725 ndash 722 (m 3H) 719 ndash 715 (m 3H)

707 ndash 695 (m 8H) 675 ndash 673 (m 4H) 449 (t J = 80 Hz 1H CHCH2CH3) 379 ndash

378 (m 12H) 232 (s 6H indole-Me) 223 (p J = 76 Hz 2H CHCH2CH3) 187 ndash

S10

177 (m 2H) 147 (d J = 20 Hz 6H OMe) 144 (s 18H) 142 (s 18H) 100 (t J =

76 Hz 3H CHCH2CH3)

31P NMR (202 MHz CD2Cl2) δ 13934

13C NMR (101 MHz CD2Cl2) δ 16523 15650 15264 (d J = 62 Hz) 14306 (m)

14145 (d J = 59 Hz) 13838 13658 (d J = 342 Hz) 13402 (m) 13215 13038

12937 12843 (d J = 271 Hz) 12564 12388 (d J = 79 Hz) 12338 12239 11976

(d J = 76 Hz) 11920 11614 11529 11485 11414 11336 10800 5599 4618

3574 3124 (m) 3085 2599 1265 890

HR MS (FD+(eiFi)+) calcd for C79H86N4O12P2 [M]+ 13445717 found 13445774

(S)-11rsquo-Binaphthyl-22-diyl phosphorochloridate (S)-binol-PCl

A flamed dried Schlenk flask with a Teflon stirring bar was charged with (S)-binol (1

eq 187 g 52 mmol) followed by co-evaporation with dry toluene three times Dried

and degassed THF (20 ml) was then added into the flask To this solution under -78 oC

PCl3 (15 eq 691 uL 78 mmol) and triethylamine (30 eq 221 mL 156 mmol) was

added dropwise After stirring under -78 oC for 30 min the reaction mixture was slowly

warmed up to room temperature and stirred for another 60 min After completion

(monitored by 31P NMR) the volatiles were evaporated under vacuum and further co-

evaporated with dry toluene three times The product was formed quantitatively as white

solid and used directly without further purification

S11

(Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide) of 11-Bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L3)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 115 g 20 mmol) followed by co-evaporation with dry toluene three times Then

25 ml dried and degassed THF was added into the flask To this solution under -78 oC

(S)-binol-PCl (20 eq 140 g 40 mmol) and triethylamine (30 eq 084 mL 60 mmol)

in THF (20 mL) was added dropwise After stirring under -78 oC for 15 min the reaction

mixture was slowly warmed up to room temperature and stirred for overnight The

reaction mixture was evaporated and to the solid residue THF (40 ml) was added The

suspension was filtered through a plug of celite which was subsequently washed with

THF (40 ml) The combined organic fractions were concentrated hexane (30 ml) was

added followed by evaporation of all volatiles to dryness yielding 258g (95) of

L3middotTHFmiddotC6H14 NOTE Ligand L3 is sensitive to moisture and thus should be stored in

inert conditions at low temperatures preferably

1H NMR (400 MHz CD2Cl2) δ 950 (m 2H indole-NH) 821 (s 1H amide-NH) 816

(s 1H amide-NH) 807 ndash 781 (m 8H) 762 ndash 714 (m 26H) 699 (t J = 77 Hz 1H)

694 ndash 677 (m 3H) 449 (d J = 79 Hz 1H CHCH2CH3) 233 (s 3H aryl-Me) 232

(s 3H aryl-Me) 226 ndash 206 (m 2H CHCH2CH3) 100 (t J = 73 Hz 3H CHCH2CH3)

S12

31P NMR (162 MHz CD2Cl2) δ 14408 14397

13C NMR (100MHz CD2Cl2) δ = 16524 (m) 15229 (m) 14784 (d J = 46 Hz)

14722 (m) 13674 13638 (d J = 80 Hz) 13319 13287 13236 13224 13174 (m)

13111 13050 (m) 12885 (d J = 81 Hz) 12827 (d J = 30 Hz) 12721 12708 (d J

= 30 Hz) 12690 (d J = 65 Hz) 12573 (d J = 171 Hz) 12455 (m) 12405 (d J =

81 Hz) 12375 (d J = 85 Hz) 12346 (d J = 111 Hz) 12321 (m) 12217 12197

11992 (m) 11973 (d J = 75 Hz) 11930 (d J = 40 Hz) 11815 11641 11410 (d J

= 160 Hz) 10825 (d J = 44 Hz) 3686 2599 1261 889

HR MS (FD+(eiFi)+) calcd for C75H54N4O8P2 [M]+ 120034169 found 120033967

The effectors used in this study

Scheme S3 Effectors purchased from commercial source

S13

Scheme S4 Effectors prepared except 27 purchased from commercial sources

L-(tert-butylthiocarbamoyl)-N-valine (1S)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 200 mg 170 mmol) was dissolved in 025 M NaHCO3 solution

(80 mL) followed by adding the isothiocyanate (1 eq 022 mL 17 mmol) The mixture

was heated at 80 oC for 3 hours and the progress of the reaction was monitored by TLC

(petroleum etherethyl acetate 11) After completion the reaction mixture was cooling

down and acidified to pH 2 with 1M HCl (3x80 mL) The products were extracted with

ethyl acetate (3x100 mL) The combined organic layer was dried over MgSO4 The pure

product was obtained as white powder with 50 yield after crystallization Identical to

the literature4

S14

1H NMR (400 MHz DMSO-d6) δ 750 (s 1H thiourea-NH) 738 (d J = 86 Hz 1H

thiourea-NH) 484 (dd J = 86 46 Hz 1H Ha) 208 (m 1H Hb) 142 (s 9H tert-

butyl-Me) 088 (m 6H isopropyl-Me)

D-(tert-butylthiocarbamoyl)-N-valine (1S) was prepared following the same

procedures for 1R

1H NMR (400 MHz DMSO-d6) δ 1255 (s 1H COOH) 749 (s 1H thiourea-NH)

737 (d J = 86 Hz 1H thiourea-NH) 483 (dd J = 86 46 Hz 1H Ha) 209 ndash 205

(m 1H Hb) 141 (s 9H tert-butyl) 088 -086 (m 6H isopropyl-Me)

13C NMR (126 MHz DMSO-d6) δ 18182 17342 6030 5227 3057 2889 1887

1812

HRMS (FD+(eiFi)) calcd for C10H20N2O2S1 [M]+ 2321245 found 2321201

L-N-formyl-Valine (24)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (03 g 25 mmol) formic acid (952 g 113 mmol) and acetic acid

anhydride (1 g 98 mmol) were dissolved in acetic acid (10 mL) and the reaction was

stirred for 4 hours at room temperature Afterwards all the volatiles were removed under

vacuum and the crude product was purified by recrystallization to give while power

identical to literature4

S15

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 841 (s 1H formyl-H) 798

(d J = 8 Hz 1H amide-NH) 411 (dd J = 8 Hz J = 6 Hz 1H Ha) 202 (m 1H Hb)

087 (dd J = 1 Hz J = 7 Hz 6H isopropyl-Me)

L-N-trimethylacetyl-Valine (25)

The compound was prepared as follow based on reported procedure5 A round bottom flask

equipped with a magnetic stirring bar was charged with distilled water and NaHCO3

The resulting reaction mixtures was cooled to 0 oC in an ice bath L-Valine methyl ester

hydrochloride (300 mg 256 mmol) was added and the solution was stirred until

homogeneous The flask was equipped with an addition funnel The corresponding

trimethylacetyl chloride which was prepared from the corresponding pivalic acid in

14-dioxane (4 mL) was added dropwise The reaction mixture was then allowed to stir

at room temperature overnight Next the reaction was extracted with Et2O (2x20 mL)

to remove the impurities The aqueous layer was again cooled to 0 oC in an ice bath and

1M HCl was added until pH 3 The product was extracted with ethyl acetate (3x100 mL)

The organic layer was washed with brine (50 mL) dried over Na2SO4 filtered and

concentrated under vacuum to give the product as white powder Identical to the

literature5

1H NMR (400 MHz CDCl3) δ 970 (s 1H COOH) 624 (d J = 85 Hz 1H amide-

NH) 456 (dd J = 85 47 Hz 1H Ha) 223 (m 1H Hb) 122 (s 9H tert-butyl-Me)

106 ndash 093 (m 6H isopropyl-Me)

S16

L-(tert-butylcarbamoyl)-N-valine methyl ester (26a)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (10 g 762 mmol) was dissolved in dry DCM (100 mL) and the

isocyanate was added The mixture was stirred and the progress of the reaction was

monitored by TLC (petroleum etherethyl acetate 11) After completion the solvents

were removed under vacuum and the crude product was dissolved in DCM (80 mL)

washed with 1M HCl (3x80 mL) dried over MgSO4 The pure product was obtained as

white powder with 96 yield Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 604 (d J = 88 Hz 1H urea-NH) 594 (s 1H urea-

NH) 403 (dd J = 88 53 Hz 1H Ha) 362 (s 3H OMe) 209 ndash 183 (m 1H Hb)

120 (s 9H tert-butyl) 083 (m 6H isopropyl-Me)

L-(tert-butylcarbamoyl)-N-valine (26)

The compound was prepared as follow based on reported procedure4 To a solution of L-

(tert-butylcarbamoyl)-N-valine methyl ester (1 eq 074 g 322 mmol) in

methanolTHFwater (111 30 mL) mixture was added LiOHH2O (1 eq 135 mg 322

mmol) After overnight stirring at room temperature the resulting reaction mixtures was

partially concentrated under vacuum followed by the addition of water (20 mL) The

mixture was acidified with 1M HCl to pH 4 and then the product was extracted with

ethyl acetate (3x30 mL) The combined organic layer was washed with brine (30 mL)

dried over MgSO4 The pure product was obtained as white powder with 80 yield

Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 1241 (s 1H COOH) 591 (s 1H urea-NH) 587

(d J = 91 Hz 1H urea-NH) 399 (dd J = 89 48 Hz 1H Ha) 199 ndash 188 (m 1H

Hb) 120 (s 9H tert-butyl) 085 - 081 (m 6H isopropyl-Me)

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 2: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S2

Table of Contents

General Information S3

Synthesis of DIM-ligands L1-3 S3

The effectors used in this study S12

General procedures for the hydroformylation reaction S18

Hydroformylation results S19

S3

General Information

All reactions involving air- or moisture sensitive materials were carried out under nitrogen

atmosphere using standard Schlenk techniques or in Glove-box THF pentane hexane and

toluene were distilled from sodium-benzophenone under nitrogen atmosphere

dichloromethane methanol were distilled from CaH2 under nitrogen atmosphere triethylamine

was distilled from KOH pellets under nitrogen Toluene-d8 CD2Cl2 and NN-

diisopropylethylamine were dried over molecular sieves (3Aring) and degassed by three freeze-

pump-thaw cycles 1H NMR 13C NMR 31P NMR 1H31P NMR experiments were performed

on Bruker AMX 300 MHz Bruker AMX 400 MHz or Bruker AMX 500 MHz 1H NMR

chemical shifts are given in ppm and were calibrated by using the residual solvent as internal

reference (CHCl3 726 ppm CH2Cl2 532 ppm) 13C NMR chemical shifts were reported in ppm

with the solvent peaks used as internal reference (CHCl3 7716 ppm CH2Cl2 5384 ppm) Mass

spectra were collected on an AccuTOF GC v 4g JMS-T100GCV Mass spectrometer (JEOL

Japan) If not stated otherwise syngas referred to a 11 mixture of H2 and CO and the pressure

refers to a sum pressure of both All reagents were purchased from commercial suppliers and

used without further purification unless otherwise noted

Synthesis of DIM-ligands L1-3

Scheme S1 Synthesis of Ligand L11) C2H5CHO CH3CO2H reflux 2 hours 2) C2H5CHO

conc HCl reflux 2 hours 3) 1 bar H2 PdC THFMeOH RT 4) 4-

(Diphenylphosphino)benzoic acid 4-pyrrolidinopyridine 4-Dimethylaminopyridine NNrsquo-

diisopropylcarbodiimide DCM RT

S4

11-Bis-(3-methyl-7-nitro-1H-indol-2-yl)-propane (L1-1)

The compound was prepared as follow based on reported procedure1 A mixture of 2-

nitrophenylhydrazine moistened with 30 water as received from Sigma Aldrich (60 g 038

mol 10 eq) propionaldehyde (50 mL 070 mol 18 eq) acetic acid (20 mL 003 mol 009

eq) and ethanol (05 L) was refluxed for 2 hours After completion (monitored by TLC) the

volatiles were removed under vacuum The yellow solid residue was carefully suspended in

concentrated aqueous HCl (35-37 06 L) by sonication for 1 hour (in the fume hood) After

adding 100 mL ethanol into the mixture the suspension was carefully () warmed up to 100 oC

while vigorously stirring Propionaldehyde (45 mL 063 mol 17 eq) was added dropwise via

a syringe controlled by an injection pump while the heating was continued for 1 hour After

cooling down the reaction mixture was poured into a beaker containing water (1 L) and CHCl3

(300 mL) The reaction mixture was carefully neutralized with Na2CO3 until pH 7 (careful)

After phase separation the water phase was extracted with CHCl3 (2x800 mL) The combined

organic phase was dried over MgSO4 filtrated and evaporated The oil like black residue was

dissolved in hot 12-dichloroethane (50 mL) and slowly cooled down The solid was filtered

off washed thoroughly with hexane until almost all the black impurities were removed (be

patient) and then with a small amount DCM or cold methanol yielding 50 of the desired

compound L1-1 as orange crystals identical to the literature1

1H NMR (400 MHz CDCl3) δ 962 (s 2H indole-NH) 809 (d J = 81 Hz 2H) 784 (d J =

77 Hz 2H) 718 (t J = 79 Hz 2H) 452 (t J = 80 Hz 1H CHCH2CH3) 240 ndash 249 (m 8H

ArCH3 and CHCH2CH3) 107 (t J = 73 Hz 3H CHCH2CH3)

1-Bis-(4-(diphenylphosphino)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-

propane (ParaDIMPhos (L1))

The compound was prepared as follow based on reported procedure2 11-Bis-(3-methyl-7-

nitro-1H-indol-2-yl)-propane (L1-1) (121 g 308 mmol 10 eq) was suspended in

methanolTHF (11 50 mL) and 10 palladium on charcoal was added (039 g) The reaction

S5

mixture was vigorously stirred under 1 bar of H2 atmosphere with a balloon The progress of

the reaction was monitored by TLC and after completion (about 2 hours) the catalyst was

filtered off The solvent was evaporated and the crude diamine was immediately used in the

subsequent reaction without further purification To a solution of the crude diamine (3000 mg

11 mmol 1 eq) 4-(Diphenylphospino)benzoic acid (7660 mg 24 mmol 22 eq) 4-

Dimethylaminopyridine (690 mg 06 mmol 05 eq) and 4-pyrrolidinopyridine (688 mg 05

mmol 04 eq) in dichloromethane (20 ml) NNrsquo-diisopropylcarbodiimide (14 ml 88 mmol

80 eq) was added slowly while stirring at 0 oC under N2 and the mixture was then stirred

overnight The precipitate was filtered off the solvent was evaporated and the solid residue

was purified by column chromatography on silica gel (100 g) with a hexanedichloromethane

(13) mixture to pure dichloromethane as an eluent Then dissolve the product with a minimum

amount of dichloromethane and add pentanehexane slowly until precipitation appears

followed by crystallization under -20 oC overnight After quickly filtration pure compound

was obtained Yield 91 yellow powder Identical to the literature2

1H NMR (400 MHz CD2Cl2) δ 942 (s 2H indole-NH) 821 (s 2H amide-NH) 762 (d J

= 79 Hz 4H) 743 ndash 726 (m 22H) 722 (t J = 74 Hz 4H) 702 (t J = 76 Hz 2H) 694 (d

J = 76 Hz 2H) 448 (t J = 82 Hz 1H CHCH2CH3) 230 (s 6H aryl-Me) 216 (t J = 76

Hz 2H CHCH2CH3) 099 (t J = 73 Hz 3H CHCH2CH3)

13C NMR (126 MHz CD2Cl2) δ 16594 13632 13443 13437 13427 13422 13378

13364 13210 12978 12920 12915 12804 12771 12766 12238 11930 11615

11406 10820 3688 2794 1260 886

31P NMR (162 MHz CD2Cl2) δ -562

S6

Scheme S2 Synthesis of the DIMphosphite L2 and L3 a 1 bar H2 PdC THFMeOH

b 3-benzyloxybenzoyl chloride TEA DCM RT c 1 bar H2 PdC THFMeOH d (S)-

binol-PCl or Diphenyl-PCl THF -78 oC to RT

Bis-(3-(benzyloxy)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-

propane (L2a)

S7

The compound was prepared as follow based on reported procedure3 11-Bis-(-3-methyl-7-

nitro-1H-indol-2-yl)propane (10 g 25 mmol) was suspended in

methanoltetrahydrofuran (11 15 ml) and 10 palladium on charcoal was added (02

g) The reaction mixture was flushed with hydrogen and then vigorously stirred under

1 bar of hydrogen with a balloon The progress of the reaction was monitored by TLC

(DCMMethanol 101) and after completion (~2 hours) the catalyst was filtered off

over Celite The solvent was evaporated and the crude diamine was immediately used

in the subsequent reaction without further purification

To the solution of the crude diamine (25 mmol) and triethylamine (50 mmol) in

dichloromethane (10 ml) a solution of 3-(benzyloxy)benzoyl chloride (16 g 65 mmol)

in dichloromethane (10 ml) was slowly added while stirring and the mixture was

allowed to continue stirring overnight After completion (TLC pentane ethyl acetate

21) the solvent was evaporated and the crude mixture was purified by chromatography

with pentaneethyl acetate (31) to dichloromethanemethanol (201) as the eluent The

product was then dissolved in a minimum amount of chloromethanemethanol and

followed by the addition of hexane to precipitate the compounds which was filtrated

through filter and washed with hexane to obtain pure compound L2a Identical to the

literature3

1H NMR (400 MHz CDCl3) δ 951 (s 2H indole-NH) 815 (s 2H amide-NH) 740

ndash 731 (m 16H) 724 ndash 714 (m 1H) 703 (t J = 68 Hz 5H) 694 (d J = 74 Hz 2H)

503 ndash 489 (m 4H Bn-CH2) 450 ndash 442 (m 1H CHCH2CH3) 231 (s 6H aryl-CH3)

223 ndash 214 (m 2H CHCH2CH3) 099 (t J = 76 Hz 3H CHCH2CH3)

S8

1-Bis-(3-(hydroxyl)benzoamide of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-

propane (L2b)

The compound was prepared as follow based on reported procedure3 Bis-(3-

(benzyloxy)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane (L2a)

(123 g 16 mmol) was suspended in methanol (30 ml) and 10 palladium on charcoal

was added (03 g) The reaction mixture was flushed with hydrogen and then vigorously

stirred under 1 bar hydrogen with a balloon The progress of the reaction was monitored

by TLC (DCMMethanol 101) and after overnight reaction the catalyst was filtered

off over Celite The solvent was evaporated and the pure product was obtained by

crystallization with dichloromethane and hexane Identical to the literature3

1H NMR (500 MHz Methanol-d4) δ 743 ndash 732 (m 6H) 730 ndash 721 (m 4H) 700 (q

J = 80 Hz 4H) 453 (t J = 80 Hz 1H CHCH2CH3) 235 ndash 217 (m 8H aryl-CH3 amp

CHCH2CH3) 099 (t J = 73 Hz 3H CHCH2CH3)

48-Di-tert-butyl-6-chloro-210-dimethoxydibenzo[df][132]dioxaphosphepine

(Diphenyl-PCl)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with 33-di-tert-

butyl-55-dimethoxy-[11-biphenyl]-22-diol (1 eq 1878 mg 052 mmol) followed

by co-evaporation with dry toluene three times Then 5 ml dried and degassed THF was

added into the flask To this solution under -78 oC PCl3 (15 eq 691 uL 078 mmol)

and triethylamine (30 eq 221 uL 156 mmol) was added dropwise After stirring under

-78 oC for 15 min the reaction mixture was slowly warmed up to room temperature and

stirred for another 45 min After completion (monitored by 31P NMR) the volatiles were

evaporated under vacuum and further co-evaporated with dry toluene three times The

product was formed quantitatively and used directly

S9

(Bis-3-((48-Di-tert-butyl-210-dimethoxydibenzo[df][132]dioxaphosphepin-6-

yl)oxyl)benzoamide of 11-bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L2)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 1500 mg 026 mmol) followed by co-evaporation with dry toluene three times

Then 5 ml dried and degassed THF was added into the flask To this solution under -78

oC Diphenyl-PCl (20 eq 052 mmol) and triethylamine (30 eq 221 uL 156 mmol)

in THF was added dropwise After stirring under -78 oC for 15 min the reaction mixture

was slowly warmed up to room temperature and stirred for another 45 min After

completion (monitored by 31P NMR) the volatiles were evaporated under vacuum and

further co-evaporated with dry toluene three times The reaction mixture was evaporated

and to the solid residue THF (5 ml) was added The suspension was filtered through a

plug of celite which was subsequently washed with THF (10 ml) The combined organic

fractions were concentrated hexane (10 ml) was added followed by evaporation of all

volatiles to dryness The product was formed quantitatively without further purification

1H NMR (500 MHz CD2Cl2) δ 982 (s 2H indole-NH) 834 (s 2H amide-NH) 760

ndash 750 (m 2H) 735 (dd J = 65 23 Hz 2H) 725 ndash 722 (m 3H) 719 ndash 715 (m 3H)

707 ndash 695 (m 8H) 675 ndash 673 (m 4H) 449 (t J = 80 Hz 1H CHCH2CH3) 379 ndash

378 (m 12H) 232 (s 6H indole-Me) 223 (p J = 76 Hz 2H CHCH2CH3) 187 ndash

S10

177 (m 2H) 147 (d J = 20 Hz 6H OMe) 144 (s 18H) 142 (s 18H) 100 (t J =

76 Hz 3H CHCH2CH3)

31P NMR (202 MHz CD2Cl2) δ 13934

13C NMR (101 MHz CD2Cl2) δ 16523 15650 15264 (d J = 62 Hz) 14306 (m)

14145 (d J = 59 Hz) 13838 13658 (d J = 342 Hz) 13402 (m) 13215 13038

12937 12843 (d J = 271 Hz) 12564 12388 (d J = 79 Hz) 12338 12239 11976

(d J = 76 Hz) 11920 11614 11529 11485 11414 11336 10800 5599 4618

3574 3124 (m) 3085 2599 1265 890

HR MS (FD+(eiFi)+) calcd for C79H86N4O12P2 [M]+ 13445717 found 13445774

(S)-11rsquo-Binaphthyl-22-diyl phosphorochloridate (S)-binol-PCl

A flamed dried Schlenk flask with a Teflon stirring bar was charged with (S)-binol (1

eq 187 g 52 mmol) followed by co-evaporation with dry toluene three times Dried

and degassed THF (20 ml) was then added into the flask To this solution under -78 oC

PCl3 (15 eq 691 uL 78 mmol) and triethylamine (30 eq 221 mL 156 mmol) was

added dropwise After stirring under -78 oC for 30 min the reaction mixture was slowly

warmed up to room temperature and stirred for another 60 min After completion

(monitored by 31P NMR) the volatiles were evaporated under vacuum and further co-

evaporated with dry toluene three times The product was formed quantitatively as white

solid and used directly without further purification

S11

(Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide) of 11-Bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L3)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 115 g 20 mmol) followed by co-evaporation with dry toluene three times Then

25 ml dried and degassed THF was added into the flask To this solution under -78 oC

(S)-binol-PCl (20 eq 140 g 40 mmol) and triethylamine (30 eq 084 mL 60 mmol)

in THF (20 mL) was added dropwise After stirring under -78 oC for 15 min the reaction

mixture was slowly warmed up to room temperature and stirred for overnight The

reaction mixture was evaporated and to the solid residue THF (40 ml) was added The

suspension was filtered through a plug of celite which was subsequently washed with

THF (40 ml) The combined organic fractions were concentrated hexane (30 ml) was

added followed by evaporation of all volatiles to dryness yielding 258g (95) of

L3middotTHFmiddotC6H14 NOTE Ligand L3 is sensitive to moisture and thus should be stored in

inert conditions at low temperatures preferably

1H NMR (400 MHz CD2Cl2) δ 950 (m 2H indole-NH) 821 (s 1H amide-NH) 816

(s 1H amide-NH) 807 ndash 781 (m 8H) 762 ndash 714 (m 26H) 699 (t J = 77 Hz 1H)

694 ndash 677 (m 3H) 449 (d J = 79 Hz 1H CHCH2CH3) 233 (s 3H aryl-Me) 232

(s 3H aryl-Me) 226 ndash 206 (m 2H CHCH2CH3) 100 (t J = 73 Hz 3H CHCH2CH3)

S12

31P NMR (162 MHz CD2Cl2) δ 14408 14397

13C NMR (100MHz CD2Cl2) δ = 16524 (m) 15229 (m) 14784 (d J = 46 Hz)

14722 (m) 13674 13638 (d J = 80 Hz) 13319 13287 13236 13224 13174 (m)

13111 13050 (m) 12885 (d J = 81 Hz) 12827 (d J = 30 Hz) 12721 12708 (d J

= 30 Hz) 12690 (d J = 65 Hz) 12573 (d J = 171 Hz) 12455 (m) 12405 (d J =

81 Hz) 12375 (d J = 85 Hz) 12346 (d J = 111 Hz) 12321 (m) 12217 12197

11992 (m) 11973 (d J = 75 Hz) 11930 (d J = 40 Hz) 11815 11641 11410 (d J

= 160 Hz) 10825 (d J = 44 Hz) 3686 2599 1261 889

HR MS (FD+(eiFi)+) calcd for C75H54N4O8P2 [M]+ 120034169 found 120033967

The effectors used in this study

Scheme S3 Effectors purchased from commercial source

S13

Scheme S4 Effectors prepared except 27 purchased from commercial sources

L-(tert-butylthiocarbamoyl)-N-valine (1S)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 200 mg 170 mmol) was dissolved in 025 M NaHCO3 solution

(80 mL) followed by adding the isothiocyanate (1 eq 022 mL 17 mmol) The mixture

was heated at 80 oC for 3 hours and the progress of the reaction was monitored by TLC

(petroleum etherethyl acetate 11) After completion the reaction mixture was cooling

down and acidified to pH 2 with 1M HCl (3x80 mL) The products were extracted with

ethyl acetate (3x100 mL) The combined organic layer was dried over MgSO4 The pure

product was obtained as white powder with 50 yield after crystallization Identical to

the literature4

S14

1H NMR (400 MHz DMSO-d6) δ 750 (s 1H thiourea-NH) 738 (d J = 86 Hz 1H

thiourea-NH) 484 (dd J = 86 46 Hz 1H Ha) 208 (m 1H Hb) 142 (s 9H tert-

butyl-Me) 088 (m 6H isopropyl-Me)

D-(tert-butylthiocarbamoyl)-N-valine (1S) was prepared following the same

procedures for 1R

1H NMR (400 MHz DMSO-d6) δ 1255 (s 1H COOH) 749 (s 1H thiourea-NH)

737 (d J = 86 Hz 1H thiourea-NH) 483 (dd J = 86 46 Hz 1H Ha) 209 ndash 205

(m 1H Hb) 141 (s 9H tert-butyl) 088 -086 (m 6H isopropyl-Me)

13C NMR (126 MHz DMSO-d6) δ 18182 17342 6030 5227 3057 2889 1887

1812

HRMS (FD+(eiFi)) calcd for C10H20N2O2S1 [M]+ 2321245 found 2321201

L-N-formyl-Valine (24)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (03 g 25 mmol) formic acid (952 g 113 mmol) and acetic acid

anhydride (1 g 98 mmol) were dissolved in acetic acid (10 mL) and the reaction was

stirred for 4 hours at room temperature Afterwards all the volatiles were removed under

vacuum and the crude product was purified by recrystallization to give while power

identical to literature4

S15

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 841 (s 1H formyl-H) 798

(d J = 8 Hz 1H amide-NH) 411 (dd J = 8 Hz J = 6 Hz 1H Ha) 202 (m 1H Hb)

087 (dd J = 1 Hz J = 7 Hz 6H isopropyl-Me)

L-N-trimethylacetyl-Valine (25)

The compound was prepared as follow based on reported procedure5 A round bottom flask

equipped with a magnetic stirring bar was charged with distilled water and NaHCO3

The resulting reaction mixtures was cooled to 0 oC in an ice bath L-Valine methyl ester

hydrochloride (300 mg 256 mmol) was added and the solution was stirred until

homogeneous The flask was equipped with an addition funnel The corresponding

trimethylacetyl chloride which was prepared from the corresponding pivalic acid in

14-dioxane (4 mL) was added dropwise The reaction mixture was then allowed to stir

at room temperature overnight Next the reaction was extracted with Et2O (2x20 mL)

to remove the impurities The aqueous layer was again cooled to 0 oC in an ice bath and

1M HCl was added until pH 3 The product was extracted with ethyl acetate (3x100 mL)

The organic layer was washed with brine (50 mL) dried over Na2SO4 filtered and

concentrated under vacuum to give the product as white powder Identical to the

literature5

1H NMR (400 MHz CDCl3) δ 970 (s 1H COOH) 624 (d J = 85 Hz 1H amide-

NH) 456 (dd J = 85 47 Hz 1H Ha) 223 (m 1H Hb) 122 (s 9H tert-butyl-Me)

106 ndash 093 (m 6H isopropyl-Me)

S16

L-(tert-butylcarbamoyl)-N-valine methyl ester (26a)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (10 g 762 mmol) was dissolved in dry DCM (100 mL) and the

isocyanate was added The mixture was stirred and the progress of the reaction was

monitored by TLC (petroleum etherethyl acetate 11) After completion the solvents

were removed under vacuum and the crude product was dissolved in DCM (80 mL)

washed with 1M HCl (3x80 mL) dried over MgSO4 The pure product was obtained as

white powder with 96 yield Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 604 (d J = 88 Hz 1H urea-NH) 594 (s 1H urea-

NH) 403 (dd J = 88 53 Hz 1H Ha) 362 (s 3H OMe) 209 ndash 183 (m 1H Hb)

120 (s 9H tert-butyl) 083 (m 6H isopropyl-Me)

L-(tert-butylcarbamoyl)-N-valine (26)

The compound was prepared as follow based on reported procedure4 To a solution of L-

(tert-butylcarbamoyl)-N-valine methyl ester (1 eq 074 g 322 mmol) in

methanolTHFwater (111 30 mL) mixture was added LiOHH2O (1 eq 135 mg 322

mmol) After overnight stirring at room temperature the resulting reaction mixtures was

partially concentrated under vacuum followed by the addition of water (20 mL) The

mixture was acidified with 1M HCl to pH 4 and then the product was extracted with

ethyl acetate (3x30 mL) The combined organic layer was washed with brine (30 mL)

dried over MgSO4 The pure product was obtained as white powder with 80 yield

Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 1241 (s 1H COOH) 591 (s 1H urea-NH) 587

(d J = 91 Hz 1H urea-NH) 399 (dd J = 89 48 Hz 1H Ha) 199 ndash 188 (m 1H

Hb) 120 (s 9H tert-butyl) 085 - 081 (m 6H isopropyl-Me)

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 3: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S3

General Information

All reactions involving air- or moisture sensitive materials were carried out under nitrogen

atmosphere using standard Schlenk techniques or in Glove-box THF pentane hexane and

toluene were distilled from sodium-benzophenone under nitrogen atmosphere

dichloromethane methanol were distilled from CaH2 under nitrogen atmosphere triethylamine

was distilled from KOH pellets under nitrogen Toluene-d8 CD2Cl2 and NN-

diisopropylethylamine were dried over molecular sieves (3Aring) and degassed by three freeze-

pump-thaw cycles 1H NMR 13C NMR 31P NMR 1H31P NMR experiments were performed

on Bruker AMX 300 MHz Bruker AMX 400 MHz or Bruker AMX 500 MHz 1H NMR

chemical shifts are given in ppm and were calibrated by using the residual solvent as internal

reference (CHCl3 726 ppm CH2Cl2 532 ppm) 13C NMR chemical shifts were reported in ppm

with the solvent peaks used as internal reference (CHCl3 7716 ppm CH2Cl2 5384 ppm) Mass

spectra were collected on an AccuTOF GC v 4g JMS-T100GCV Mass spectrometer (JEOL

Japan) If not stated otherwise syngas referred to a 11 mixture of H2 and CO and the pressure

refers to a sum pressure of both All reagents were purchased from commercial suppliers and

used without further purification unless otherwise noted

Synthesis of DIM-ligands L1-3

Scheme S1 Synthesis of Ligand L11) C2H5CHO CH3CO2H reflux 2 hours 2) C2H5CHO

conc HCl reflux 2 hours 3) 1 bar H2 PdC THFMeOH RT 4) 4-

(Diphenylphosphino)benzoic acid 4-pyrrolidinopyridine 4-Dimethylaminopyridine NNrsquo-

diisopropylcarbodiimide DCM RT

S4

11-Bis-(3-methyl-7-nitro-1H-indol-2-yl)-propane (L1-1)

The compound was prepared as follow based on reported procedure1 A mixture of 2-

nitrophenylhydrazine moistened with 30 water as received from Sigma Aldrich (60 g 038

mol 10 eq) propionaldehyde (50 mL 070 mol 18 eq) acetic acid (20 mL 003 mol 009

eq) and ethanol (05 L) was refluxed for 2 hours After completion (monitored by TLC) the

volatiles were removed under vacuum The yellow solid residue was carefully suspended in

concentrated aqueous HCl (35-37 06 L) by sonication for 1 hour (in the fume hood) After

adding 100 mL ethanol into the mixture the suspension was carefully () warmed up to 100 oC

while vigorously stirring Propionaldehyde (45 mL 063 mol 17 eq) was added dropwise via

a syringe controlled by an injection pump while the heating was continued for 1 hour After

cooling down the reaction mixture was poured into a beaker containing water (1 L) and CHCl3

(300 mL) The reaction mixture was carefully neutralized with Na2CO3 until pH 7 (careful)

After phase separation the water phase was extracted with CHCl3 (2x800 mL) The combined

organic phase was dried over MgSO4 filtrated and evaporated The oil like black residue was

dissolved in hot 12-dichloroethane (50 mL) and slowly cooled down The solid was filtered

off washed thoroughly with hexane until almost all the black impurities were removed (be

patient) and then with a small amount DCM or cold methanol yielding 50 of the desired

compound L1-1 as orange crystals identical to the literature1

1H NMR (400 MHz CDCl3) δ 962 (s 2H indole-NH) 809 (d J = 81 Hz 2H) 784 (d J =

77 Hz 2H) 718 (t J = 79 Hz 2H) 452 (t J = 80 Hz 1H CHCH2CH3) 240 ndash 249 (m 8H

ArCH3 and CHCH2CH3) 107 (t J = 73 Hz 3H CHCH2CH3)

1-Bis-(4-(diphenylphosphino)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-

propane (ParaDIMPhos (L1))

The compound was prepared as follow based on reported procedure2 11-Bis-(3-methyl-7-

nitro-1H-indol-2-yl)-propane (L1-1) (121 g 308 mmol 10 eq) was suspended in

methanolTHF (11 50 mL) and 10 palladium on charcoal was added (039 g) The reaction

S5

mixture was vigorously stirred under 1 bar of H2 atmosphere with a balloon The progress of

the reaction was monitored by TLC and after completion (about 2 hours) the catalyst was

filtered off The solvent was evaporated and the crude diamine was immediately used in the

subsequent reaction without further purification To a solution of the crude diamine (3000 mg

11 mmol 1 eq) 4-(Diphenylphospino)benzoic acid (7660 mg 24 mmol 22 eq) 4-

Dimethylaminopyridine (690 mg 06 mmol 05 eq) and 4-pyrrolidinopyridine (688 mg 05

mmol 04 eq) in dichloromethane (20 ml) NNrsquo-diisopropylcarbodiimide (14 ml 88 mmol

80 eq) was added slowly while stirring at 0 oC under N2 and the mixture was then stirred

overnight The precipitate was filtered off the solvent was evaporated and the solid residue

was purified by column chromatography on silica gel (100 g) with a hexanedichloromethane

(13) mixture to pure dichloromethane as an eluent Then dissolve the product with a minimum

amount of dichloromethane and add pentanehexane slowly until precipitation appears

followed by crystallization under -20 oC overnight After quickly filtration pure compound

was obtained Yield 91 yellow powder Identical to the literature2

1H NMR (400 MHz CD2Cl2) δ 942 (s 2H indole-NH) 821 (s 2H amide-NH) 762 (d J

= 79 Hz 4H) 743 ndash 726 (m 22H) 722 (t J = 74 Hz 4H) 702 (t J = 76 Hz 2H) 694 (d

J = 76 Hz 2H) 448 (t J = 82 Hz 1H CHCH2CH3) 230 (s 6H aryl-Me) 216 (t J = 76

Hz 2H CHCH2CH3) 099 (t J = 73 Hz 3H CHCH2CH3)

13C NMR (126 MHz CD2Cl2) δ 16594 13632 13443 13437 13427 13422 13378

13364 13210 12978 12920 12915 12804 12771 12766 12238 11930 11615

11406 10820 3688 2794 1260 886

31P NMR (162 MHz CD2Cl2) δ -562

S6

Scheme S2 Synthesis of the DIMphosphite L2 and L3 a 1 bar H2 PdC THFMeOH

b 3-benzyloxybenzoyl chloride TEA DCM RT c 1 bar H2 PdC THFMeOH d (S)-

binol-PCl or Diphenyl-PCl THF -78 oC to RT

Bis-(3-(benzyloxy)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-

propane (L2a)

S7

The compound was prepared as follow based on reported procedure3 11-Bis-(-3-methyl-7-

nitro-1H-indol-2-yl)propane (10 g 25 mmol) was suspended in

methanoltetrahydrofuran (11 15 ml) and 10 palladium on charcoal was added (02

g) The reaction mixture was flushed with hydrogen and then vigorously stirred under

1 bar of hydrogen with a balloon The progress of the reaction was monitored by TLC

(DCMMethanol 101) and after completion (~2 hours) the catalyst was filtered off

over Celite The solvent was evaporated and the crude diamine was immediately used

in the subsequent reaction without further purification

To the solution of the crude diamine (25 mmol) and triethylamine (50 mmol) in

dichloromethane (10 ml) a solution of 3-(benzyloxy)benzoyl chloride (16 g 65 mmol)

in dichloromethane (10 ml) was slowly added while stirring and the mixture was

allowed to continue stirring overnight After completion (TLC pentane ethyl acetate

21) the solvent was evaporated and the crude mixture was purified by chromatography

with pentaneethyl acetate (31) to dichloromethanemethanol (201) as the eluent The

product was then dissolved in a minimum amount of chloromethanemethanol and

followed by the addition of hexane to precipitate the compounds which was filtrated

through filter and washed with hexane to obtain pure compound L2a Identical to the

literature3

1H NMR (400 MHz CDCl3) δ 951 (s 2H indole-NH) 815 (s 2H amide-NH) 740

ndash 731 (m 16H) 724 ndash 714 (m 1H) 703 (t J = 68 Hz 5H) 694 (d J = 74 Hz 2H)

503 ndash 489 (m 4H Bn-CH2) 450 ndash 442 (m 1H CHCH2CH3) 231 (s 6H aryl-CH3)

223 ndash 214 (m 2H CHCH2CH3) 099 (t J = 76 Hz 3H CHCH2CH3)

S8

1-Bis-(3-(hydroxyl)benzoamide of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-

propane (L2b)

The compound was prepared as follow based on reported procedure3 Bis-(3-

(benzyloxy)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane (L2a)

(123 g 16 mmol) was suspended in methanol (30 ml) and 10 palladium on charcoal

was added (03 g) The reaction mixture was flushed with hydrogen and then vigorously

stirred under 1 bar hydrogen with a balloon The progress of the reaction was monitored

by TLC (DCMMethanol 101) and after overnight reaction the catalyst was filtered

off over Celite The solvent was evaporated and the pure product was obtained by

crystallization with dichloromethane and hexane Identical to the literature3

1H NMR (500 MHz Methanol-d4) δ 743 ndash 732 (m 6H) 730 ndash 721 (m 4H) 700 (q

J = 80 Hz 4H) 453 (t J = 80 Hz 1H CHCH2CH3) 235 ndash 217 (m 8H aryl-CH3 amp

CHCH2CH3) 099 (t J = 73 Hz 3H CHCH2CH3)

48-Di-tert-butyl-6-chloro-210-dimethoxydibenzo[df][132]dioxaphosphepine

(Diphenyl-PCl)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with 33-di-tert-

butyl-55-dimethoxy-[11-biphenyl]-22-diol (1 eq 1878 mg 052 mmol) followed

by co-evaporation with dry toluene three times Then 5 ml dried and degassed THF was

added into the flask To this solution under -78 oC PCl3 (15 eq 691 uL 078 mmol)

and triethylamine (30 eq 221 uL 156 mmol) was added dropwise After stirring under

-78 oC for 15 min the reaction mixture was slowly warmed up to room temperature and

stirred for another 45 min After completion (monitored by 31P NMR) the volatiles were

evaporated under vacuum and further co-evaporated with dry toluene three times The

product was formed quantitatively and used directly

S9

(Bis-3-((48-Di-tert-butyl-210-dimethoxydibenzo[df][132]dioxaphosphepin-6-

yl)oxyl)benzoamide of 11-bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L2)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 1500 mg 026 mmol) followed by co-evaporation with dry toluene three times

Then 5 ml dried and degassed THF was added into the flask To this solution under -78

oC Diphenyl-PCl (20 eq 052 mmol) and triethylamine (30 eq 221 uL 156 mmol)

in THF was added dropwise After stirring under -78 oC for 15 min the reaction mixture

was slowly warmed up to room temperature and stirred for another 45 min After

completion (monitored by 31P NMR) the volatiles were evaporated under vacuum and

further co-evaporated with dry toluene three times The reaction mixture was evaporated

and to the solid residue THF (5 ml) was added The suspension was filtered through a

plug of celite which was subsequently washed with THF (10 ml) The combined organic

fractions were concentrated hexane (10 ml) was added followed by evaporation of all

volatiles to dryness The product was formed quantitatively without further purification

1H NMR (500 MHz CD2Cl2) δ 982 (s 2H indole-NH) 834 (s 2H amide-NH) 760

ndash 750 (m 2H) 735 (dd J = 65 23 Hz 2H) 725 ndash 722 (m 3H) 719 ndash 715 (m 3H)

707 ndash 695 (m 8H) 675 ndash 673 (m 4H) 449 (t J = 80 Hz 1H CHCH2CH3) 379 ndash

378 (m 12H) 232 (s 6H indole-Me) 223 (p J = 76 Hz 2H CHCH2CH3) 187 ndash

S10

177 (m 2H) 147 (d J = 20 Hz 6H OMe) 144 (s 18H) 142 (s 18H) 100 (t J =

76 Hz 3H CHCH2CH3)

31P NMR (202 MHz CD2Cl2) δ 13934

13C NMR (101 MHz CD2Cl2) δ 16523 15650 15264 (d J = 62 Hz) 14306 (m)

14145 (d J = 59 Hz) 13838 13658 (d J = 342 Hz) 13402 (m) 13215 13038

12937 12843 (d J = 271 Hz) 12564 12388 (d J = 79 Hz) 12338 12239 11976

(d J = 76 Hz) 11920 11614 11529 11485 11414 11336 10800 5599 4618

3574 3124 (m) 3085 2599 1265 890

HR MS (FD+(eiFi)+) calcd for C79H86N4O12P2 [M]+ 13445717 found 13445774

(S)-11rsquo-Binaphthyl-22-diyl phosphorochloridate (S)-binol-PCl

A flamed dried Schlenk flask with a Teflon stirring bar was charged with (S)-binol (1

eq 187 g 52 mmol) followed by co-evaporation with dry toluene three times Dried

and degassed THF (20 ml) was then added into the flask To this solution under -78 oC

PCl3 (15 eq 691 uL 78 mmol) and triethylamine (30 eq 221 mL 156 mmol) was

added dropwise After stirring under -78 oC for 30 min the reaction mixture was slowly

warmed up to room temperature and stirred for another 60 min After completion

(monitored by 31P NMR) the volatiles were evaporated under vacuum and further co-

evaporated with dry toluene three times The product was formed quantitatively as white

solid and used directly without further purification

S11

(Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide) of 11-Bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L3)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 115 g 20 mmol) followed by co-evaporation with dry toluene three times Then

25 ml dried and degassed THF was added into the flask To this solution under -78 oC

(S)-binol-PCl (20 eq 140 g 40 mmol) and triethylamine (30 eq 084 mL 60 mmol)

in THF (20 mL) was added dropwise After stirring under -78 oC for 15 min the reaction

mixture was slowly warmed up to room temperature and stirred for overnight The

reaction mixture was evaporated and to the solid residue THF (40 ml) was added The

suspension was filtered through a plug of celite which was subsequently washed with

THF (40 ml) The combined organic fractions were concentrated hexane (30 ml) was

added followed by evaporation of all volatiles to dryness yielding 258g (95) of

L3middotTHFmiddotC6H14 NOTE Ligand L3 is sensitive to moisture and thus should be stored in

inert conditions at low temperatures preferably

1H NMR (400 MHz CD2Cl2) δ 950 (m 2H indole-NH) 821 (s 1H amide-NH) 816

(s 1H amide-NH) 807 ndash 781 (m 8H) 762 ndash 714 (m 26H) 699 (t J = 77 Hz 1H)

694 ndash 677 (m 3H) 449 (d J = 79 Hz 1H CHCH2CH3) 233 (s 3H aryl-Me) 232

(s 3H aryl-Me) 226 ndash 206 (m 2H CHCH2CH3) 100 (t J = 73 Hz 3H CHCH2CH3)

S12

31P NMR (162 MHz CD2Cl2) δ 14408 14397

13C NMR (100MHz CD2Cl2) δ = 16524 (m) 15229 (m) 14784 (d J = 46 Hz)

14722 (m) 13674 13638 (d J = 80 Hz) 13319 13287 13236 13224 13174 (m)

13111 13050 (m) 12885 (d J = 81 Hz) 12827 (d J = 30 Hz) 12721 12708 (d J

= 30 Hz) 12690 (d J = 65 Hz) 12573 (d J = 171 Hz) 12455 (m) 12405 (d J =

81 Hz) 12375 (d J = 85 Hz) 12346 (d J = 111 Hz) 12321 (m) 12217 12197

11992 (m) 11973 (d J = 75 Hz) 11930 (d J = 40 Hz) 11815 11641 11410 (d J

= 160 Hz) 10825 (d J = 44 Hz) 3686 2599 1261 889

HR MS (FD+(eiFi)+) calcd for C75H54N4O8P2 [M]+ 120034169 found 120033967

The effectors used in this study

Scheme S3 Effectors purchased from commercial source

S13

Scheme S4 Effectors prepared except 27 purchased from commercial sources

L-(tert-butylthiocarbamoyl)-N-valine (1S)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 200 mg 170 mmol) was dissolved in 025 M NaHCO3 solution

(80 mL) followed by adding the isothiocyanate (1 eq 022 mL 17 mmol) The mixture

was heated at 80 oC for 3 hours and the progress of the reaction was monitored by TLC

(petroleum etherethyl acetate 11) After completion the reaction mixture was cooling

down and acidified to pH 2 with 1M HCl (3x80 mL) The products were extracted with

ethyl acetate (3x100 mL) The combined organic layer was dried over MgSO4 The pure

product was obtained as white powder with 50 yield after crystallization Identical to

the literature4

S14

1H NMR (400 MHz DMSO-d6) δ 750 (s 1H thiourea-NH) 738 (d J = 86 Hz 1H

thiourea-NH) 484 (dd J = 86 46 Hz 1H Ha) 208 (m 1H Hb) 142 (s 9H tert-

butyl-Me) 088 (m 6H isopropyl-Me)

D-(tert-butylthiocarbamoyl)-N-valine (1S) was prepared following the same

procedures for 1R

1H NMR (400 MHz DMSO-d6) δ 1255 (s 1H COOH) 749 (s 1H thiourea-NH)

737 (d J = 86 Hz 1H thiourea-NH) 483 (dd J = 86 46 Hz 1H Ha) 209 ndash 205

(m 1H Hb) 141 (s 9H tert-butyl) 088 -086 (m 6H isopropyl-Me)

13C NMR (126 MHz DMSO-d6) δ 18182 17342 6030 5227 3057 2889 1887

1812

HRMS (FD+(eiFi)) calcd for C10H20N2O2S1 [M]+ 2321245 found 2321201

L-N-formyl-Valine (24)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (03 g 25 mmol) formic acid (952 g 113 mmol) and acetic acid

anhydride (1 g 98 mmol) were dissolved in acetic acid (10 mL) and the reaction was

stirred for 4 hours at room temperature Afterwards all the volatiles were removed under

vacuum and the crude product was purified by recrystallization to give while power

identical to literature4

S15

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 841 (s 1H formyl-H) 798

(d J = 8 Hz 1H amide-NH) 411 (dd J = 8 Hz J = 6 Hz 1H Ha) 202 (m 1H Hb)

087 (dd J = 1 Hz J = 7 Hz 6H isopropyl-Me)

L-N-trimethylacetyl-Valine (25)

The compound was prepared as follow based on reported procedure5 A round bottom flask

equipped with a magnetic stirring bar was charged with distilled water and NaHCO3

The resulting reaction mixtures was cooled to 0 oC in an ice bath L-Valine methyl ester

hydrochloride (300 mg 256 mmol) was added and the solution was stirred until

homogeneous The flask was equipped with an addition funnel The corresponding

trimethylacetyl chloride which was prepared from the corresponding pivalic acid in

14-dioxane (4 mL) was added dropwise The reaction mixture was then allowed to stir

at room temperature overnight Next the reaction was extracted with Et2O (2x20 mL)

to remove the impurities The aqueous layer was again cooled to 0 oC in an ice bath and

1M HCl was added until pH 3 The product was extracted with ethyl acetate (3x100 mL)

The organic layer was washed with brine (50 mL) dried over Na2SO4 filtered and

concentrated under vacuum to give the product as white powder Identical to the

literature5

1H NMR (400 MHz CDCl3) δ 970 (s 1H COOH) 624 (d J = 85 Hz 1H amide-

NH) 456 (dd J = 85 47 Hz 1H Ha) 223 (m 1H Hb) 122 (s 9H tert-butyl-Me)

106 ndash 093 (m 6H isopropyl-Me)

S16

L-(tert-butylcarbamoyl)-N-valine methyl ester (26a)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (10 g 762 mmol) was dissolved in dry DCM (100 mL) and the

isocyanate was added The mixture was stirred and the progress of the reaction was

monitored by TLC (petroleum etherethyl acetate 11) After completion the solvents

were removed under vacuum and the crude product was dissolved in DCM (80 mL)

washed with 1M HCl (3x80 mL) dried over MgSO4 The pure product was obtained as

white powder with 96 yield Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 604 (d J = 88 Hz 1H urea-NH) 594 (s 1H urea-

NH) 403 (dd J = 88 53 Hz 1H Ha) 362 (s 3H OMe) 209 ndash 183 (m 1H Hb)

120 (s 9H tert-butyl) 083 (m 6H isopropyl-Me)

L-(tert-butylcarbamoyl)-N-valine (26)

The compound was prepared as follow based on reported procedure4 To a solution of L-

(tert-butylcarbamoyl)-N-valine methyl ester (1 eq 074 g 322 mmol) in

methanolTHFwater (111 30 mL) mixture was added LiOHH2O (1 eq 135 mg 322

mmol) After overnight stirring at room temperature the resulting reaction mixtures was

partially concentrated under vacuum followed by the addition of water (20 mL) The

mixture was acidified with 1M HCl to pH 4 and then the product was extracted with

ethyl acetate (3x30 mL) The combined organic layer was washed with brine (30 mL)

dried over MgSO4 The pure product was obtained as white powder with 80 yield

Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 1241 (s 1H COOH) 591 (s 1H urea-NH) 587

(d J = 91 Hz 1H urea-NH) 399 (dd J = 89 48 Hz 1H Ha) 199 ndash 188 (m 1H

Hb) 120 (s 9H tert-butyl) 085 - 081 (m 6H isopropyl-Me)

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 4: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S4

11-Bis-(3-methyl-7-nitro-1H-indol-2-yl)-propane (L1-1)

The compound was prepared as follow based on reported procedure1 A mixture of 2-

nitrophenylhydrazine moistened with 30 water as received from Sigma Aldrich (60 g 038

mol 10 eq) propionaldehyde (50 mL 070 mol 18 eq) acetic acid (20 mL 003 mol 009

eq) and ethanol (05 L) was refluxed for 2 hours After completion (monitored by TLC) the

volatiles were removed under vacuum The yellow solid residue was carefully suspended in

concentrated aqueous HCl (35-37 06 L) by sonication for 1 hour (in the fume hood) After

adding 100 mL ethanol into the mixture the suspension was carefully () warmed up to 100 oC

while vigorously stirring Propionaldehyde (45 mL 063 mol 17 eq) was added dropwise via

a syringe controlled by an injection pump while the heating was continued for 1 hour After

cooling down the reaction mixture was poured into a beaker containing water (1 L) and CHCl3

(300 mL) The reaction mixture was carefully neutralized with Na2CO3 until pH 7 (careful)

After phase separation the water phase was extracted with CHCl3 (2x800 mL) The combined

organic phase was dried over MgSO4 filtrated and evaporated The oil like black residue was

dissolved in hot 12-dichloroethane (50 mL) and slowly cooled down The solid was filtered

off washed thoroughly with hexane until almost all the black impurities were removed (be

patient) and then with a small amount DCM or cold methanol yielding 50 of the desired

compound L1-1 as orange crystals identical to the literature1

1H NMR (400 MHz CDCl3) δ 962 (s 2H indole-NH) 809 (d J = 81 Hz 2H) 784 (d J =

77 Hz 2H) 718 (t J = 79 Hz 2H) 452 (t J = 80 Hz 1H CHCH2CH3) 240 ndash 249 (m 8H

ArCH3 and CHCH2CH3) 107 (t J = 73 Hz 3H CHCH2CH3)

1-Bis-(4-(diphenylphosphino)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-

propane (ParaDIMPhos (L1))

The compound was prepared as follow based on reported procedure2 11-Bis-(3-methyl-7-

nitro-1H-indol-2-yl)-propane (L1-1) (121 g 308 mmol 10 eq) was suspended in

methanolTHF (11 50 mL) and 10 palladium on charcoal was added (039 g) The reaction

S5

mixture was vigorously stirred under 1 bar of H2 atmosphere with a balloon The progress of

the reaction was monitored by TLC and after completion (about 2 hours) the catalyst was

filtered off The solvent was evaporated and the crude diamine was immediately used in the

subsequent reaction without further purification To a solution of the crude diamine (3000 mg

11 mmol 1 eq) 4-(Diphenylphospino)benzoic acid (7660 mg 24 mmol 22 eq) 4-

Dimethylaminopyridine (690 mg 06 mmol 05 eq) and 4-pyrrolidinopyridine (688 mg 05

mmol 04 eq) in dichloromethane (20 ml) NNrsquo-diisopropylcarbodiimide (14 ml 88 mmol

80 eq) was added slowly while stirring at 0 oC under N2 and the mixture was then stirred

overnight The precipitate was filtered off the solvent was evaporated and the solid residue

was purified by column chromatography on silica gel (100 g) with a hexanedichloromethane

(13) mixture to pure dichloromethane as an eluent Then dissolve the product with a minimum

amount of dichloromethane and add pentanehexane slowly until precipitation appears

followed by crystallization under -20 oC overnight After quickly filtration pure compound

was obtained Yield 91 yellow powder Identical to the literature2

1H NMR (400 MHz CD2Cl2) δ 942 (s 2H indole-NH) 821 (s 2H amide-NH) 762 (d J

= 79 Hz 4H) 743 ndash 726 (m 22H) 722 (t J = 74 Hz 4H) 702 (t J = 76 Hz 2H) 694 (d

J = 76 Hz 2H) 448 (t J = 82 Hz 1H CHCH2CH3) 230 (s 6H aryl-Me) 216 (t J = 76

Hz 2H CHCH2CH3) 099 (t J = 73 Hz 3H CHCH2CH3)

13C NMR (126 MHz CD2Cl2) δ 16594 13632 13443 13437 13427 13422 13378

13364 13210 12978 12920 12915 12804 12771 12766 12238 11930 11615

11406 10820 3688 2794 1260 886

31P NMR (162 MHz CD2Cl2) δ -562

S6

Scheme S2 Synthesis of the DIMphosphite L2 and L3 a 1 bar H2 PdC THFMeOH

b 3-benzyloxybenzoyl chloride TEA DCM RT c 1 bar H2 PdC THFMeOH d (S)-

binol-PCl or Diphenyl-PCl THF -78 oC to RT

Bis-(3-(benzyloxy)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-

propane (L2a)

S7

The compound was prepared as follow based on reported procedure3 11-Bis-(-3-methyl-7-

nitro-1H-indol-2-yl)propane (10 g 25 mmol) was suspended in

methanoltetrahydrofuran (11 15 ml) and 10 palladium on charcoal was added (02

g) The reaction mixture was flushed with hydrogen and then vigorously stirred under

1 bar of hydrogen with a balloon The progress of the reaction was monitored by TLC

(DCMMethanol 101) and after completion (~2 hours) the catalyst was filtered off

over Celite The solvent was evaporated and the crude diamine was immediately used

in the subsequent reaction without further purification

To the solution of the crude diamine (25 mmol) and triethylamine (50 mmol) in

dichloromethane (10 ml) a solution of 3-(benzyloxy)benzoyl chloride (16 g 65 mmol)

in dichloromethane (10 ml) was slowly added while stirring and the mixture was

allowed to continue stirring overnight After completion (TLC pentane ethyl acetate

21) the solvent was evaporated and the crude mixture was purified by chromatography

with pentaneethyl acetate (31) to dichloromethanemethanol (201) as the eluent The

product was then dissolved in a minimum amount of chloromethanemethanol and

followed by the addition of hexane to precipitate the compounds which was filtrated

through filter and washed with hexane to obtain pure compound L2a Identical to the

literature3

1H NMR (400 MHz CDCl3) δ 951 (s 2H indole-NH) 815 (s 2H amide-NH) 740

ndash 731 (m 16H) 724 ndash 714 (m 1H) 703 (t J = 68 Hz 5H) 694 (d J = 74 Hz 2H)

503 ndash 489 (m 4H Bn-CH2) 450 ndash 442 (m 1H CHCH2CH3) 231 (s 6H aryl-CH3)

223 ndash 214 (m 2H CHCH2CH3) 099 (t J = 76 Hz 3H CHCH2CH3)

S8

1-Bis-(3-(hydroxyl)benzoamide of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-

propane (L2b)

The compound was prepared as follow based on reported procedure3 Bis-(3-

(benzyloxy)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane (L2a)

(123 g 16 mmol) was suspended in methanol (30 ml) and 10 palladium on charcoal

was added (03 g) The reaction mixture was flushed with hydrogen and then vigorously

stirred under 1 bar hydrogen with a balloon The progress of the reaction was monitored

by TLC (DCMMethanol 101) and after overnight reaction the catalyst was filtered

off over Celite The solvent was evaporated and the pure product was obtained by

crystallization with dichloromethane and hexane Identical to the literature3

1H NMR (500 MHz Methanol-d4) δ 743 ndash 732 (m 6H) 730 ndash 721 (m 4H) 700 (q

J = 80 Hz 4H) 453 (t J = 80 Hz 1H CHCH2CH3) 235 ndash 217 (m 8H aryl-CH3 amp

CHCH2CH3) 099 (t J = 73 Hz 3H CHCH2CH3)

48-Di-tert-butyl-6-chloro-210-dimethoxydibenzo[df][132]dioxaphosphepine

(Diphenyl-PCl)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with 33-di-tert-

butyl-55-dimethoxy-[11-biphenyl]-22-diol (1 eq 1878 mg 052 mmol) followed

by co-evaporation with dry toluene three times Then 5 ml dried and degassed THF was

added into the flask To this solution under -78 oC PCl3 (15 eq 691 uL 078 mmol)

and triethylamine (30 eq 221 uL 156 mmol) was added dropwise After stirring under

-78 oC for 15 min the reaction mixture was slowly warmed up to room temperature and

stirred for another 45 min After completion (monitored by 31P NMR) the volatiles were

evaporated under vacuum and further co-evaporated with dry toluene three times The

product was formed quantitatively and used directly

S9

(Bis-3-((48-Di-tert-butyl-210-dimethoxydibenzo[df][132]dioxaphosphepin-6-

yl)oxyl)benzoamide of 11-bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L2)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 1500 mg 026 mmol) followed by co-evaporation with dry toluene three times

Then 5 ml dried and degassed THF was added into the flask To this solution under -78

oC Diphenyl-PCl (20 eq 052 mmol) and triethylamine (30 eq 221 uL 156 mmol)

in THF was added dropwise After stirring under -78 oC for 15 min the reaction mixture

was slowly warmed up to room temperature and stirred for another 45 min After

completion (monitored by 31P NMR) the volatiles were evaporated under vacuum and

further co-evaporated with dry toluene three times The reaction mixture was evaporated

and to the solid residue THF (5 ml) was added The suspension was filtered through a

plug of celite which was subsequently washed with THF (10 ml) The combined organic

fractions were concentrated hexane (10 ml) was added followed by evaporation of all

volatiles to dryness The product was formed quantitatively without further purification

1H NMR (500 MHz CD2Cl2) δ 982 (s 2H indole-NH) 834 (s 2H amide-NH) 760

ndash 750 (m 2H) 735 (dd J = 65 23 Hz 2H) 725 ndash 722 (m 3H) 719 ndash 715 (m 3H)

707 ndash 695 (m 8H) 675 ndash 673 (m 4H) 449 (t J = 80 Hz 1H CHCH2CH3) 379 ndash

378 (m 12H) 232 (s 6H indole-Me) 223 (p J = 76 Hz 2H CHCH2CH3) 187 ndash

S10

177 (m 2H) 147 (d J = 20 Hz 6H OMe) 144 (s 18H) 142 (s 18H) 100 (t J =

76 Hz 3H CHCH2CH3)

31P NMR (202 MHz CD2Cl2) δ 13934

13C NMR (101 MHz CD2Cl2) δ 16523 15650 15264 (d J = 62 Hz) 14306 (m)

14145 (d J = 59 Hz) 13838 13658 (d J = 342 Hz) 13402 (m) 13215 13038

12937 12843 (d J = 271 Hz) 12564 12388 (d J = 79 Hz) 12338 12239 11976

(d J = 76 Hz) 11920 11614 11529 11485 11414 11336 10800 5599 4618

3574 3124 (m) 3085 2599 1265 890

HR MS (FD+(eiFi)+) calcd for C79H86N4O12P2 [M]+ 13445717 found 13445774

(S)-11rsquo-Binaphthyl-22-diyl phosphorochloridate (S)-binol-PCl

A flamed dried Schlenk flask with a Teflon stirring bar was charged with (S)-binol (1

eq 187 g 52 mmol) followed by co-evaporation with dry toluene three times Dried

and degassed THF (20 ml) was then added into the flask To this solution under -78 oC

PCl3 (15 eq 691 uL 78 mmol) and triethylamine (30 eq 221 mL 156 mmol) was

added dropwise After stirring under -78 oC for 30 min the reaction mixture was slowly

warmed up to room temperature and stirred for another 60 min After completion

(monitored by 31P NMR) the volatiles were evaporated under vacuum and further co-

evaporated with dry toluene three times The product was formed quantitatively as white

solid and used directly without further purification

S11

(Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide) of 11-Bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L3)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 115 g 20 mmol) followed by co-evaporation with dry toluene three times Then

25 ml dried and degassed THF was added into the flask To this solution under -78 oC

(S)-binol-PCl (20 eq 140 g 40 mmol) and triethylamine (30 eq 084 mL 60 mmol)

in THF (20 mL) was added dropwise After stirring under -78 oC for 15 min the reaction

mixture was slowly warmed up to room temperature and stirred for overnight The

reaction mixture was evaporated and to the solid residue THF (40 ml) was added The

suspension was filtered through a plug of celite which was subsequently washed with

THF (40 ml) The combined organic fractions were concentrated hexane (30 ml) was

added followed by evaporation of all volatiles to dryness yielding 258g (95) of

L3middotTHFmiddotC6H14 NOTE Ligand L3 is sensitive to moisture and thus should be stored in

inert conditions at low temperatures preferably

1H NMR (400 MHz CD2Cl2) δ 950 (m 2H indole-NH) 821 (s 1H amide-NH) 816

(s 1H amide-NH) 807 ndash 781 (m 8H) 762 ndash 714 (m 26H) 699 (t J = 77 Hz 1H)

694 ndash 677 (m 3H) 449 (d J = 79 Hz 1H CHCH2CH3) 233 (s 3H aryl-Me) 232

(s 3H aryl-Me) 226 ndash 206 (m 2H CHCH2CH3) 100 (t J = 73 Hz 3H CHCH2CH3)

S12

31P NMR (162 MHz CD2Cl2) δ 14408 14397

13C NMR (100MHz CD2Cl2) δ = 16524 (m) 15229 (m) 14784 (d J = 46 Hz)

14722 (m) 13674 13638 (d J = 80 Hz) 13319 13287 13236 13224 13174 (m)

13111 13050 (m) 12885 (d J = 81 Hz) 12827 (d J = 30 Hz) 12721 12708 (d J

= 30 Hz) 12690 (d J = 65 Hz) 12573 (d J = 171 Hz) 12455 (m) 12405 (d J =

81 Hz) 12375 (d J = 85 Hz) 12346 (d J = 111 Hz) 12321 (m) 12217 12197

11992 (m) 11973 (d J = 75 Hz) 11930 (d J = 40 Hz) 11815 11641 11410 (d J

= 160 Hz) 10825 (d J = 44 Hz) 3686 2599 1261 889

HR MS (FD+(eiFi)+) calcd for C75H54N4O8P2 [M]+ 120034169 found 120033967

The effectors used in this study

Scheme S3 Effectors purchased from commercial source

S13

Scheme S4 Effectors prepared except 27 purchased from commercial sources

L-(tert-butylthiocarbamoyl)-N-valine (1S)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 200 mg 170 mmol) was dissolved in 025 M NaHCO3 solution

(80 mL) followed by adding the isothiocyanate (1 eq 022 mL 17 mmol) The mixture

was heated at 80 oC for 3 hours and the progress of the reaction was monitored by TLC

(petroleum etherethyl acetate 11) After completion the reaction mixture was cooling

down and acidified to pH 2 with 1M HCl (3x80 mL) The products were extracted with

ethyl acetate (3x100 mL) The combined organic layer was dried over MgSO4 The pure

product was obtained as white powder with 50 yield after crystallization Identical to

the literature4

S14

1H NMR (400 MHz DMSO-d6) δ 750 (s 1H thiourea-NH) 738 (d J = 86 Hz 1H

thiourea-NH) 484 (dd J = 86 46 Hz 1H Ha) 208 (m 1H Hb) 142 (s 9H tert-

butyl-Me) 088 (m 6H isopropyl-Me)

D-(tert-butylthiocarbamoyl)-N-valine (1S) was prepared following the same

procedures for 1R

1H NMR (400 MHz DMSO-d6) δ 1255 (s 1H COOH) 749 (s 1H thiourea-NH)

737 (d J = 86 Hz 1H thiourea-NH) 483 (dd J = 86 46 Hz 1H Ha) 209 ndash 205

(m 1H Hb) 141 (s 9H tert-butyl) 088 -086 (m 6H isopropyl-Me)

13C NMR (126 MHz DMSO-d6) δ 18182 17342 6030 5227 3057 2889 1887

1812

HRMS (FD+(eiFi)) calcd for C10H20N2O2S1 [M]+ 2321245 found 2321201

L-N-formyl-Valine (24)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (03 g 25 mmol) formic acid (952 g 113 mmol) and acetic acid

anhydride (1 g 98 mmol) were dissolved in acetic acid (10 mL) and the reaction was

stirred for 4 hours at room temperature Afterwards all the volatiles were removed under

vacuum and the crude product was purified by recrystallization to give while power

identical to literature4

S15

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 841 (s 1H formyl-H) 798

(d J = 8 Hz 1H amide-NH) 411 (dd J = 8 Hz J = 6 Hz 1H Ha) 202 (m 1H Hb)

087 (dd J = 1 Hz J = 7 Hz 6H isopropyl-Me)

L-N-trimethylacetyl-Valine (25)

The compound was prepared as follow based on reported procedure5 A round bottom flask

equipped with a magnetic stirring bar was charged with distilled water and NaHCO3

The resulting reaction mixtures was cooled to 0 oC in an ice bath L-Valine methyl ester

hydrochloride (300 mg 256 mmol) was added and the solution was stirred until

homogeneous The flask was equipped with an addition funnel The corresponding

trimethylacetyl chloride which was prepared from the corresponding pivalic acid in

14-dioxane (4 mL) was added dropwise The reaction mixture was then allowed to stir

at room temperature overnight Next the reaction was extracted with Et2O (2x20 mL)

to remove the impurities The aqueous layer was again cooled to 0 oC in an ice bath and

1M HCl was added until pH 3 The product was extracted with ethyl acetate (3x100 mL)

The organic layer was washed with brine (50 mL) dried over Na2SO4 filtered and

concentrated under vacuum to give the product as white powder Identical to the

literature5

1H NMR (400 MHz CDCl3) δ 970 (s 1H COOH) 624 (d J = 85 Hz 1H amide-

NH) 456 (dd J = 85 47 Hz 1H Ha) 223 (m 1H Hb) 122 (s 9H tert-butyl-Me)

106 ndash 093 (m 6H isopropyl-Me)

S16

L-(tert-butylcarbamoyl)-N-valine methyl ester (26a)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (10 g 762 mmol) was dissolved in dry DCM (100 mL) and the

isocyanate was added The mixture was stirred and the progress of the reaction was

monitored by TLC (petroleum etherethyl acetate 11) After completion the solvents

were removed under vacuum and the crude product was dissolved in DCM (80 mL)

washed with 1M HCl (3x80 mL) dried over MgSO4 The pure product was obtained as

white powder with 96 yield Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 604 (d J = 88 Hz 1H urea-NH) 594 (s 1H urea-

NH) 403 (dd J = 88 53 Hz 1H Ha) 362 (s 3H OMe) 209 ndash 183 (m 1H Hb)

120 (s 9H tert-butyl) 083 (m 6H isopropyl-Me)

L-(tert-butylcarbamoyl)-N-valine (26)

The compound was prepared as follow based on reported procedure4 To a solution of L-

(tert-butylcarbamoyl)-N-valine methyl ester (1 eq 074 g 322 mmol) in

methanolTHFwater (111 30 mL) mixture was added LiOHH2O (1 eq 135 mg 322

mmol) After overnight stirring at room temperature the resulting reaction mixtures was

partially concentrated under vacuum followed by the addition of water (20 mL) The

mixture was acidified with 1M HCl to pH 4 and then the product was extracted with

ethyl acetate (3x30 mL) The combined organic layer was washed with brine (30 mL)

dried over MgSO4 The pure product was obtained as white powder with 80 yield

Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 1241 (s 1H COOH) 591 (s 1H urea-NH) 587

(d J = 91 Hz 1H urea-NH) 399 (dd J = 89 48 Hz 1H Ha) 199 ndash 188 (m 1H

Hb) 120 (s 9H tert-butyl) 085 - 081 (m 6H isopropyl-Me)

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 5: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S5

mixture was vigorously stirred under 1 bar of H2 atmosphere with a balloon The progress of

the reaction was monitored by TLC and after completion (about 2 hours) the catalyst was

filtered off The solvent was evaporated and the crude diamine was immediately used in the

subsequent reaction without further purification To a solution of the crude diamine (3000 mg

11 mmol 1 eq) 4-(Diphenylphospino)benzoic acid (7660 mg 24 mmol 22 eq) 4-

Dimethylaminopyridine (690 mg 06 mmol 05 eq) and 4-pyrrolidinopyridine (688 mg 05

mmol 04 eq) in dichloromethane (20 ml) NNrsquo-diisopropylcarbodiimide (14 ml 88 mmol

80 eq) was added slowly while stirring at 0 oC under N2 and the mixture was then stirred

overnight The precipitate was filtered off the solvent was evaporated and the solid residue

was purified by column chromatography on silica gel (100 g) with a hexanedichloromethane

(13) mixture to pure dichloromethane as an eluent Then dissolve the product with a minimum

amount of dichloromethane and add pentanehexane slowly until precipitation appears

followed by crystallization under -20 oC overnight After quickly filtration pure compound

was obtained Yield 91 yellow powder Identical to the literature2

1H NMR (400 MHz CD2Cl2) δ 942 (s 2H indole-NH) 821 (s 2H amide-NH) 762 (d J

= 79 Hz 4H) 743 ndash 726 (m 22H) 722 (t J = 74 Hz 4H) 702 (t J = 76 Hz 2H) 694 (d

J = 76 Hz 2H) 448 (t J = 82 Hz 1H CHCH2CH3) 230 (s 6H aryl-Me) 216 (t J = 76

Hz 2H CHCH2CH3) 099 (t J = 73 Hz 3H CHCH2CH3)

13C NMR (126 MHz CD2Cl2) δ 16594 13632 13443 13437 13427 13422 13378

13364 13210 12978 12920 12915 12804 12771 12766 12238 11930 11615

11406 10820 3688 2794 1260 886

31P NMR (162 MHz CD2Cl2) δ -562

S6

Scheme S2 Synthesis of the DIMphosphite L2 and L3 a 1 bar H2 PdC THFMeOH

b 3-benzyloxybenzoyl chloride TEA DCM RT c 1 bar H2 PdC THFMeOH d (S)-

binol-PCl or Diphenyl-PCl THF -78 oC to RT

Bis-(3-(benzyloxy)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-

propane (L2a)

S7

The compound was prepared as follow based on reported procedure3 11-Bis-(-3-methyl-7-

nitro-1H-indol-2-yl)propane (10 g 25 mmol) was suspended in

methanoltetrahydrofuran (11 15 ml) and 10 palladium on charcoal was added (02

g) The reaction mixture was flushed with hydrogen and then vigorously stirred under

1 bar of hydrogen with a balloon The progress of the reaction was monitored by TLC

(DCMMethanol 101) and after completion (~2 hours) the catalyst was filtered off

over Celite The solvent was evaporated and the crude diamine was immediately used

in the subsequent reaction without further purification

To the solution of the crude diamine (25 mmol) and triethylamine (50 mmol) in

dichloromethane (10 ml) a solution of 3-(benzyloxy)benzoyl chloride (16 g 65 mmol)

in dichloromethane (10 ml) was slowly added while stirring and the mixture was

allowed to continue stirring overnight After completion (TLC pentane ethyl acetate

21) the solvent was evaporated and the crude mixture was purified by chromatography

with pentaneethyl acetate (31) to dichloromethanemethanol (201) as the eluent The

product was then dissolved in a minimum amount of chloromethanemethanol and

followed by the addition of hexane to precipitate the compounds which was filtrated

through filter and washed with hexane to obtain pure compound L2a Identical to the

literature3

1H NMR (400 MHz CDCl3) δ 951 (s 2H indole-NH) 815 (s 2H amide-NH) 740

ndash 731 (m 16H) 724 ndash 714 (m 1H) 703 (t J = 68 Hz 5H) 694 (d J = 74 Hz 2H)

503 ndash 489 (m 4H Bn-CH2) 450 ndash 442 (m 1H CHCH2CH3) 231 (s 6H aryl-CH3)

223 ndash 214 (m 2H CHCH2CH3) 099 (t J = 76 Hz 3H CHCH2CH3)

S8

1-Bis-(3-(hydroxyl)benzoamide of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-

propane (L2b)

The compound was prepared as follow based on reported procedure3 Bis-(3-

(benzyloxy)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane (L2a)

(123 g 16 mmol) was suspended in methanol (30 ml) and 10 palladium on charcoal

was added (03 g) The reaction mixture was flushed with hydrogen and then vigorously

stirred under 1 bar hydrogen with a balloon The progress of the reaction was monitored

by TLC (DCMMethanol 101) and after overnight reaction the catalyst was filtered

off over Celite The solvent was evaporated and the pure product was obtained by

crystallization with dichloromethane and hexane Identical to the literature3

1H NMR (500 MHz Methanol-d4) δ 743 ndash 732 (m 6H) 730 ndash 721 (m 4H) 700 (q

J = 80 Hz 4H) 453 (t J = 80 Hz 1H CHCH2CH3) 235 ndash 217 (m 8H aryl-CH3 amp

CHCH2CH3) 099 (t J = 73 Hz 3H CHCH2CH3)

48-Di-tert-butyl-6-chloro-210-dimethoxydibenzo[df][132]dioxaphosphepine

(Diphenyl-PCl)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with 33-di-tert-

butyl-55-dimethoxy-[11-biphenyl]-22-diol (1 eq 1878 mg 052 mmol) followed

by co-evaporation with dry toluene three times Then 5 ml dried and degassed THF was

added into the flask To this solution under -78 oC PCl3 (15 eq 691 uL 078 mmol)

and triethylamine (30 eq 221 uL 156 mmol) was added dropwise After stirring under

-78 oC for 15 min the reaction mixture was slowly warmed up to room temperature and

stirred for another 45 min After completion (monitored by 31P NMR) the volatiles were

evaporated under vacuum and further co-evaporated with dry toluene three times The

product was formed quantitatively and used directly

S9

(Bis-3-((48-Di-tert-butyl-210-dimethoxydibenzo[df][132]dioxaphosphepin-6-

yl)oxyl)benzoamide of 11-bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L2)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 1500 mg 026 mmol) followed by co-evaporation with dry toluene three times

Then 5 ml dried and degassed THF was added into the flask To this solution under -78

oC Diphenyl-PCl (20 eq 052 mmol) and triethylamine (30 eq 221 uL 156 mmol)

in THF was added dropwise After stirring under -78 oC for 15 min the reaction mixture

was slowly warmed up to room temperature and stirred for another 45 min After

completion (monitored by 31P NMR) the volatiles were evaporated under vacuum and

further co-evaporated with dry toluene three times The reaction mixture was evaporated

and to the solid residue THF (5 ml) was added The suspension was filtered through a

plug of celite which was subsequently washed with THF (10 ml) The combined organic

fractions were concentrated hexane (10 ml) was added followed by evaporation of all

volatiles to dryness The product was formed quantitatively without further purification

1H NMR (500 MHz CD2Cl2) δ 982 (s 2H indole-NH) 834 (s 2H amide-NH) 760

ndash 750 (m 2H) 735 (dd J = 65 23 Hz 2H) 725 ndash 722 (m 3H) 719 ndash 715 (m 3H)

707 ndash 695 (m 8H) 675 ndash 673 (m 4H) 449 (t J = 80 Hz 1H CHCH2CH3) 379 ndash

378 (m 12H) 232 (s 6H indole-Me) 223 (p J = 76 Hz 2H CHCH2CH3) 187 ndash

S10

177 (m 2H) 147 (d J = 20 Hz 6H OMe) 144 (s 18H) 142 (s 18H) 100 (t J =

76 Hz 3H CHCH2CH3)

31P NMR (202 MHz CD2Cl2) δ 13934

13C NMR (101 MHz CD2Cl2) δ 16523 15650 15264 (d J = 62 Hz) 14306 (m)

14145 (d J = 59 Hz) 13838 13658 (d J = 342 Hz) 13402 (m) 13215 13038

12937 12843 (d J = 271 Hz) 12564 12388 (d J = 79 Hz) 12338 12239 11976

(d J = 76 Hz) 11920 11614 11529 11485 11414 11336 10800 5599 4618

3574 3124 (m) 3085 2599 1265 890

HR MS (FD+(eiFi)+) calcd for C79H86N4O12P2 [M]+ 13445717 found 13445774

(S)-11rsquo-Binaphthyl-22-diyl phosphorochloridate (S)-binol-PCl

A flamed dried Schlenk flask with a Teflon stirring bar was charged with (S)-binol (1

eq 187 g 52 mmol) followed by co-evaporation with dry toluene three times Dried

and degassed THF (20 ml) was then added into the flask To this solution under -78 oC

PCl3 (15 eq 691 uL 78 mmol) and triethylamine (30 eq 221 mL 156 mmol) was

added dropwise After stirring under -78 oC for 30 min the reaction mixture was slowly

warmed up to room temperature and stirred for another 60 min After completion

(monitored by 31P NMR) the volatiles were evaporated under vacuum and further co-

evaporated with dry toluene three times The product was formed quantitatively as white

solid and used directly without further purification

S11

(Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide) of 11-Bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L3)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 115 g 20 mmol) followed by co-evaporation with dry toluene three times Then

25 ml dried and degassed THF was added into the flask To this solution under -78 oC

(S)-binol-PCl (20 eq 140 g 40 mmol) and triethylamine (30 eq 084 mL 60 mmol)

in THF (20 mL) was added dropwise After stirring under -78 oC for 15 min the reaction

mixture was slowly warmed up to room temperature and stirred for overnight The

reaction mixture was evaporated and to the solid residue THF (40 ml) was added The

suspension was filtered through a plug of celite which was subsequently washed with

THF (40 ml) The combined organic fractions were concentrated hexane (30 ml) was

added followed by evaporation of all volatiles to dryness yielding 258g (95) of

L3middotTHFmiddotC6H14 NOTE Ligand L3 is sensitive to moisture and thus should be stored in

inert conditions at low temperatures preferably

1H NMR (400 MHz CD2Cl2) δ 950 (m 2H indole-NH) 821 (s 1H amide-NH) 816

(s 1H amide-NH) 807 ndash 781 (m 8H) 762 ndash 714 (m 26H) 699 (t J = 77 Hz 1H)

694 ndash 677 (m 3H) 449 (d J = 79 Hz 1H CHCH2CH3) 233 (s 3H aryl-Me) 232

(s 3H aryl-Me) 226 ndash 206 (m 2H CHCH2CH3) 100 (t J = 73 Hz 3H CHCH2CH3)

S12

31P NMR (162 MHz CD2Cl2) δ 14408 14397

13C NMR (100MHz CD2Cl2) δ = 16524 (m) 15229 (m) 14784 (d J = 46 Hz)

14722 (m) 13674 13638 (d J = 80 Hz) 13319 13287 13236 13224 13174 (m)

13111 13050 (m) 12885 (d J = 81 Hz) 12827 (d J = 30 Hz) 12721 12708 (d J

= 30 Hz) 12690 (d J = 65 Hz) 12573 (d J = 171 Hz) 12455 (m) 12405 (d J =

81 Hz) 12375 (d J = 85 Hz) 12346 (d J = 111 Hz) 12321 (m) 12217 12197

11992 (m) 11973 (d J = 75 Hz) 11930 (d J = 40 Hz) 11815 11641 11410 (d J

= 160 Hz) 10825 (d J = 44 Hz) 3686 2599 1261 889

HR MS (FD+(eiFi)+) calcd for C75H54N4O8P2 [M]+ 120034169 found 120033967

The effectors used in this study

Scheme S3 Effectors purchased from commercial source

S13

Scheme S4 Effectors prepared except 27 purchased from commercial sources

L-(tert-butylthiocarbamoyl)-N-valine (1S)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 200 mg 170 mmol) was dissolved in 025 M NaHCO3 solution

(80 mL) followed by adding the isothiocyanate (1 eq 022 mL 17 mmol) The mixture

was heated at 80 oC for 3 hours and the progress of the reaction was monitored by TLC

(petroleum etherethyl acetate 11) After completion the reaction mixture was cooling

down and acidified to pH 2 with 1M HCl (3x80 mL) The products were extracted with

ethyl acetate (3x100 mL) The combined organic layer was dried over MgSO4 The pure

product was obtained as white powder with 50 yield after crystallization Identical to

the literature4

S14

1H NMR (400 MHz DMSO-d6) δ 750 (s 1H thiourea-NH) 738 (d J = 86 Hz 1H

thiourea-NH) 484 (dd J = 86 46 Hz 1H Ha) 208 (m 1H Hb) 142 (s 9H tert-

butyl-Me) 088 (m 6H isopropyl-Me)

D-(tert-butylthiocarbamoyl)-N-valine (1S) was prepared following the same

procedures for 1R

1H NMR (400 MHz DMSO-d6) δ 1255 (s 1H COOH) 749 (s 1H thiourea-NH)

737 (d J = 86 Hz 1H thiourea-NH) 483 (dd J = 86 46 Hz 1H Ha) 209 ndash 205

(m 1H Hb) 141 (s 9H tert-butyl) 088 -086 (m 6H isopropyl-Me)

13C NMR (126 MHz DMSO-d6) δ 18182 17342 6030 5227 3057 2889 1887

1812

HRMS (FD+(eiFi)) calcd for C10H20N2O2S1 [M]+ 2321245 found 2321201

L-N-formyl-Valine (24)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (03 g 25 mmol) formic acid (952 g 113 mmol) and acetic acid

anhydride (1 g 98 mmol) were dissolved in acetic acid (10 mL) and the reaction was

stirred for 4 hours at room temperature Afterwards all the volatiles were removed under

vacuum and the crude product was purified by recrystallization to give while power

identical to literature4

S15

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 841 (s 1H formyl-H) 798

(d J = 8 Hz 1H amide-NH) 411 (dd J = 8 Hz J = 6 Hz 1H Ha) 202 (m 1H Hb)

087 (dd J = 1 Hz J = 7 Hz 6H isopropyl-Me)

L-N-trimethylacetyl-Valine (25)

The compound was prepared as follow based on reported procedure5 A round bottom flask

equipped with a magnetic stirring bar was charged with distilled water and NaHCO3

The resulting reaction mixtures was cooled to 0 oC in an ice bath L-Valine methyl ester

hydrochloride (300 mg 256 mmol) was added and the solution was stirred until

homogeneous The flask was equipped with an addition funnel The corresponding

trimethylacetyl chloride which was prepared from the corresponding pivalic acid in

14-dioxane (4 mL) was added dropwise The reaction mixture was then allowed to stir

at room temperature overnight Next the reaction was extracted with Et2O (2x20 mL)

to remove the impurities The aqueous layer was again cooled to 0 oC in an ice bath and

1M HCl was added until pH 3 The product was extracted with ethyl acetate (3x100 mL)

The organic layer was washed with brine (50 mL) dried over Na2SO4 filtered and

concentrated under vacuum to give the product as white powder Identical to the

literature5

1H NMR (400 MHz CDCl3) δ 970 (s 1H COOH) 624 (d J = 85 Hz 1H amide-

NH) 456 (dd J = 85 47 Hz 1H Ha) 223 (m 1H Hb) 122 (s 9H tert-butyl-Me)

106 ndash 093 (m 6H isopropyl-Me)

S16

L-(tert-butylcarbamoyl)-N-valine methyl ester (26a)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (10 g 762 mmol) was dissolved in dry DCM (100 mL) and the

isocyanate was added The mixture was stirred and the progress of the reaction was

monitored by TLC (petroleum etherethyl acetate 11) After completion the solvents

were removed under vacuum and the crude product was dissolved in DCM (80 mL)

washed with 1M HCl (3x80 mL) dried over MgSO4 The pure product was obtained as

white powder with 96 yield Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 604 (d J = 88 Hz 1H urea-NH) 594 (s 1H urea-

NH) 403 (dd J = 88 53 Hz 1H Ha) 362 (s 3H OMe) 209 ndash 183 (m 1H Hb)

120 (s 9H tert-butyl) 083 (m 6H isopropyl-Me)

L-(tert-butylcarbamoyl)-N-valine (26)

The compound was prepared as follow based on reported procedure4 To a solution of L-

(tert-butylcarbamoyl)-N-valine methyl ester (1 eq 074 g 322 mmol) in

methanolTHFwater (111 30 mL) mixture was added LiOHH2O (1 eq 135 mg 322

mmol) After overnight stirring at room temperature the resulting reaction mixtures was

partially concentrated under vacuum followed by the addition of water (20 mL) The

mixture was acidified with 1M HCl to pH 4 and then the product was extracted with

ethyl acetate (3x30 mL) The combined organic layer was washed with brine (30 mL)

dried over MgSO4 The pure product was obtained as white powder with 80 yield

Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 1241 (s 1H COOH) 591 (s 1H urea-NH) 587

(d J = 91 Hz 1H urea-NH) 399 (dd J = 89 48 Hz 1H Ha) 199 ndash 188 (m 1H

Hb) 120 (s 9H tert-butyl) 085 - 081 (m 6H isopropyl-Me)

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 6: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S6

Scheme S2 Synthesis of the DIMphosphite L2 and L3 a 1 bar H2 PdC THFMeOH

b 3-benzyloxybenzoyl chloride TEA DCM RT c 1 bar H2 PdC THFMeOH d (S)-

binol-PCl or Diphenyl-PCl THF -78 oC to RT

Bis-(3-(benzyloxy)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-

propane (L2a)

S7

The compound was prepared as follow based on reported procedure3 11-Bis-(-3-methyl-7-

nitro-1H-indol-2-yl)propane (10 g 25 mmol) was suspended in

methanoltetrahydrofuran (11 15 ml) and 10 palladium on charcoal was added (02

g) The reaction mixture was flushed with hydrogen and then vigorously stirred under

1 bar of hydrogen with a balloon The progress of the reaction was monitored by TLC

(DCMMethanol 101) and after completion (~2 hours) the catalyst was filtered off

over Celite The solvent was evaporated and the crude diamine was immediately used

in the subsequent reaction without further purification

To the solution of the crude diamine (25 mmol) and triethylamine (50 mmol) in

dichloromethane (10 ml) a solution of 3-(benzyloxy)benzoyl chloride (16 g 65 mmol)

in dichloromethane (10 ml) was slowly added while stirring and the mixture was

allowed to continue stirring overnight After completion (TLC pentane ethyl acetate

21) the solvent was evaporated and the crude mixture was purified by chromatography

with pentaneethyl acetate (31) to dichloromethanemethanol (201) as the eluent The

product was then dissolved in a minimum amount of chloromethanemethanol and

followed by the addition of hexane to precipitate the compounds which was filtrated

through filter and washed with hexane to obtain pure compound L2a Identical to the

literature3

1H NMR (400 MHz CDCl3) δ 951 (s 2H indole-NH) 815 (s 2H amide-NH) 740

ndash 731 (m 16H) 724 ndash 714 (m 1H) 703 (t J = 68 Hz 5H) 694 (d J = 74 Hz 2H)

503 ndash 489 (m 4H Bn-CH2) 450 ndash 442 (m 1H CHCH2CH3) 231 (s 6H aryl-CH3)

223 ndash 214 (m 2H CHCH2CH3) 099 (t J = 76 Hz 3H CHCH2CH3)

S8

1-Bis-(3-(hydroxyl)benzoamide of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-

propane (L2b)

The compound was prepared as follow based on reported procedure3 Bis-(3-

(benzyloxy)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane (L2a)

(123 g 16 mmol) was suspended in methanol (30 ml) and 10 palladium on charcoal

was added (03 g) The reaction mixture was flushed with hydrogen and then vigorously

stirred under 1 bar hydrogen with a balloon The progress of the reaction was monitored

by TLC (DCMMethanol 101) and after overnight reaction the catalyst was filtered

off over Celite The solvent was evaporated and the pure product was obtained by

crystallization with dichloromethane and hexane Identical to the literature3

1H NMR (500 MHz Methanol-d4) δ 743 ndash 732 (m 6H) 730 ndash 721 (m 4H) 700 (q

J = 80 Hz 4H) 453 (t J = 80 Hz 1H CHCH2CH3) 235 ndash 217 (m 8H aryl-CH3 amp

CHCH2CH3) 099 (t J = 73 Hz 3H CHCH2CH3)

48-Di-tert-butyl-6-chloro-210-dimethoxydibenzo[df][132]dioxaphosphepine

(Diphenyl-PCl)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with 33-di-tert-

butyl-55-dimethoxy-[11-biphenyl]-22-diol (1 eq 1878 mg 052 mmol) followed

by co-evaporation with dry toluene three times Then 5 ml dried and degassed THF was

added into the flask To this solution under -78 oC PCl3 (15 eq 691 uL 078 mmol)

and triethylamine (30 eq 221 uL 156 mmol) was added dropwise After stirring under

-78 oC for 15 min the reaction mixture was slowly warmed up to room temperature and

stirred for another 45 min After completion (monitored by 31P NMR) the volatiles were

evaporated under vacuum and further co-evaporated with dry toluene three times The

product was formed quantitatively and used directly

S9

(Bis-3-((48-Di-tert-butyl-210-dimethoxydibenzo[df][132]dioxaphosphepin-6-

yl)oxyl)benzoamide of 11-bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L2)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 1500 mg 026 mmol) followed by co-evaporation with dry toluene three times

Then 5 ml dried and degassed THF was added into the flask To this solution under -78

oC Diphenyl-PCl (20 eq 052 mmol) and triethylamine (30 eq 221 uL 156 mmol)

in THF was added dropwise After stirring under -78 oC for 15 min the reaction mixture

was slowly warmed up to room temperature and stirred for another 45 min After

completion (monitored by 31P NMR) the volatiles were evaporated under vacuum and

further co-evaporated with dry toluene three times The reaction mixture was evaporated

and to the solid residue THF (5 ml) was added The suspension was filtered through a

plug of celite which was subsequently washed with THF (10 ml) The combined organic

fractions were concentrated hexane (10 ml) was added followed by evaporation of all

volatiles to dryness The product was formed quantitatively without further purification

1H NMR (500 MHz CD2Cl2) δ 982 (s 2H indole-NH) 834 (s 2H amide-NH) 760

ndash 750 (m 2H) 735 (dd J = 65 23 Hz 2H) 725 ndash 722 (m 3H) 719 ndash 715 (m 3H)

707 ndash 695 (m 8H) 675 ndash 673 (m 4H) 449 (t J = 80 Hz 1H CHCH2CH3) 379 ndash

378 (m 12H) 232 (s 6H indole-Me) 223 (p J = 76 Hz 2H CHCH2CH3) 187 ndash

S10

177 (m 2H) 147 (d J = 20 Hz 6H OMe) 144 (s 18H) 142 (s 18H) 100 (t J =

76 Hz 3H CHCH2CH3)

31P NMR (202 MHz CD2Cl2) δ 13934

13C NMR (101 MHz CD2Cl2) δ 16523 15650 15264 (d J = 62 Hz) 14306 (m)

14145 (d J = 59 Hz) 13838 13658 (d J = 342 Hz) 13402 (m) 13215 13038

12937 12843 (d J = 271 Hz) 12564 12388 (d J = 79 Hz) 12338 12239 11976

(d J = 76 Hz) 11920 11614 11529 11485 11414 11336 10800 5599 4618

3574 3124 (m) 3085 2599 1265 890

HR MS (FD+(eiFi)+) calcd for C79H86N4O12P2 [M]+ 13445717 found 13445774

(S)-11rsquo-Binaphthyl-22-diyl phosphorochloridate (S)-binol-PCl

A flamed dried Schlenk flask with a Teflon stirring bar was charged with (S)-binol (1

eq 187 g 52 mmol) followed by co-evaporation with dry toluene three times Dried

and degassed THF (20 ml) was then added into the flask To this solution under -78 oC

PCl3 (15 eq 691 uL 78 mmol) and triethylamine (30 eq 221 mL 156 mmol) was

added dropwise After stirring under -78 oC for 30 min the reaction mixture was slowly

warmed up to room temperature and stirred for another 60 min After completion

(monitored by 31P NMR) the volatiles were evaporated under vacuum and further co-

evaporated with dry toluene three times The product was formed quantitatively as white

solid and used directly without further purification

S11

(Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide) of 11-Bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L3)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 115 g 20 mmol) followed by co-evaporation with dry toluene three times Then

25 ml dried and degassed THF was added into the flask To this solution under -78 oC

(S)-binol-PCl (20 eq 140 g 40 mmol) and triethylamine (30 eq 084 mL 60 mmol)

in THF (20 mL) was added dropwise After stirring under -78 oC for 15 min the reaction

mixture was slowly warmed up to room temperature and stirred for overnight The

reaction mixture was evaporated and to the solid residue THF (40 ml) was added The

suspension was filtered through a plug of celite which was subsequently washed with

THF (40 ml) The combined organic fractions were concentrated hexane (30 ml) was

added followed by evaporation of all volatiles to dryness yielding 258g (95) of

L3middotTHFmiddotC6H14 NOTE Ligand L3 is sensitive to moisture and thus should be stored in

inert conditions at low temperatures preferably

1H NMR (400 MHz CD2Cl2) δ 950 (m 2H indole-NH) 821 (s 1H amide-NH) 816

(s 1H amide-NH) 807 ndash 781 (m 8H) 762 ndash 714 (m 26H) 699 (t J = 77 Hz 1H)

694 ndash 677 (m 3H) 449 (d J = 79 Hz 1H CHCH2CH3) 233 (s 3H aryl-Me) 232

(s 3H aryl-Me) 226 ndash 206 (m 2H CHCH2CH3) 100 (t J = 73 Hz 3H CHCH2CH3)

S12

31P NMR (162 MHz CD2Cl2) δ 14408 14397

13C NMR (100MHz CD2Cl2) δ = 16524 (m) 15229 (m) 14784 (d J = 46 Hz)

14722 (m) 13674 13638 (d J = 80 Hz) 13319 13287 13236 13224 13174 (m)

13111 13050 (m) 12885 (d J = 81 Hz) 12827 (d J = 30 Hz) 12721 12708 (d J

= 30 Hz) 12690 (d J = 65 Hz) 12573 (d J = 171 Hz) 12455 (m) 12405 (d J =

81 Hz) 12375 (d J = 85 Hz) 12346 (d J = 111 Hz) 12321 (m) 12217 12197

11992 (m) 11973 (d J = 75 Hz) 11930 (d J = 40 Hz) 11815 11641 11410 (d J

= 160 Hz) 10825 (d J = 44 Hz) 3686 2599 1261 889

HR MS (FD+(eiFi)+) calcd for C75H54N4O8P2 [M]+ 120034169 found 120033967

The effectors used in this study

Scheme S3 Effectors purchased from commercial source

S13

Scheme S4 Effectors prepared except 27 purchased from commercial sources

L-(tert-butylthiocarbamoyl)-N-valine (1S)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 200 mg 170 mmol) was dissolved in 025 M NaHCO3 solution

(80 mL) followed by adding the isothiocyanate (1 eq 022 mL 17 mmol) The mixture

was heated at 80 oC for 3 hours and the progress of the reaction was monitored by TLC

(petroleum etherethyl acetate 11) After completion the reaction mixture was cooling

down and acidified to pH 2 with 1M HCl (3x80 mL) The products were extracted with

ethyl acetate (3x100 mL) The combined organic layer was dried over MgSO4 The pure

product was obtained as white powder with 50 yield after crystallization Identical to

the literature4

S14

1H NMR (400 MHz DMSO-d6) δ 750 (s 1H thiourea-NH) 738 (d J = 86 Hz 1H

thiourea-NH) 484 (dd J = 86 46 Hz 1H Ha) 208 (m 1H Hb) 142 (s 9H tert-

butyl-Me) 088 (m 6H isopropyl-Me)

D-(tert-butylthiocarbamoyl)-N-valine (1S) was prepared following the same

procedures for 1R

1H NMR (400 MHz DMSO-d6) δ 1255 (s 1H COOH) 749 (s 1H thiourea-NH)

737 (d J = 86 Hz 1H thiourea-NH) 483 (dd J = 86 46 Hz 1H Ha) 209 ndash 205

(m 1H Hb) 141 (s 9H tert-butyl) 088 -086 (m 6H isopropyl-Me)

13C NMR (126 MHz DMSO-d6) δ 18182 17342 6030 5227 3057 2889 1887

1812

HRMS (FD+(eiFi)) calcd for C10H20N2O2S1 [M]+ 2321245 found 2321201

L-N-formyl-Valine (24)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (03 g 25 mmol) formic acid (952 g 113 mmol) and acetic acid

anhydride (1 g 98 mmol) were dissolved in acetic acid (10 mL) and the reaction was

stirred for 4 hours at room temperature Afterwards all the volatiles were removed under

vacuum and the crude product was purified by recrystallization to give while power

identical to literature4

S15

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 841 (s 1H formyl-H) 798

(d J = 8 Hz 1H amide-NH) 411 (dd J = 8 Hz J = 6 Hz 1H Ha) 202 (m 1H Hb)

087 (dd J = 1 Hz J = 7 Hz 6H isopropyl-Me)

L-N-trimethylacetyl-Valine (25)

The compound was prepared as follow based on reported procedure5 A round bottom flask

equipped with a magnetic stirring bar was charged with distilled water and NaHCO3

The resulting reaction mixtures was cooled to 0 oC in an ice bath L-Valine methyl ester

hydrochloride (300 mg 256 mmol) was added and the solution was stirred until

homogeneous The flask was equipped with an addition funnel The corresponding

trimethylacetyl chloride which was prepared from the corresponding pivalic acid in

14-dioxane (4 mL) was added dropwise The reaction mixture was then allowed to stir

at room temperature overnight Next the reaction was extracted with Et2O (2x20 mL)

to remove the impurities The aqueous layer was again cooled to 0 oC in an ice bath and

1M HCl was added until pH 3 The product was extracted with ethyl acetate (3x100 mL)

The organic layer was washed with brine (50 mL) dried over Na2SO4 filtered and

concentrated under vacuum to give the product as white powder Identical to the

literature5

1H NMR (400 MHz CDCl3) δ 970 (s 1H COOH) 624 (d J = 85 Hz 1H amide-

NH) 456 (dd J = 85 47 Hz 1H Ha) 223 (m 1H Hb) 122 (s 9H tert-butyl-Me)

106 ndash 093 (m 6H isopropyl-Me)

S16

L-(tert-butylcarbamoyl)-N-valine methyl ester (26a)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (10 g 762 mmol) was dissolved in dry DCM (100 mL) and the

isocyanate was added The mixture was stirred and the progress of the reaction was

monitored by TLC (petroleum etherethyl acetate 11) After completion the solvents

were removed under vacuum and the crude product was dissolved in DCM (80 mL)

washed with 1M HCl (3x80 mL) dried over MgSO4 The pure product was obtained as

white powder with 96 yield Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 604 (d J = 88 Hz 1H urea-NH) 594 (s 1H urea-

NH) 403 (dd J = 88 53 Hz 1H Ha) 362 (s 3H OMe) 209 ndash 183 (m 1H Hb)

120 (s 9H tert-butyl) 083 (m 6H isopropyl-Me)

L-(tert-butylcarbamoyl)-N-valine (26)

The compound was prepared as follow based on reported procedure4 To a solution of L-

(tert-butylcarbamoyl)-N-valine methyl ester (1 eq 074 g 322 mmol) in

methanolTHFwater (111 30 mL) mixture was added LiOHH2O (1 eq 135 mg 322

mmol) After overnight stirring at room temperature the resulting reaction mixtures was

partially concentrated under vacuum followed by the addition of water (20 mL) The

mixture was acidified with 1M HCl to pH 4 and then the product was extracted with

ethyl acetate (3x30 mL) The combined organic layer was washed with brine (30 mL)

dried over MgSO4 The pure product was obtained as white powder with 80 yield

Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 1241 (s 1H COOH) 591 (s 1H urea-NH) 587

(d J = 91 Hz 1H urea-NH) 399 (dd J = 89 48 Hz 1H Ha) 199 ndash 188 (m 1H

Hb) 120 (s 9H tert-butyl) 085 - 081 (m 6H isopropyl-Me)

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 7: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S7

The compound was prepared as follow based on reported procedure3 11-Bis-(-3-methyl-7-

nitro-1H-indol-2-yl)propane (10 g 25 mmol) was suspended in

methanoltetrahydrofuran (11 15 ml) and 10 palladium on charcoal was added (02

g) The reaction mixture was flushed with hydrogen and then vigorously stirred under

1 bar of hydrogen with a balloon The progress of the reaction was monitored by TLC

(DCMMethanol 101) and after completion (~2 hours) the catalyst was filtered off

over Celite The solvent was evaporated and the crude diamine was immediately used

in the subsequent reaction without further purification

To the solution of the crude diamine (25 mmol) and triethylamine (50 mmol) in

dichloromethane (10 ml) a solution of 3-(benzyloxy)benzoyl chloride (16 g 65 mmol)

in dichloromethane (10 ml) was slowly added while stirring and the mixture was

allowed to continue stirring overnight After completion (TLC pentane ethyl acetate

21) the solvent was evaporated and the crude mixture was purified by chromatography

with pentaneethyl acetate (31) to dichloromethanemethanol (201) as the eluent The

product was then dissolved in a minimum amount of chloromethanemethanol and

followed by the addition of hexane to precipitate the compounds which was filtrated

through filter and washed with hexane to obtain pure compound L2a Identical to the

literature3

1H NMR (400 MHz CDCl3) δ 951 (s 2H indole-NH) 815 (s 2H amide-NH) 740

ndash 731 (m 16H) 724 ndash 714 (m 1H) 703 (t J = 68 Hz 5H) 694 (d J = 74 Hz 2H)

503 ndash 489 (m 4H Bn-CH2) 450 ndash 442 (m 1H CHCH2CH3) 231 (s 6H aryl-CH3)

223 ndash 214 (m 2H CHCH2CH3) 099 (t J = 76 Hz 3H CHCH2CH3)

S8

1-Bis-(3-(hydroxyl)benzoamide of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-

propane (L2b)

The compound was prepared as follow based on reported procedure3 Bis-(3-

(benzyloxy)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane (L2a)

(123 g 16 mmol) was suspended in methanol (30 ml) and 10 palladium on charcoal

was added (03 g) The reaction mixture was flushed with hydrogen and then vigorously

stirred under 1 bar hydrogen with a balloon The progress of the reaction was monitored

by TLC (DCMMethanol 101) and after overnight reaction the catalyst was filtered

off over Celite The solvent was evaporated and the pure product was obtained by

crystallization with dichloromethane and hexane Identical to the literature3

1H NMR (500 MHz Methanol-d4) δ 743 ndash 732 (m 6H) 730 ndash 721 (m 4H) 700 (q

J = 80 Hz 4H) 453 (t J = 80 Hz 1H CHCH2CH3) 235 ndash 217 (m 8H aryl-CH3 amp

CHCH2CH3) 099 (t J = 73 Hz 3H CHCH2CH3)

48-Di-tert-butyl-6-chloro-210-dimethoxydibenzo[df][132]dioxaphosphepine

(Diphenyl-PCl)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with 33-di-tert-

butyl-55-dimethoxy-[11-biphenyl]-22-diol (1 eq 1878 mg 052 mmol) followed

by co-evaporation with dry toluene three times Then 5 ml dried and degassed THF was

added into the flask To this solution under -78 oC PCl3 (15 eq 691 uL 078 mmol)

and triethylamine (30 eq 221 uL 156 mmol) was added dropwise After stirring under

-78 oC for 15 min the reaction mixture was slowly warmed up to room temperature and

stirred for another 45 min After completion (monitored by 31P NMR) the volatiles were

evaporated under vacuum and further co-evaporated with dry toluene three times The

product was formed quantitatively and used directly

S9

(Bis-3-((48-Di-tert-butyl-210-dimethoxydibenzo[df][132]dioxaphosphepin-6-

yl)oxyl)benzoamide of 11-bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L2)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 1500 mg 026 mmol) followed by co-evaporation with dry toluene three times

Then 5 ml dried and degassed THF was added into the flask To this solution under -78

oC Diphenyl-PCl (20 eq 052 mmol) and triethylamine (30 eq 221 uL 156 mmol)

in THF was added dropwise After stirring under -78 oC for 15 min the reaction mixture

was slowly warmed up to room temperature and stirred for another 45 min After

completion (monitored by 31P NMR) the volatiles were evaporated under vacuum and

further co-evaporated with dry toluene three times The reaction mixture was evaporated

and to the solid residue THF (5 ml) was added The suspension was filtered through a

plug of celite which was subsequently washed with THF (10 ml) The combined organic

fractions were concentrated hexane (10 ml) was added followed by evaporation of all

volatiles to dryness The product was formed quantitatively without further purification

1H NMR (500 MHz CD2Cl2) δ 982 (s 2H indole-NH) 834 (s 2H amide-NH) 760

ndash 750 (m 2H) 735 (dd J = 65 23 Hz 2H) 725 ndash 722 (m 3H) 719 ndash 715 (m 3H)

707 ndash 695 (m 8H) 675 ndash 673 (m 4H) 449 (t J = 80 Hz 1H CHCH2CH3) 379 ndash

378 (m 12H) 232 (s 6H indole-Me) 223 (p J = 76 Hz 2H CHCH2CH3) 187 ndash

S10

177 (m 2H) 147 (d J = 20 Hz 6H OMe) 144 (s 18H) 142 (s 18H) 100 (t J =

76 Hz 3H CHCH2CH3)

31P NMR (202 MHz CD2Cl2) δ 13934

13C NMR (101 MHz CD2Cl2) δ 16523 15650 15264 (d J = 62 Hz) 14306 (m)

14145 (d J = 59 Hz) 13838 13658 (d J = 342 Hz) 13402 (m) 13215 13038

12937 12843 (d J = 271 Hz) 12564 12388 (d J = 79 Hz) 12338 12239 11976

(d J = 76 Hz) 11920 11614 11529 11485 11414 11336 10800 5599 4618

3574 3124 (m) 3085 2599 1265 890

HR MS (FD+(eiFi)+) calcd for C79H86N4O12P2 [M]+ 13445717 found 13445774

(S)-11rsquo-Binaphthyl-22-diyl phosphorochloridate (S)-binol-PCl

A flamed dried Schlenk flask with a Teflon stirring bar was charged with (S)-binol (1

eq 187 g 52 mmol) followed by co-evaporation with dry toluene three times Dried

and degassed THF (20 ml) was then added into the flask To this solution under -78 oC

PCl3 (15 eq 691 uL 78 mmol) and triethylamine (30 eq 221 mL 156 mmol) was

added dropwise After stirring under -78 oC for 30 min the reaction mixture was slowly

warmed up to room temperature and stirred for another 60 min After completion

(monitored by 31P NMR) the volatiles were evaporated under vacuum and further co-

evaporated with dry toluene three times The product was formed quantitatively as white

solid and used directly without further purification

S11

(Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide) of 11-Bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L3)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 115 g 20 mmol) followed by co-evaporation with dry toluene three times Then

25 ml dried and degassed THF was added into the flask To this solution under -78 oC

(S)-binol-PCl (20 eq 140 g 40 mmol) and triethylamine (30 eq 084 mL 60 mmol)

in THF (20 mL) was added dropwise After stirring under -78 oC for 15 min the reaction

mixture was slowly warmed up to room temperature and stirred for overnight The

reaction mixture was evaporated and to the solid residue THF (40 ml) was added The

suspension was filtered through a plug of celite which was subsequently washed with

THF (40 ml) The combined organic fractions were concentrated hexane (30 ml) was

added followed by evaporation of all volatiles to dryness yielding 258g (95) of

L3middotTHFmiddotC6H14 NOTE Ligand L3 is sensitive to moisture and thus should be stored in

inert conditions at low temperatures preferably

1H NMR (400 MHz CD2Cl2) δ 950 (m 2H indole-NH) 821 (s 1H amide-NH) 816

(s 1H amide-NH) 807 ndash 781 (m 8H) 762 ndash 714 (m 26H) 699 (t J = 77 Hz 1H)

694 ndash 677 (m 3H) 449 (d J = 79 Hz 1H CHCH2CH3) 233 (s 3H aryl-Me) 232

(s 3H aryl-Me) 226 ndash 206 (m 2H CHCH2CH3) 100 (t J = 73 Hz 3H CHCH2CH3)

S12

31P NMR (162 MHz CD2Cl2) δ 14408 14397

13C NMR (100MHz CD2Cl2) δ = 16524 (m) 15229 (m) 14784 (d J = 46 Hz)

14722 (m) 13674 13638 (d J = 80 Hz) 13319 13287 13236 13224 13174 (m)

13111 13050 (m) 12885 (d J = 81 Hz) 12827 (d J = 30 Hz) 12721 12708 (d J

= 30 Hz) 12690 (d J = 65 Hz) 12573 (d J = 171 Hz) 12455 (m) 12405 (d J =

81 Hz) 12375 (d J = 85 Hz) 12346 (d J = 111 Hz) 12321 (m) 12217 12197

11992 (m) 11973 (d J = 75 Hz) 11930 (d J = 40 Hz) 11815 11641 11410 (d J

= 160 Hz) 10825 (d J = 44 Hz) 3686 2599 1261 889

HR MS (FD+(eiFi)+) calcd for C75H54N4O8P2 [M]+ 120034169 found 120033967

The effectors used in this study

Scheme S3 Effectors purchased from commercial source

S13

Scheme S4 Effectors prepared except 27 purchased from commercial sources

L-(tert-butylthiocarbamoyl)-N-valine (1S)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 200 mg 170 mmol) was dissolved in 025 M NaHCO3 solution

(80 mL) followed by adding the isothiocyanate (1 eq 022 mL 17 mmol) The mixture

was heated at 80 oC for 3 hours and the progress of the reaction was monitored by TLC

(petroleum etherethyl acetate 11) After completion the reaction mixture was cooling

down and acidified to pH 2 with 1M HCl (3x80 mL) The products were extracted with

ethyl acetate (3x100 mL) The combined organic layer was dried over MgSO4 The pure

product was obtained as white powder with 50 yield after crystallization Identical to

the literature4

S14

1H NMR (400 MHz DMSO-d6) δ 750 (s 1H thiourea-NH) 738 (d J = 86 Hz 1H

thiourea-NH) 484 (dd J = 86 46 Hz 1H Ha) 208 (m 1H Hb) 142 (s 9H tert-

butyl-Me) 088 (m 6H isopropyl-Me)

D-(tert-butylthiocarbamoyl)-N-valine (1S) was prepared following the same

procedures for 1R

1H NMR (400 MHz DMSO-d6) δ 1255 (s 1H COOH) 749 (s 1H thiourea-NH)

737 (d J = 86 Hz 1H thiourea-NH) 483 (dd J = 86 46 Hz 1H Ha) 209 ndash 205

(m 1H Hb) 141 (s 9H tert-butyl) 088 -086 (m 6H isopropyl-Me)

13C NMR (126 MHz DMSO-d6) δ 18182 17342 6030 5227 3057 2889 1887

1812

HRMS (FD+(eiFi)) calcd for C10H20N2O2S1 [M]+ 2321245 found 2321201

L-N-formyl-Valine (24)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (03 g 25 mmol) formic acid (952 g 113 mmol) and acetic acid

anhydride (1 g 98 mmol) were dissolved in acetic acid (10 mL) and the reaction was

stirred for 4 hours at room temperature Afterwards all the volatiles were removed under

vacuum and the crude product was purified by recrystallization to give while power

identical to literature4

S15

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 841 (s 1H formyl-H) 798

(d J = 8 Hz 1H amide-NH) 411 (dd J = 8 Hz J = 6 Hz 1H Ha) 202 (m 1H Hb)

087 (dd J = 1 Hz J = 7 Hz 6H isopropyl-Me)

L-N-trimethylacetyl-Valine (25)

The compound was prepared as follow based on reported procedure5 A round bottom flask

equipped with a magnetic stirring bar was charged with distilled water and NaHCO3

The resulting reaction mixtures was cooled to 0 oC in an ice bath L-Valine methyl ester

hydrochloride (300 mg 256 mmol) was added and the solution was stirred until

homogeneous The flask was equipped with an addition funnel The corresponding

trimethylacetyl chloride which was prepared from the corresponding pivalic acid in

14-dioxane (4 mL) was added dropwise The reaction mixture was then allowed to stir

at room temperature overnight Next the reaction was extracted with Et2O (2x20 mL)

to remove the impurities The aqueous layer was again cooled to 0 oC in an ice bath and

1M HCl was added until pH 3 The product was extracted with ethyl acetate (3x100 mL)

The organic layer was washed with brine (50 mL) dried over Na2SO4 filtered and

concentrated under vacuum to give the product as white powder Identical to the

literature5

1H NMR (400 MHz CDCl3) δ 970 (s 1H COOH) 624 (d J = 85 Hz 1H amide-

NH) 456 (dd J = 85 47 Hz 1H Ha) 223 (m 1H Hb) 122 (s 9H tert-butyl-Me)

106 ndash 093 (m 6H isopropyl-Me)

S16

L-(tert-butylcarbamoyl)-N-valine methyl ester (26a)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (10 g 762 mmol) was dissolved in dry DCM (100 mL) and the

isocyanate was added The mixture was stirred and the progress of the reaction was

monitored by TLC (petroleum etherethyl acetate 11) After completion the solvents

were removed under vacuum and the crude product was dissolved in DCM (80 mL)

washed with 1M HCl (3x80 mL) dried over MgSO4 The pure product was obtained as

white powder with 96 yield Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 604 (d J = 88 Hz 1H urea-NH) 594 (s 1H urea-

NH) 403 (dd J = 88 53 Hz 1H Ha) 362 (s 3H OMe) 209 ndash 183 (m 1H Hb)

120 (s 9H tert-butyl) 083 (m 6H isopropyl-Me)

L-(tert-butylcarbamoyl)-N-valine (26)

The compound was prepared as follow based on reported procedure4 To a solution of L-

(tert-butylcarbamoyl)-N-valine methyl ester (1 eq 074 g 322 mmol) in

methanolTHFwater (111 30 mL) mixture was added LiOHH2O (1 eq 135 mg 322

mmol) After overnight stirring at room temperature the resulting reaction mixtures was

partially concentrated under vacuum followed by the addition of water (20 mL) The

mixture was acidified with 1M HCl to pH 4 and then the product was extracted with

ethyl acetate (3x30 mL) The combined organic layer was washed with brine (30 mL)

dried over MgSO4 The pure product was obtained as white powder with 80 yield

Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 1241 (s 1H COOH) 591 (s 1H urea-NH) 587

(d J = 91 Hz 1H urea-NH) 399 (dd J = 89 48 Hz 1H Ha) 199 ndash 188 (m 1H

Hb) 120 (s 9H tert-butyl) 085 - 081 (m 6H isopropyl-Me)

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 8: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S8

1-Bis-(3-(hydroxyl)benzoamide of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-

propane (L2b)

The compound was prepared as follow based on reported procedure3 Bis-(3-

(benzyloxy)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane (L2a)

(123 g 16 mmol) was suspended in methanol (30 ml) and 10 palladium on charcoal

was added (03 g) The reaction mixture was flushed with hydrogen and then vigorously

stirred under 1 bar hydrogen with a balloon The progress of the reaction was monitored

by TLC (DCMMethanol 101) and after overnight reaction the catalyst was filtered

off over Celite The solvent was evaporated and the pure product was obtained by

crystallization with dichloromethane and hexane Identical to the literature3

1H NMR (500 MHz Methanol-d4) δ 743 ndash 732 (m 6H) 730 ndash 721 (m 4H) 700 (q

J = 80 Hz 4H) 453 (t J = 80 Hz 1H CHCH2CH3) 235 ndash 217 (m 8H aryl-CH3 amp

CHCH2CH3) 099 (t J = 73 Hz 3H CHCH2CH3)

48-Di-tert-butyl-6-chloro-210-dimethoxydibenzo[df][132]dioxaphosphepine

(Diphenyl-PCl)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with 33-di-tert-

butyl-55-dimethoxy-[11-biphenyl]-22-diol (1 eq 1878 mg 052 mmol) followed

by co-evaporation with dry toluene three times Then 5 ml dried and degassed THF was

added into the flask To this solution under -78 oC PCl3 (15 eq 691 uL 078 mmol)

and triethylamine (30 eq 221 uL 156 mmol) was added dropwise After stirring under

-78 oC for 15 min the reaction mixture was slowly warmed up to room temperature and

stirred for another 45 min After completion (monitored by 31P NMR) the volatiles were

evaporated under vacuum and further co-evaporated with dry toluene three times The

product was formed quantitatively and used directly

S9

(Bis-3-((48-Di-tert-butyl-210-dimethoxydibenzo[df][132]dioxaphosphepin-6-

yl)oxyl)benzoamide of 11-bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L2)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 1500 mg 026 mmol) followed by co-evaporation with dry toluene three times

Then 5 ml dried and degassed THF was added into the flask To this solution under -78

oC Diphenyl-PCl (20 eq 052 mmol) and triethylamine (30 eq 221 uL 156 mmol)

in THF was added dropwise After stirring under -78 oC for 15 min the reaction mixture

was slowly warmed up to room temperature and stirred for another 45 min After

completion (monitored by 31P NMR) the volatiles were evaporated under vacuum and

further co-evaporated with dry toluene three times The reaction mixture was evaporated

and to the solid residue THF (5 ml) was added The suspension was filtered through a

plug of celite which was subsequently washed with THF (10 ml) The combined organic

fractions were concentrated hexane (10 ml) was added followed by evaporation of all

volatiles to dryness The product was formed quantitatively without further purification

1H NMR (500 MHz CD2Cl2) δ 982 (s 2H indole-NH) 834 (s 2H amide-NH) 760

ndash 750 (m 2H) 735 (dd J = 65 23 Hz 2H) 725 ndash 722 (m 3H) 719 ndash 715 (m 3H)

707 ndash 695 (m 8H) 675 ndash 673 (m 4H) 449 (t J = 80 Hz 1H CHCH2CH3) 379 ndash

378 (m 12H) 232 (s 6H indole-Me) 223 (p J = 76 Hz 2H CHCH2CH3) 187 ndash

S10

177 (m 2H) 147 (d J = 20 Hz 6H OMe) 144 (s 18H) 142 (s 18H) 100 (t J =

76 Hz 3H CHCH2CH3)

31P NMR (202 MHz CD2Cl2) δ 13934

13C NMR (101 MHz CD2Cl2) δ 16523 15650 15264 (d J = 62 Hz) 14306 (m)

14145 (d J = 59 Hz) 13838 13658 (d J = 342 Hz) 13402 (m) 13215 13038

12937 12843 (d J = 271 Hz) 12564 12388 (d J = 79 Hz) 12338 12239 11976

(d J = 76 Hz) 11920 11614 11529 11485 11414 11336 10800 5599 4618

3574 3124 (m) 3085 2599 1265 890

HR MS (FD+(eiFi)+) calcd for C79H86N4O12P2 [M]+ 13445717 found 13445774

(S)-11rsquo-Binaphthyl-22-diyl phosphorochloridate (S)-binol-PCl

A flamed dried Schlenk flask with a Teflon stirring bar was charged with (S)-binol (1

eq 187 g 52 mmol) followed by co-evaporation with dry toluene three times Dried

and degassed THF (20 ml) was then added into the flask To this solution under -78 oC

PCl3 (15 eq 691 uL 78 mmol) and triethylamine (30 eq 221 mL 156 mmol) was

added dropwise After stirring under -78 oC for 30 min the reaction mixture was slowly

warmed up to room temperature and stirred for another 60 min After completion

(monitored by 31P NMR) the volatiles were evaporated under vacuum and further co-

evaporated with dry toluene three times The product was formed quantitatively as white

solid and used directly without further purification

S11

(Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide) of 11-Bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L3)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 115 g 20 mmol) followed by co-evaporation with dry toluene three times Then

25 ml dried and degassed THF was added into the flask To this solution under -78 oC

(S)-binol-PCl (20 eq 140 g 40 mmol) and triethylamine (30 eq 084 mL 60 mmol)

in THF (20 mL) was added dropwise After stirring under -78 oC for 15 min the reaction

mixture was slowly warmed up to room temperature and stirred for overnight The

reaction mixture was evaporated and to the solid residue THF (40 ml) was added The

suspension was filtered through a plug of celite which was subsequently washed with

THF (40 ml) The combined organic fractions were concentrated hexane (30 ml) was

added followed by evaporation of all volatiles to dryness yielding 258g (95) of

L3middotTHFmiddotC6H14 NOTE Ligand L3 is sensitive to moisture and thus should be stored in

inert conditions at low temperatures preferably

1H NMR (400 MHz CD2Cl2) δ 950 (m 2H indole-NH) 821 (s 1H amide-NH) 816

(s 1H amide-NH) 807 ndash 781 (m 8H) 762 ndash 714 (m 26H) 699 (t J = 77 Hz 1H)

694 ndash 677 (m 3H) 449 (d J = 79 Hz 1H CHCH2CH3) 233 (s 3H aryl-Me) 232

(s 3H aryl-Me) 226 ndash 206 (m 2H CHCH2CH3) 100 (t J = 73 Hz 3H CHCH2CH3)

S12

31P NMR (162 MHz CD2Cl2) δ 14408 14397

13C NMR (100MHz CD2Cl2) δ = 16524 (m) 15229 (m) 14784 (d J = 46 Hz)

14722 (m) 13674 13638 (d J = 80 Hz) 13319 13287 13236 13224 13174 (m)

13111 13050 (m) 12885 (d J = 81 Hz) 12827 (d J = 30 Hz) 12721 12708 (d J

= 30 Hz) 12690 (d J = 65 Hz) 12573 (d J = 171 Hz) 12455 (m) 12405 (d J =

81 Hz) 12375 (d J = 85 Hz) 12346 (d J = 111 Hz) 12321 (m) 12217 12197

11992 (m) 11973 (d J = 75 Hz) 11930 (d J = 40 Hz) 11815 11641 11410 (d J

= 160 Hz) 10825 (d J = 44 Hz) 3686 2599 1261 889

HR MS (FD+(eiFi)+) calcd for C75H54N4O8P2 [M]+ 120034169 found 120033967

The effectors used in this study

Scheme S3 Effectors purchased from commercial source

S13

Scheme S4 Effectors prepared except 27 purchased from commercial sources

L-(tert-butylthiocarbamoyl)-N-valine (1S)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 200 mg 170 mmol) was dissolved in 025 M NaHCO3 solution

(80 mL) followed by adding the isothiocyanate (1 eq 022 mL 17 mmol) The mixture

was heated at 80 oC for 3 hours and the progress of the reaction was monitored by TLC

(petroleum etherethyl acetate 11) After completion the reaction mixture was cooling

down and acidified to pH 2 with 1M HCl (3x80 mL) The products were extracted with

ethyl acetate (3x100 mL) The combined organic layer was dried over MgSO4 The pure

product was obtained as white powder with 50 yield after crystallization Identical to

the literature4

S14

1H NMR (400 MHz DMSO-d6) δ 750 (s 1H thiourea-NH) 738 (d J = 86 Hz 1H

thiourea-NH) 484 (dd J = 86 46 Hz 1H Ha) 208 (m 1H Hb) 142 (s 9H tert-

butyl-Me) 088 (m 6H isopropyl-Me)

D-(tert-butylthiocarbamoyl)-N-valine (1S) was prepared following the same

procedures for 1R

1H NMR (400 MHz DMSO-d6) δ 1255 (s 1H COOH) 749 (s 1H thiourea-NH)

737 (d J = 86 Hz 1H thiourea-NH) 483 (dd J = 86 46 Hz 1H Ha) 209 ndash 205

(m 1H Hb) 141 (s 9H tert-butyl) 088 -086 (m 6H isopropyl-Me)

13C NMR (126 MHz DMSO-d6) δ 18182 17342 6030 5227 3057 2889 1887

1812

HRMS (FD+(eiFi)) calcd for C10H20N2O2S1 [M]+ 2321245 found 2321201

L-N-formyl-Valine (24)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (03 g 25 mmol) formic acid (952 g 113 mmol) and acetic acid

anhydride (1 g 98 mmol) were dissolved in acetic acid (10 mL) and the reaction was

stirred for 4 hours at room temperature Afterwards all the volatiles were removed under

vacuum and the crude product was purified by recrystallization to give while power

identical to literature4

S15

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 841 (s 1H formyl-H) 798

(d J = 8 Hz 1H amide-NH) 411 (dd J = 8 Hz J = 6 Hz 1H Ha) 202 (m 1H Hb)

087 (dd J = 1 Hz J = 7 Hz 6H isopropyl-Me)

L-N-trimethylacetyl-Valine (25)

The compound was prepared as follow based on reported procedure5 A round bottom flask

equipped with a magnetic stirring bar was charged with distilled water and NaHCO3

The resulting reaction mixtures was cooled to 0 oC in an ice bath L-Valine methyl ester

hydrochloride (300 mg 256 mmol) was added and the solution was stirred until

homogeneous The flask was equipped with an addition funnel The corresponding

trimethylacetyl chloride which was prepared from the corresponding pivalic acid in

14-dioxane (4 mL) was added dropwise The reaction mixture was then allowed to stir

at room temperature overnight Next the reaction was extracted with Et2O (2x20 mL)

to remove the impurities The aqueous layer was again cooled to 0 oC in an ice bath and

1M HCl was added until pH 3 The product was extracted with ethyl acetate (3x100 mL)

The organic layer was washed with brine (50 mL) dried over Na2SO4 filtered and

concentrated under vacuum to give the product as white powder Identical to the

literature5

1H NMR (400 MHz CDCl3) δ 970 (s 1H COOH) 624 (d J = 85 Hz 1H amide-

NH) 456 (dd J = 85 47 Hz 1H Ha) 223 (m 1H Hb) 122 (s 9H tert-butyl-Me)

106 ndash 093 (m 6H isopropyl-Me)

S16

L-(tert-butylcarbamoyl)-N-valine methyl ester (26a)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (10 g 762 mmol) was dissolved in dry DCM (100 mL) and the

isocyanate was added The mixture was stirred and the progress of the reaction was

monitored by TLC (petroleum etherethyl acetate 11) After completion the solvents

were removed under vacuum and the crude product was dissolved in DCM (80 mL)

washed with 1M HCl (3x80 mL) dried over MgSO4 The pure product was obtained as

white powder with 96 yield Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 604 (d J = 88 Hz 1H urea-NH) 594 (s 1H urea-

NH) 403 (dd J = 88 53 Hz 1H Ha) 362 (s 3H OMe) 209 ndash 183 (m 1H Hb)

120 (s 9H tert-butyl) 083 (m 6H isopropyl-Me)

L-(tert-butylcarbamoyl)-N-valine (26)

The compound was prepared as follow based on reported procedure4 To a solution of L-

(tert-butylcarbamoyl)-N-valine methyl ester (1 eq 074 g 322 mmol) in

methanolTHFwater (111 30 mL) mixture was added LiOHH2O (1 eq 135 mg 322

mmol) After overnight stirring at room temperature the resulting reaction mixtures was

partially concentrated under vacuum followed by the addition of water (20 mL) The

mixture was acidified with 1M HCl to pH 4 and then the product was extracted with

ethyl acetate (3x30 mL) The combined organic layer was washed with brine (30 mL)

dried over MgSO4 The pure product was obtained as white powder with 80 yield

Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 1241 (s 1H COOH) 591 (s 1H urea-NH) 587

(d J = 91 Hz 1H urea-NH) 399 (dd J = 89 48 Hz 1H Ha) 199 ndash 188 (m 1H

Hb) 120 (s 9H tert-butyl) 085 - 081 (m 6H isopropyl-Me)

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 9: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S9

(Bis-3-((48-Di-tert-butyl-210-dimethoxydibenzo[df][132]dioxaphosphepin-6-

yl)oxyl)benzoamide of 11-bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L2)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 1500 mg 026 mmol) followed by co-evaporation with dry toluene three times

Then 5 ml dried and degassed THF was added into the flask To this solution under -78

oC Diphenyl-PCl (20 eq 052 mmol) and triethylamine (30 eq 221 uL 156 mmol)

in THF was added dropwise After stirring under -78 oC for 15 min the reaction mixture

was slowly warmed up to room temperature and stirred for another 45 min After

completion (monitored by 31P NMR) the volatiles were evaporated under vacuum and

further co-evaporated with dry toluene three times The reaction mixture was evaporated

and to the solid residue THF (5 ml) was added The suspension was filtered through a

plug of celite which was subsequently washed with THF (10 ml) The combined organic

fractions were concentrated hexane (10 ml) was added followed by evaporation of all

volatiles to dryness The product was formed quantitatively without further purification

1H NMR (500 MHz CD2Cl2) δ 982 (s 2H indole-NH) 834 (s 2H amide-NH) 760

ndash 750 (m 2H) 735 (dd J = 65 23 Hz 2H) 725 ndash 722 (m 3H) 719 ndash 715 (m 3H)

707 ndash 695 (m 8H) 675 ndash 673 (m 4H) 449 (t J = 80 Hz 1H CHCH2CH3) 379 ndash

378 (m 12H) 232 (s 6H indole-Me) 223 (p J = 76 Hz 2H CHCH2CH3) 187 ndash

S10

177 (m 2H) 147 (d J = 20 Hz 6H OMe) 144 (s 18H) 142 (s 18H) 100 (t J =

76 Hz 3H CHCH2CH3)

31P NMR (202 MHz CD2Cl2) δ 13934

13C NMR (101 MHz CD2Cl2) δ 16523 15650 15264 (d J = 62 Hz) 14306 (m)

14145 (d J = 59 Hz) 13838 13658 (d J = 342 Hz) 13402 (m) 13215 13038

12937 12843 (d J = 271 Hz) 12564 12388 (d J = 79 Hz) 12338 12239 11976

(d J = 76 Hz) 11920 11614 11529 11485 11414 11336 10800 5599 4618

3574 3124 (m) 3085 2599 1265 890

HR MS (FD+(eiFi)+) calcd for C79H86N4O12P2 [M]+ 13445717 found 13445774

(S)-11rsquo-Binaphthyl-22-diyl phosphorochloridate (S)-binol-PCl

A flamed dried Schlenk flask with a Teflon stirring bar was charged with (S)-binol (1

eq 187 g 52 mmol) followed by co-evaporation with dry toluene three times Dried

and degassed THF (20 ml) was then added into the flask To this solution under -78 oC

PCl3 (15 eq 691 uL 78 mmol) and triethylamine (30 eq 221 mL 156 mmol) was

added dropwise After stirring under -78 oC for 30 min the reaction mixture was slowly

warmed up to room temperature and stirred for another 60 min After completion

(monitored by 31P NMR) the volatiles were evaporated under vacuum and further co-

evaporated with dry toluene three times The product was formed quantitatively as white

solid and used directly without further purification

S11

(Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide) of 11-Bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L3)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 115 g 20 mmol) followed by co-evaporation with dry toluene three times Then

25 ml dried and degassed THF was added into the flask To this solution under -78 oC

(S)-binol-PCl (20 eq 140 g 40 mmol) and triethylamine (30 eq 084 mL 60 mmol)

in THF (20 mL) was added dropwise After stirring under -78 oC for 15 min the reaction

mixture was slowly warmed up to room temperature and stirred for overnight The

reaction mixture was evaporated and to the solid residue THF (40 ml) was added The

suspension was filtered through a plug of celite which was subsequently washed with

THF (40 ml) The combined organic fractions were concentrated hexane (30 ml) was

added followed by evaporation of all volatiles to dryness yielding 258g (95) of

L3middotTHFmiddotC6H14 NOTE Ligand L3 is sensitive to moisture and thus should be stored in

inert conditions at low temperatures preferably

1H NMR (400 MHz CD2Cl2) δ 950 (m 2H indole-NH) 821 (s 1H amide-NH) 816

(s 1H amide-NH) 807 ndash 781 (m 8H) 762 ndash 714 (m 26H) 699 (t J = 77 Hz 1H)

694 ndash 677 (m 3H) 449 (d J = 79 Hz 1H CHCH2CH3) 233 (s 3H aryl-Me) 232

(s 3H aryl-Me) 226 ndash 206 (m 2H CHCH2CH3) 100 (t J = 73 Hz 3H CHCH2CH3)

S12

31P NMR (162 MHz CD2Cl2) δ 14408 14397

13C NMR (100MHz CD2Cl2) δ = 16524 (m) 15229 (m) 14784 (d J = 46 Hz)

14722 (m) 13674 13638 (d J = 80 Hz) 13319 13287 13236 13224 13174 (m)

13111 13050 (m) 12885 (d J = 81 Hz) 12827 (d J = 30 Hz) 12721 12708 (d J

= 30 Hz) 12690 (d J = 65 Hz) 12573 (d J = 171 Hz) 12455 (m) 12405 (d J =

81 Hz) 12375 (d J = 85 Hz) 12346 (d J = 111 Hz) 12321 (m) 12217 12197

11992 (m) 11973 (d J = 75 Hz) 11930 (d J = 40 Hz) 11815 11641 11410 (d J

= 160 Hz) 10825 (d J = 44 Hz) 3686 2599 1261 889

HR MS (FD+(eiFi)+) calcd for C75H54N4O8P2 [M]+ 120034169 found 120033967

The effectors used in this study

Scheme S3 Effectors purchased from commercial source

S13

Scheme S4 Effectors prepared except 27 purchased from commercial sources

L-(tert-butylthiocarbamoyl)-N-valine (1S)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 200 mg 170 mmol) was dissolved in 025 M NaHCO3 solution

(80 mL) followed by adding the isothiocyanate (1 eq 022 mL 17 mmol) The mixture

was heated at 80 oC for 3 hours and the progress of the reaction was monitored by TLC

(petroleum etherethyl acetate 11) After completion the reaction mixture was cooling

down and acidified to pH 2 with 1M HCl (3x80 mL) The products were extracted with

ethyl acetate (3x100 mL) The combined organic layer was dried over MgSO4 The pure

product was obtained as white powder with 50 yield after crystallization Identical to

the literature4

S14

1H NMR (400 MHz DMSO-d6) δ 750 (s 1H thiourea-NH) 738 (d J = 86 Hz 1H

thiourea-NH) 484 (dd J = 86 46 Hz 1H Ha) 208 (m 1H Hb) 142 (s 9H tert-

butyl-Me) 088 (m 6H isopropyl-Me)

D-(tert-butylthiocarbamoyl)-N-valine (1S) was prepared following the same

procedures for 1R

1H NMR (400 MHz DMSO-d6) δ 1255 (s 1H COOH) 749 (s 1H thiourea-NH)

737 (d J = 86 Hz 1H thiourea-NH) 483 (dd J = 86 46 Hz 1H Ha) 209 ndash 205

(m 1H Hb) 141 (s 9H tert-butyl) 088 -086 (m 6H isopropyl-Me)

13C NMR (126 MHz DMSO-d6) δ 18182 17342 6030 5227 3057 2889 1887

1812

HRMS (FD+(eiFi)) calcd for C10H20N2O2S1 [M]+ 2321245 found 2321201

L-N-formyl-Valine (24)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (03 g 25 mmol) formic acid (952 g 113 mmol) and acetic acid

anhydride (1 g 98 mmol) were dissolved in acetic acid (10 mL) and the reaction was

stirred for 4 hours at room temperature Afterwards all the volatiles were removed under

vacuum and the crude product was purified by recrystallization to give while power

identical to literature4

S15

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 841 (s 1H formyl-H) 798

(d J = 8 Hz 1H amide-NH) 411 (dd J = 8 Hz J = 6 Hz 1H Ha) 202 (m 1H Hb)

087 (dd J = 1 Hz J = 7 Hz 6H isopropyl-Me)

L-N-trimethylacetyl-Valine (25)

The compound was prepared as follow based on reported procedure5 A round bottom flask

equipped with a magnetic stirring bar was charged with distilled water and NaHCO3

The resulting reaction mixtures was cooled to 0 oC in an ice bath L-Valine methyl ester

hydrochloride (300 mg 256 mmol) was added and the solution was stirred until

homogeneous The flask was equipped with an addition funnel The corresponding

trimethylacetyl chloride which was prepared from the corresponding pivalic acid in

14-dioxane (4 mL) was added dropwise The reaction mixture was then allowed to stir

at room temperature overnight Next the reaction was extracted with Et2O (2x20 mL)

to remove the impurities The aqueous layer was again cooled to 0 oC in an ice bath and

1M HCl was added until pH 3 The product was extracted with ethyl acetate (3x100 mL)

The organic layer was washed with brine (50 mL) dried over Na2SO4 filtered and

concentrated under vacuum to give the product as white powder Identical to the

literature5

1H NMR (400 MHz CDCl3) δ 970 (s 1H COOH) 624 (d J = 85 Hz 1H amide-

NH) 456 (dd J = 85 47 Hz 1H Ha) 223 (m 1H Hb) 122 (s 9H tert-butyl-Me)

106 ndash 093 (m 6H isopropyl-Me)

S16

L-(tert-butylcarbamoyl)-N-valine methyl ester (26a)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (10 g 762 mmol) was dissolved in dry DCM (100 mL) and the

isocyanate was added The mixture was stirred and the progress of the reaction was

monitored by TLC (petroleum etherethyl acetate 11) After completion the solvents

were removed under vacuum and the crude product was dissolved in DCM (80 mL)

washed with 1M HCl (3x80 mL) dried over MgSO4 The pure product was obtained as

white powder with 96 yield Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 604 (d J = 88 Hz 1H urea-NH) 594 (s 1H urea-

NH) 403 (dd J = 88 53 Hz 1H Ha) 362 (s 3H OMe) 209 ndash 183 (m 1H Hb)

120 (s 9H tert-butyl) 083 (m 6H isopropyl-Me)

L-(tert-butylcarbamoyl)-N-valine (26)

The compound was prepared as follow based on reported procedure4 To a solution of L-

(tert-butylcarbamoyl)-N-valine methyl ester (1 eq 074 g 322 mmol) in

methanolTHFwater (111 30 mL) mixture was added LiOHH2O (1 eq 135 mg 322

mmol) After overnight stirring at room temperature the resulting reaction mixtures was

partially concentrated under vacuum followed by the addition of water (20 mL) The

mixture was acidified with 1M HCl to pH 4 and then the product was extracted with

ethyl acetate (3x30 mL) The combined organic layer was washed with brine (30 mL)

dried over MgSO4 The pure product was obtained as white powder with 80 yield

Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 1241 (s 1H COOH) 591 (s 1H urea-NH) 587

(d J = 91 Hz 1H urea-NH) 399 (dd J = 89 48 Hz 1H Ha) 199 ndash 188 (m 1H

Hb) 120 (s 9H tert-butyl) 085 - 081 (m 6H isopropyl-Me)

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 10: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S10

177 (m 2H) 147 (d J = 20 Hz 6H OMe) 144 (s 18H) 142 (s 18H) 100 (t J =

76 Hz 3H CHCH2CH3)

31P NMR (202 MHz CD2Cl2) δ 13934

13C NMR (101 MHz CD2Cl2) δ 16523 15650 15264 (d J = 62 Hz) 14306 (m)

14145 (d J = 59 Hz) 13838 13658 (d J = 342 Hz) 13402 (m) 13215 13038

12937 12843 (d J = 271 Hz) 12564 12388 (d J = 79 Hz) 12338 12239 11976

(d J = 76 Hz) 11920 11614 11529 11485 11414 11336 10800 5599 4618

3574 3124 (m) 3085 2599 1265 890

HR MS (FD+(eiFi)+) calcd for C79H86N4O12P2 [M]+ 13445717 found 13445774

(S)-11rsquo-Binaphthyl-22-diyl phosphorochloridate (S)-binol-PCl

A flamed dried Schlenk flask with a Teflon stirring bar was charged with (S)-binol (1

eq 187 g 52 mmol) followed by co-evaporation with dry toluene three times Dried

and degassed THF (20 ml) was then added into the flask To this solution under -78 oC

PCl3 (15 eq 691 uL 78 mmol) and triethylamine (30 eq 221 mL 156 mmol) was

added dropwise After stirring under -78 oC for 30 min the reaction mixture was slowly

warmed up to room temperature and stirred for another 60 min After completion

(monitored by 31P NMR) the volatiles were evaporated under vacuum and further co-

evaporated with dry toluene three times The product was formed quantitatively as white

solid and used directly without further purification

S11

(Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide) of 11-Bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L3)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 115 g 20 mmol) followed by co-evaporation with dry toluene three times Then

25 ml dried and degassed THF was added into the flask To this solution under -78 oC

(S)-binol-PCl (20 eq 140 g 40 mmol) and triethylamine (30 eq 084 mL 60 mmol)

in THF (20 mL) was added dropwise After stirring under -78 oC for 15 min the reaction

mixture was slowly warmed up to room temperature and stirred for overnight The

reaction mixture was evaporated and to the solid residue THF (40 ml) was added The

suspension was filtered through a plug of celite which was subsequently washed with

THF (40 ml) The combined organic fractions were concentrated hexane (30 ml) was

added followed by evaporation of all volatiles to dryness yielding 258g (95) of

L3middotTHFmiddotC6H14 NOTE Ligand L3 is sensitive to moisture and thus should be stored in

inert conditions at low temperatures preferably

1H NMR (400 MHz CD2Cl2) δ 950 (m 2H indole-NH) 821 (s 1H amide-NH) 816

(s 1H amide-NH) 807 ndash 781 (m 8H) 762 ndash 714 (m 26H) 699 (t J = 77 Hz 1H)

694 ndash 677 (m 3H) 449 (d J = 79 Hz 1H CHCH2CH3) 233 (s 3H aryl-Me) 232

(s 3H aryl-Me) 226 ndash 206 (m 2H CHCH2CH3) 100 (t J = 73 Hz 3H CHCH2CH3)

S12

31P NMR (162 MHz CD2Cl2) δ 14408 14397

13C NMR (100MHz CD2Cl2) δ = 16524 (m) 15229 (m) 14784 (d J = 46 Hz)

14722 (m) 13674 13638 (d J = 80 Hz) 13319 13287 13236 13224 13174 (m)

13111 13050 (m) 12885 (d J = 81 Hz) 12827 (d J = 30 Hz) 12721 12708 (d J

= 30 Hz) 12690 (d J = 65 Hz) 12573 (d J = 171 Hz) 12455 (m) 12405 (d J =

81 Hz) 12375 (d J = 85 Hz) 12346 (d J = 111 Hz) 12321 (m) 12217 12197

11992 (m) 11973 (d J = 75 Hz) 11930 (d J = 40 Hz) 11815 11641 11410 (d J

= 160 Hz) 10825 (d J = 44 Hz) 3686 2599 1261 889

HR MS (FD+(eiFi)+) calcd for C75H54N4O8P2 [M]+ 120034169 found 120033967

The effectors used in this study

Scheme S3 Effectors purchased from commercial source

S13

Scheme S4 Effectors prepared except 27 purchased from commercial sources

L-(tert-butylthiocarbamoyl)-N-valine (1S)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 200 mg 170 mmol) was dissolved in 025 M NaHCO3 solution

(80 mL) followed by adding the isothiocyanate (1 eq 022 mL 17 mmol) The mixture

was heated at 80 oC for 3 hours and the progress of the reaction was monitored by TLC

(petroleum etherethyl acetate 11) After completion the reaction mixture was cooling

down and acidified to pH 2 with 1M HCl (3x80 mL) The products were extracted with

ethyl acetate (3x100 mL) The combined organic layer was dried over MgSO4 The pure

product was obtained as white powder with 50 yield after crystallization Identical to

the literature4

S14

1H NMR (400 MHz DMSO-d6) δ 750 (s 1H thiourea-NH) 738 (d J = 86 Hz 1H

thiourea-NH) 484 (dd J = 86 46 Hz 1H Ha) 208 (m 1H Hb) 142 (s 9H tert-

butyl-Me) 088 (m 6H isopropyl-Me)

D-(tert-butylthiocarbamoyl)-N-valine (1S) was prepared following the same

procedures for 1R

1H NMR (400 MHz DMSO-d6) δ 1255 (s 1H COOH) 749 (s 1H thiourea-NH)

737 (d J = 86 Hz 1H thiourea-NH) 483 (dd J = 86 46 Hz 1H Ha) 209 ndash 205

(m 1H Hb) 141 (s 9H tert-butyl) 088 -086 (m 6H isopropyl-Me)

13C NMR (126 MHz DMSO-d6) δ 18182 17342 6030 5227 3057 2889 1887

1812

HRMS (FD+(eiFi)) calcd for C10H20N2O2S1 [M]+ 2321245 found 2321201

L-N-formyl-Valine (24)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (03 g 25 mmol) formic acid (952 g 113 mmol) and acetic acid

anhydride (1 g 98 mmol) were dissolved in acetic acid (10 mL) and the reaction was

stirred for 4 hours at room temperature Afterwards all the volatiles were removed under

vacuum and the crude product was purified by recrystallization to give while power

identical to literature4

S15

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 841 (s 1H formyl-H) 798

(d J = 8 Hz 1H amide-NH) 411 (dd J = 8 Hz J = 6 Hz 1H Ha) 202 (m 1H Hb)

087 (dd J = 1 Hz J = 7 Hz 6H isopropyl-Me)

L-N-trimethylacetyl-Valine (25)

The compound was prepared as follow based on reported procedure5 A round bottom flask

equipped with a magnetic stirring bar was charged with distilled water and NaHCO3

The resulting reaction mixtures was cooled to 0 oC in an ice bath L-Valine methyl ester

hydrochloride (300 mg 256 mmol) was added and the solution was stirred until

homogeneous The flask was equipped with an addition funnel The corresponding

trimethylacetyl chloride which was prepared from the corresponding pivalic acid in

14-dioxane (4 mL) was added dropwise The reaction mixture was then allowed to stir

at room temperature overnight Next the reaction was extracted with Et2O (2x20 mL)

to remove the impurities The aqueous layer was again cooled to 0 oC in an ice bath and

1M HCl was added until pH 3 The product was extracted with ethyl acetate (3x100 mL)

The organic layer was washed with brine (50 mL) dried over Na2SO4 filtered and

concentrated under vacuum to give the product as white powder Identical to the

literature5

1H NMR (400 MHz CDCl3) δ 970 (s 1H COOH) 624 (d J = 85 Hz 1H amide-

NH) 456 (dd J = 85 47 Hz 1H Ha) 223 (m 1H Hb) 122 (s 9H tert-butyl-Me)

106 ndash 093 (m 6H isopropyl-Me)

S16

L-(tert-butylcarbamoyl)-N-valine methyl ester (26a)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (10 g 762 mmol) was dissolved in dry DCM (100 mL) and the

isocyanate was added The mixture was stirred and the progress of the reaction was

monitored by TLC (petroleum etherethyl acetate 11) After completion the solvents

were removed under vacuum and the crude product was dissolved in DCM (80 mL)

washed with 1M HCl (3x80 mL) dried over MgSO4 The pure product was obtained as

white powder with 96 yield Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 604 (d J = 88 Hz 1H urea-NH) 594 (s 1H urea-

NH) 403 (dd J = 88 53 Hz 1H Ha) 362 (s 3H OMe) 209 ndash 183 (m 1H Hb)

120 (s 9H tert-butyl) 083 (m 6H isopropyl-Me)

L-(tert-butylcarbamoyl)-N-valine (26)

The compound was prepared as follow based on reported procedure4 To a solution of L-

(tert-butylcarbamoyl)-N-valine methyl ester (1 eq 074 g 322 mmol) in

methanolTHFwater (111 30 mL) mixture was added LiOHH2O (1 eq 135 mg 322

mmol) After overnight stirring at room temperature the resulting reaction mixtures was

partially concentrated under vacuum followed by the addition of water (20 mL) The

mixture was acidified with 1M HCl to pH 4 and then the product was extracted with

ethyl acetate (3x30 mL) The combined organic layer was washed with brine (30 mL)

dried over MgSO4 The pure product was obtained as white powder with 80 yield

Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 1241 (s 1H COOH) 591 (s 1H urea-NH) 587

(d J = 91 Hz 1H urea-NH) 399 (dd J = 89 48 Hz 1H Ha) 199 ndash 188 (m 1H

Hb) 120 (s 9H tert-butyl) 085 - 081 (m 6H isopropyl-Me)

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 11: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S11

(Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide) of 11-Bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L3)

A flamed dried Schlenk flask with a Teflon stirring bar was charged with bis-(3-

(hydroxyl)benzoamide) of 11-bis-(-7-amino-3-methyl-1H-indol-2-yl)-propane L2b (1

eq 115 g 20 mmol) followed by co-evaporation with dry toluene three times Then

25 ml dried and degassed THF was added into the flask To this solution under -78 oC

(S)-binol-PCl (20 eq 140 g 40 mmol) and triethylamine (30 eq 084 mL 60 mmol)

in THF (20 mL) was added dropwise After stirring under -78 oC for 15 min the reaction

mixture was slowly warmed up to room temperature and stirred for overnight The

reaction mixture was evaporated and to the solid residue THF (40 ml) was added The

suspension was filtered through a plug of celite which was subsequently washed with

THF (40 ml) The combined organic fractions were concentrated hexane (30 ml) was

added followed by evaporation of all volatiles to dryness yielding 258g (95) of

L3middotTHFmiddotC6H14 NOTE Ligand L3 is sensitive to moisture and thus should be stored in

inert conditions at low temperatures preferably

1H NMR (400 MHz CD2Cl2) δ 950 (m 2H indole-NH) 821 (s 1H amide-NH) 816

(s 1H amide-NH) 807 ndash 781 (m 8H) 762 ndash 714 (m 26H) 699 (t J = 77 Hz 1H)

694 ndash 677 (m 3H) 449 (d J = 79 Hz 1H CHCH2CH3) 233 (s 3H aryl-Me) 232

(s 3H aryl-Me) 226 ndash 206 (m 2H CHCH2CH3) 100 (t J = 73 Hz 3H CHCH2CH3)

S12

31P NMR (162 MHz CD2Cl2) δ 14408 14397

13C NMR (100MHz CD2Cl2) δ = 16524 (m) 15229 (m) 14784 (d J = 46 Hz)

14722 (m) 13674 13638 (d J = 80 Hz) 13319 13287 13236 13224 13174 (m)

13111 13050 (m) 12885 (d J = 81 Hz) 12827 (d J = 30 Hz) 12721 12708 (d J

= 30 Hz) 12690 (d J = 65 Hz) 12573 (d J = 171 Hz) 12455 (m) 12405 (d J =

81 Hz) 12375 (d J = 85 Hz) 12346 (d J = 111 Hz) 12321 (m) 12217 12197

11992 (m) 11973 (d J = 75 Hz) 11930 (d J = 40 Hz) 11815 11641 11410 (d J

= 160 Hz) 10825 (d J = 44 Hz) 3686 2599 1261 889

HR MS (FD+(eiFi)+) calcd for C75H54N4O8P2 [M]+ 120034169 found 120033967

The effectors used in this study

Scheme S3 Effectors purchased from commercial source

S13

Scheme S4 Effectors prepared except 27 purchased from commercial sources

L-(tert-butylthiocarbamoyl)-N-valine (1S)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 200 mg 170 mmol) was dissolved in 025 M NaHCO3 solution

(80 mL) followed by adding the isothiocyanate (1 eq 022 mL 17 mmol) The mixture

was heated at 80 oC for 3 hours and the progress of the reaction was monitored by TLC

(petroleum etherethyl acetate 11) After completion the reaction mixture was cooling

down and acidified to pH 2 with 1M HCl (3x80 mL) The products were extracted with

ethyl acetate (3x100 mL) The combined organic layer was dried over MgSO4 The pure

product was obtained as white powder with 50 yield after crystallization Identical to

the literature4

S14

1H NMR (400 MHz DMSO-d6) δ 750 (s 1H thiourea-NH) 738 (d J = 86 Hz 1H

thiourea-NH) 484 (dd J = 86 46 Hz 1H Ha) 208 (m 1H Hb) 142 (s 9H tert-

butyl-Me) 088 (m 6H isopropyl-Me)

D-(tert-butylthiocarbamoyl)-N-valine (1S) was prepared following the same

procedures for 1R

1H NMR (400 MHz DMSO-d6) δ 1255 (s 1H COOH) 749 (s 1H thiourea-NH)

737 (d J = 86 Hz 1H thiourea-NH) 483 (dd J = 86 46 Hz 1H Ha) 209 ndash 205

(m 1H Hb) 141 (s 9H tert-butyl) 088 -086 (m 6H isopropyl-Me)

13C NMR (126 MHz DMSO-d6) δ 18182 17342 6030 5227 3057 2889 1887

1812

HRMS (FD+(eiFi)) calcd for C10H20N2O2S1 [M]+ 2321245 found 2321201

L-N-formyl-Valine (24)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (03 g 25 mmol) formic acid (952 g 113 mmol) and acetic acid

anhydride (1 g 98 mmol) were dissolved in acetic acid (10 mL) and the reaction was

stirred for 4 hours at room temperature Afterwards all the volatiles were removed under

vacuum and the crude product was purified by recrystallization to give while power

identical to literature4

S15

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 841 (s 1H formyl-H) 798

(d J = 8 Hz 1H amide-NH) 411 (dd J = 8 Hz J = 6 Hz 1H Ha) 202 (m 1H Hb)

087 (dd J = 1 Hz J = 7 Hz 6H isopropyl-Me)

L-N-trimethylacetyl-Valine (25)

The compound was prepared as follow based on reported procedure5 A round bottom flask

equipped with a magnetic stirring bar was charged with distilled water and NaHCO3

The resulting reaction mixtures was cooled to 0 oC in an ice bath L-Valine methyl ester

hydrochloride (300 mg 256 mmol) was added and the solution was stirred until

homogeneous The flask was equipped with an addition funnel The corresponding

trimethylacetyl chloride which was prepared from the corresponding pivalic acid in

14-dioxane (4 mL) was added dropwise The reaction mixture was then allowed to stir

at room temperature overnight Next the reaction was extracted with Et2O (2x20 mL)

to remove the impurities The aqueous layer was again cooled to 0 oC in an ice bath and

1M HCl was added until pH 3 The product was extracted with ethyl acetate (3x100 mL)

The organic layer was washed with brine (50 mL) dried over Na2SO4 filtered and

concentrated under vacuum to give the product as white powder Identical to the

literature5

1H NMR (400 MHz CDCl3) δ 970 (s 1H COOH) 624 (d J = 85 Hz 1H amide-

NH) 456 (dd J = 85 47 Hz 1H Ha) 223 (m 1H Hb) 122 (s 9H tert-butyl-Me)

106 ndash 093 (m 6H isopropyl-Me)

S16

L-(tert-butylcarbamoyl)-N-valine methyl ester (26a)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (10 g 762 mmol) was dissolved in dry DCM (100 mL) and the

isocyanate was added The mixture was stirred and the progress of the reaction was

monitored by TLC (petroleum etherethyl acetate 11) After completion the solvents

were removed under vacuum and the crude product was dissolved in DCM (80 mL)

washed with 1M HCl (3x80 mL) dried over MgSO4 The pure product was obtained as

white powder with 96 yield Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 604 (d J = 88 Hz 1H urea-NH) 594 (s 1H urea-

NH) 403 (dd J = 88 53 Hz 1H Ha) 362 (s 3H OMe) 209 ndash 183 (m 1H Hb)

120 (s 9H tert-butyl) 083 (m 6H isopropyl-Me)

L-(tert-butylcarbamoyl)-N-valine (26)

The compound was prepared as follow based on reported procedure4 To a solution of L-

(tert-butylcarbamoyl)-N-valine methyl ester (1 eq 074 g 322 mmol) in

methanolTHFwater (111 30 mL) mixture was added LiOHH2O (1 eq 135 mg 322

mmol) After overnight stirring at room temperature the resulting reaction mixtures was

partially concentrated under vacuum followed by the addition of water (20 mL) The

mixture was acidified with 1M HCl to pH 4 and then the product was extracted with

ethyl acetate (3x30 mL) The combined organic layer was washed with brine (30 mL)

dried over MgSO4 The pure product was obtained as white powder with 80 yield

Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 1241 (s 1H COOH) 591 (s 1H urea-NH) 587

(d J = 91 Hz 1H urea-NH) 399 (dd J = 89 48 Hz 1H Ha) 199 ndash 188 (m 1H

Hb) 120 (s 9H tert-butyl) 085 - 081 (m 6H isopropyl-Me)

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 12: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S12

31P NMR (162 MHz CD2Cl2) δ 14408 14397

13C NMR (100MHz CD2Cl2) δ = 16524 (m) 15229 (m) 14784 (d J = 46 Hz)

14722 (m) 13674 13638 (d J = 80 Hz) 13319 13287 13236 13224 13174 (m)

13111 13050 (m) 12885 (d J = 81 Hz) 12827 (d J = 30 Hz) 12721 12708 (d J

= 30 Hz) 12690 (d J = 65 Hz) 12573 (d J = 171 Hz) 12455 (m) 12405 (d J =

81 Hz) 12375 (d J = 85 Hz) 12346 (d J = 111 Hz) 12321 (m) 12217 12197

11992 (m) 11973 (d J = 75 Hz) 11930 (d J = 40 Hz) 11815 11641 11410 (d J

= 160 Hz) 10825 (d J = 44 Hz) 3686 2599 1261 889

HR MS (FD+(eiFi)+) calcd for C75H54N4O8P2 [M]+ 120034169 found 120033967

The effectors used in this study

Scheme S3 Effectors purchased from commercial source

S13

Scheme S4 Effectors prepared except 27 purchased from commercial sources

L-(tert-butylthiocarbamoyl)-N-valine (1S)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 200 mg 170 mmol) was dissolved in 025 M NaHCO3 solution

(80 mL) followed by adding the isothiocyanate (1 eq 022 mL 17 mmol) The mixture

was heated at 80 oC for 3 hours and the progress of the reaction was monitored by TLC

(petroleum etherethyl acetate 11) After completion the reaction mixture was cooling

down and acidified to pH 2 with 1M HCl (3x80 mL) The products were extracted with

ethyl acetate (3x100 mL) The combined organic layer was dried over MgSO4 The pure

product was obtained as white powder with 50 yield after crystallization Identical to

the literature4

S14

1H NMR (400 MHz DMSO-d6) δ 750 (s 1H thiourea-NH) 738 (d J = 86 Hz 1H

thiourea-NH) 484 (dd J = 86 46 Hz 1H Ha) 208 (m 1H Hb) 142 (s 9H tert-

butyl-Me) 088 (m 6H isopropyl-Me)

D-(tert-butylthiocarbamoyl)-N-valine (1S) was prepared following the same

procedures for 1R

1H NMR (400 MHz DMSO-d6) δ 1255 (s 1H COOH) 749 (s 1H thiourea-NH)

737 (d J = 86 Hz 1H thiourea-NH) 483 (dd J = 86 46 Hz 1H Ha) 209 ndash 205

(m 1H Hb) 141 (s 9H tert-butyl) 088 -086 (m 6H isopropyl-Me)

13C NMR (126 MHz DMSO-d6) δ 18182 17342 6030 5227 3057 2889 1887

1812

HRMS (FD+(eiFi)) calcd for C10H20N2O2S1 [M]+ 2321245 found 2321201

L-N-formyl-Valine (24)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (03 g 25 mmol) formic acid (952 g 113 mmol) and acetic acid

anhydride (1 g 98 mmol) were dissolved in acetic acid (10 mL) and the reaction was

stirred for 4 hours at room temperature Afterwards all the volatiles were removed under

vacuum and the crude product was purified by recrystallization to give while power

identical to literature4

S15

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 841 (s 1H formyl-H) 798

(d J = 8 Hz 1H amide-NH) 411 (dd J = 8 Hz J = 6 Hz 1H Ha) 202 (m 1H Hb)

087 (dd J = 1 Hz J = 7 Hz 6H isopropyl-Me)

L-N-trimethylacetyl-Valine (25)

The compound was prepared as follow based on reported procedure5 A round bottom flask

equipped with a magnetic stirring bar was charged with distilled water and NaHCO3

The resulting reaction mixtures was cooled to 0 oC in an ice bath L-Valine methyl ester

hydrochloride (300 mg 256 mmol) was added and the solution was stirred until

homogeneous The flask was equipped with an addition funnel The corresponding

trimethylacetyl chloride which was prepared from the corresponding pivalic acid in

14-dioxane (4 mL) was added dropwise The reaction mixture was then allowed to stir

at room temperature overnight Next the reaction was extracted with Et2O (2x20 mL)

to remove the impurities The aqueous layer was again cooled to 0 oC in an ice bath and

1M HCl was added until pH 3 The product was extracted with ethyl acetate (3x100 mL)

The organic layer was washed with brine (50 mL) dried over Na2SO4 filtered and

concentrated under vacuum to give the product as white powder Identical to the

literature5

1H NMR (400 MHz CDCl3) δ 970 (s 1H COOH) 624 (d J = 85 Hz 1H amide-

NH) 456 (dd J = 85 47 Hz 1H Ha) 223 (m 1H Hb) 122 (s 9H tert-butyl-Me)

106 ndash 093 (m 6H isopropyl-Me)

S16

L-(tert-butylcarbamoyl)-N-valine methyl ester (26a)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (10 g 762 mmol) was dissolved in dry DCM (100 mL) and the

isocyanate was added The mixture was stirred and the progress of the reaction was

monitored by TLC (petroleum etherethyl acetate 11) After completion the solvents

were removed under vacuum and the crude product was dissolved in DCM (80 mL)

washed with 1M HCl (3x80 mL) dried over MgSO4 The pure product was obtained as

white powder with 96 yield Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 604 (d J = 88 Hz 1H urea-NH) 594 (s 1H urea-

NH) 403 (dd J = 88 53 Hz 1H Ha) 362 (s 3H OMe) 209 ndash 183 (m 1H Hb)

120 (s 9H tert-butyl) 083 (m 6H isopropyl-Me)

L-(tert-butylcarbamoyl)-N-valine (26)

The compound was prepared as follow based on reported procedure4 To a solution of L-

(tert-butylcarbamoyl)-N-valine methyl ester (1 eq 074 g 322 mmol) in

methanolTHFwater (111 30 mL) mixture was added LiOHH2O (1 eq 135 mg 322

mmol) After overnight stirring at room temperature the resulting reaction mixtures was

partially concentrated under vacuum followed by the addition of water (20 mL) The

mixture was acidified with 1M HCl to pH 4 and then the product was extracted with

ethyl acetate (3x30 mL) The combined organic layer was washed with brine (30 mL)

dried over MgSO4 The pure product was obtained as white powder with 80 yield

Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 1241 (s 1H COOH) 591 (s 1H urea-NH) 587

(d J = 91 Hz 1H urea-NH) 399 (dd J = 89 48 Hz 1H Ha) 199 ndash 188 (m 1H

Hb) 120 (s 9H tert-butyl) 085 - 081 (m 6H isopropyl-Me)

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 13: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S13

Scheme S4 Effectors prepared except 27 purchased from commercial sources

L-(tert-butylthiocarbamoyl)-N-valine (1S)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 200 mg 170 mmol) was dissolved in 025 M NaHCO3 solution

(80 mL) followed by adding the isothiocyanate (1 eq 022 mL 17 mmol) The mixture

was heated at 80 oC for 3 hours and the progress of the reaction was monitored by TLC

(petroleum etherethyl acetate 11) After completion the reaction mixture was cooling

down and acidified to pH 2 with 1M HCl (3x80 mL) The products were extracted with

ethyl acetate (3x100 mL) The combined organic layer was dried over MgSO4 The pure

product was obtained as white powder with 50 yield after crystallization Identical to

the literature4

S14

1H NMR (400 MHz DMSO-d6) δ 750 (s 1H thiourea-NH) 738 (d J = 86 Hz 1H

thiourea-NH) 484 (dd J = 86 46 Hz 1H Ha) 208 (m 1H Hb) 142 (s 9H tert-

butyl-Me) 088 (m 6H isopropyl-Me)

D-(tert-butylthiocarbamoyl)-N-valine (1S) was prepared following the same

procedures for 1R

1H NMR (400 MHz DMSO-d6) δ 1255 (s 1H COOH) 749 (s 1H thiourea-NH)

737 (d J = 86 Hz 1H thiourea-NH) 483 (dd J = 86 46 Hz 1H Ha) 209 ndash 205

(m 1H Hb) 141 (s 9H tert-butyl) 088 -086 (m 6H isopropyl-Me)

13C NMR (126 MHz DMSO-d6) δ 18182 17342 6030 5227 3057 2889 1887

1812

HRMS (FD+(eiFi)) calcd for C10H20N2O2S1 [M]+ 2321245 found 2321201

L-N-formyl-Valine (24)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (03 g 25 mmol) formic acid (952 g 113 mmol) and acetic acid

anhydride (1 g 98 mmol) were dissolved in acetic acid (10 mL) and the reaction was

stirred for 4 hours at room temperature Afterwards all the volatiles were removed under

vacuum and the crude product was purified by recrystallization to give while power

identical to literature4

S15

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 841 (s 1H formyl-H) 798

(d J = 8 Hz 1H amide-NH) 411 (dd J = 8 Hz J = 6 Hz 1H Ha) 202 (m 1H Hb)

087 (dd J = 1 Hz J = 7 Hz 6H isopropyl-Me)

L-N-trimethylacetyl-Valine (25)

The compound was prepared as follow based on reported procedure5 A round bottom flask

equipped with a magnetic stirring bar was charged with distilled water and NaHCO3

The resulting reaction mixtures was cooled to 0 oC in an ice bath L-Valine methyl ester

hydrochloride (300 mg 256 mmol) was added and the solution was stirred until

homogeneous The flask was equipped with an addition funnel The corresponding

trimethylacetyl chloride which was prepared from the corresponding pivalic acid in

14-dioxane (4 mL) was added dropwise The reaction mixture was then allowed to stir

at room temperature overnight Next the reaction was extracted with Et2O (2x20 mL)

to remove the impurities The aqueous layer was again cooled to 0 oC in an ice bath and

1M HCl was added until pH 3 The product was extracted with ethyl acetate (3x100 mL)

The organic layer was washed with brine (50 mL) dried over Na2SO4 filtered and

concentrated under vacuum to give the product as white powder Identical to the

literature5

1H NMR (400 MHz CDCl3) δ 970 (s 1H COOH) 624 (d J = 85 Hz 1H amide-

NH) 456 (dd J = 85 47 Hz 1H Ha) 223 (m 1H Hb) 122 (s 9H tert-butyl-Me)

106 ndash 093 (m 6H isopropyl-Me)

S16

L-(tert-butylcarbamoyl)-N-valine methyl ester (26a)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (10 g 762 mmol) was dissolved in dry DCM (100 mL) and the

isocyanate was added The mixture was stirred and the progress of the reaction was

monitored by TLC (petroleum etherethyl acetate 11) After completion the solvents

were removed under vacuum and the crude product was dissolved in DCM (80 mL)

washed with 1M HCl (3x80 mL) dried over MgSO4 The pure product was obtained as

white powder with 96 yield Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 604 (d J = 88 Hz 1H urea-NH) 594 (s 1H urea-

NH) 403 (dd J = 88 53 Hz 1H Ha) 362 (s 3H OMe) 209 ndash 183 (m 1H Hb)

120 (s 9H tert-butyl) 083 (m 6H isopropyl-Me)

L-(tert-butylcarbamoyl)-N-valine (26)

The compound was prepared as follow based on reported procedure4 To a solution of L-

(tert-butylcarbamoyl)-N-valine methyl ester (1 eq 074 g 322 mmol) in

methanolTHFwater (111 30 mL) mixture was added LiOHH2O (1 eq 135 mg 322

mmol) After overnight stirring at room temperature the resulting reaction mixtures was

partially concentrated under vacuum followed by the addition of water (20 mL) The

mixture was acidified with 1M HCl to pH 4 and then the product was extracted with

ethyl acetate (3x30 mL) The combined organic layer was washed with brine (30 mL)

dried over MgSO4 The pure product was obtained as white powder with 80 yield

Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 1241 (s 1H COOH) 591 (s 1H urea-NH) 587

(d J = 91 Hz 1H urea-NH) 399 (dd J = 89 48 Hz 1H Ha) 199 ndash 188 (m 1H

Hb) 120 (s 9H tert-butyl) 085 - 081 (m 6H isopropyl-Me)

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 14: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S14

1H NMR (400 MHz DMSO-d6) δ 750 (s 1H thiourea-NH) 738 (d J = 86 Hz 1H

thiourea-NH) 484 (dd J = 86 46 Hz 1H Ha) 208 (m 1H Hb) 142 (s 9H tert-

butyl-Me) 088 (m 6H isopropyl-Me)

D-(tert-butylthiocarbamoyl)-N-valine (1S) was prepared following the same

procedures for 1R

1H NMR (400 MHz DMSO-d6) δ 1255 (s 1H COOH) 749 (s 1H thiourea-NH)

737 (d J = 86 Hz 1H thiourea-NH) 483 (dd J = 86 46 Hz 1H Ha) 209 ndash 205

(m 1H Hb) 141 (s 9H tert-butyl) 088 -086 (m 6H isopropyl-Me)

13C NMR (126 MHz DMSO-d6) δ 18182 17342 6030 5227 3057 2889 1887

1812

HRMS (FD+(eiFi)) calcd for C10H20N2O2S1 [M]+ 2321245 found 2321201

L-N-formyl-Valine (24)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (03 g 25 mmol) formic acid (952 g 113 mmol) and acetic acid

anhydride (1 g 98 mmol) were dissolved in acetic acid (10 mL) and the reaction was

stirred for 4 hours at room temperature Afterwards all the volatiles were removed under

vacuum and the crude product was purified by recrystallization to give while power

identical to literature4

S15

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 841 (s 1H formyl-H) 798

(d J = 8 Hz 1H amide-NH) 411 (dd J = 8 Hz J = 6 Hz 1H Ha) 202 (m 1H Hb)

087 (dd J = 1 Hz J = 7 Hz 6H isopropyl-Me)

L-N-trimethylacetyl-Valine (25)

The compound was prepared as follow based on reported procedure5 A round bottom flask

equipped with a magnetic stirring bar was charged with distilled water and NaHCO3

The resulting reaction mixtures was cooled to 0 oC in an ice bath L-Valine methyl ester

hydrochloride (300 mg 256 mmol) was added and the solution was stirred until

homogeneous The flask was equipped with an addition funnel The corresponding

trimethylacetyl chloride which was prepared from the corresponding pivalic acid in

14-dioxane (4 mL) was added dropwise The reaction mixture was then allowed to stir

at room temperature overnight Next the reaction was extracted with Et2O (2x20 mL)

to remove the impurities The aqueous layer was again cooled to 0 oC in an ice bath and

1M HCl was added until pH 3 The product was extracted with ethyl acetate (3x100 mL)

The organic layer was washed with brine (50 mL) dried over Na2SO4 filtered and

concentrated under vacuum to give the product as white powder Identical to the

literature5

1H NMR (400 MHz CDCl3) δ 970 (s 1H COOH) 624 (d J = 85 Hz 1H amide-

NH) 456 (dd J = 85 47 Hz 1H Ha) 223 (m 1H Hb) 122 (s 9H tert-butyl-Me)

106 ndash 093 (m 6H isopropyl-Me)

S16

L-(tert-butylcarbamoyl)-N-valine methyl ester (26a)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (10 g 762 mmol) was dissolved in dry DCM (100 mL) and the

isocyanate was added The mixture was stirred and the progress of the reaction was

monitored by TLC (petroleum etherethyl acetate 11) After completion the solvents

were removed under vacuum and the crude product was dissolved in DCM (80 mL)

washed with 1M HCl (3x80 mL) dried over MgSO4 The pure product was obtained as

white powder with 96 yield Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 604 (d J = 88 Hz 1H urea-NH) 594 (s 1H urea-

NH) 403 (dd J = 88 53 Hz 1H Ha) 362 (s 3H OMe) 209 ndash 183 (m 1H Hb)

120 (s 9H tert-butyl) 083 (m 6H isopropyl-Me)

L-(tert-butylcarbamoyl)-N-valine (26)

The compound was prepared as follow based on reported procedure4 To a solution of L-

(tert-butylcarbamoyl)-N-valine methyl ester (1 eq 074 g 322 mmol) in

methanolTHFwater (111 30 mL) mixture was added LiOHH2O (1 eq 135 mg 322

mmol) After overnight stirring at room temperature the resulting reaction mixtures was

partially concentrated under vacuum followed by the addition of water (20 mL) The

mixture was acidified with 1M HCl to pH 4 and then the product was extracted with

ethyl acetate (3x30 mL) The combined organic layer was washed with brine (30 mL)

dried over MgSO4 The pure product was obtained as white powder with 80 yield

Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 1241 (s 1H COOH) 591 (s 1H urea-NH) 587

(d J = 91 Hz 1H urea-NH) 399 (dd J = 89 48 Hz 1H Ha) 199 ndash 188 (m 1H

Hb) 120 (s 9H tert-butyl) 085 - 081 (m 6H isopropyl-Me)

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 15: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S15

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 841 (s 1H formyl-H) 798

(d J = 8 Hz 1H amide-NH) 411 (dd J = 8 Hz J = 6 Hz 1H Ha) 202 (m 1H Hb)

087 (dd J = 1 Hz J = 7 Hz 6H isopropyl-Me)

L-N-trimethylacetyl-Valine (25)

The compound was prepared as follow based on reported procedure5 A round bottom flask

equipped with a magnetic stirring bar was charged with distilled water and NaHCO3

The resulting reaction mixtures was cooled to 0 oC in an ice bath L-Valine methyl ester

hydrochloride (300 mg 256 mmol) was added and the solution was stirred until

homogeneous The flask was equipped with an addition funnel The corresponding

trimethylacetyl chloride which was prepared from the corresponding pivalic acid in

14-dioxane (4 mL) was added dropwise The reaction mixture was then allowed to stir

at room temperature overnight Next the reaction was extracted with Et2O (2x20 mL)

to remove the impurities The aqueous layer was again cooled to 0 oC in an ice bath and

1M HCl was added until pH 3 The product was extracted with ethyl acetate (3x100 mL)

The organic layer was washed with brine (50 mL) dried over Na2SO4 filtered and

concentrated under vacuum to give the product as white powder Identical to the

literature5

1H NMR (400 MHz CDCl3) δ 970 (s 1H COOH) 624 (d J = 85 Hz 1H amide-

NH) 456 (dd J = 85 47 Hz 1H Ha) 223 (m 1H Hb) 122 (s 9H tert-butyl-Me)

106 ndash 093 (m 6H isopropyl-Me)

S16

L-(tert-butylcarbamoyl)-N-valine methyl ester (26a)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (10 g 762 mmol) was dissolved in dry DCM (100 mL) and the

isocyanate was added The mixture was stirred and the progress of the reaction was

monitored by TLC (petroleum etherethyl acetate 11) After completion the solvents

were removed under vacuum and the crude product was dissolved in DCM (80 mL)

washed with 1M HCl (3x80 mL) dried over MgSO4 The pure product was obtained as

white powder with 96 yield Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 604 (d J = 88 Hz 1H urea-NH) 594 (s 1H urea-

NH) 403 (dd J = 88 53 Hz 1H Ha) 362 (s 3H OMe) 209 ndash 183 (m 1H Hb)

120 (s 9H tert-butyl) 083 (m 6H isopropyl-Me)

L-(tert-butylcarbamoyl)-N-valine (26)

The compound was prepared as follow based on reported procedure4 To a solution of L-

(tert-butylcarbamoyl)-N-valine methyl ester (1 eq 074 g 322 mmol) in

methanolTHFwater (111 30 mL) mixture was added LiOHH2O (1 eq 135 mg 322

mmol) After overnight stirring at room temperature the resulting reaction mixtures was

partially concentrated under vacuum followed by the addition of water (20 mL) The

mixture was acidified with 1M HCl to pH 4 and then the product was extracted with

ethyl acetate (3x30 mL) The combined organic layer was washed with brine (30 mL)

dried over MgSO4 The pure product was obtained as white powder with 80 yield

Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 1241 (s 1H COOH) 591 (s 1H urea-NH) 587

(d J = 91 Hz 1H urea-NH) 399 (dd J = 89 48 Hz 1H Ha) 199 ndash 188 (m 1H

Hb) 120 (s 9H tert-butyl) 085 - 081 (m 6H isopropyl-Me)

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 16: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S16

L-(tert-butylcarbamoyl)-N-valine methyl ester (26a)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (10 g 762 mmol) was dissolved in dry DCM (100 mL) and the

isocyanate was added The mixture was stirred and the progress of the reaction was

monitored by TLC (petroleum etherethyl acetate 11) After completion the solvents

were removed under vacuum and the crude product was dissolved in DCM (80 mL)

washed with 1M HCl (3x80 mL) dried over MgSO4 The pure product was obtained as

white powder with 96 yield Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 604 (d J = 88 Hz 1H urea-NH) 594 (s 1H urea-

NH) 403 (dd J = 88 53 Hz 1H Ha) 362 (s 3H OMe) 209 ndash 183 (m 1H Hb)

120 (s 9H tert-butyl) 083 (m 6H isopropyl-Me)

L-(tert-butylcarbamoyl)-N-valine (26)

The compound was prepared as follow based on reported procedure4 To a solution of L-

(tert-butylcarbamoyl)-N-valine methyl ester (1 eq 074 g 322 mmol) in

methanolTHFwater (111 30 mL) mixture was added LiOHH2O (1 eq 135 mg 322

mmol) After overnight stirring at room temperature the resulting reaction mixtures was

partially concentrated under vacuum followed by the addition of water (20 mL) The

mixture was acidified with 1M HCl to pH 4 and then the product was extracted with

ethyl acetate (3x30 mL) The combined organic layer was washed with brine (30 mL)

dried over MgSO4 The pure product was obtained as white powder with 80 yield

Identical to the literature4

1H NMR (400 MHz DMSO-d6) δ 1241 (s 1H COOH) 591 (s 1H urea-NH) 587

(d J = 91 Hz 1H urea-NH) 399 (dd J = 89 48 Hz 1H Ha) 199 ndash 188 (m 1H

Hb) 120 (s 9H tert-butyl) 085 - 081 (m 6H isopropyl-Me)

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 17: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S17

L-(Adamantylthiocarbamoyl)-N-valine (28)

The compound was prepared as follow based on reported procedure4 L-Valine methyl ester

hydrochloride (1 eq 05 g 43 mmol) was dissolved in a mixture of 025 M NaHCO3(aq)

solution (50 ml) and methanol (50 ml) adamantyl isothiocyanate (083 g 43 mmol)

was added and the reaction was heated at 80degC for 3 hours After cooling down the

methanol was removed under vacuum and the reaction was acidified with 1 M HCl to

reach pH = 2 The product was extracted with ethyl acetate (3 x 100ml) The combined

organic layers were dried over MgSO4 and the solvent was removed under vacuum

The crude product was dissolved in a small amount of hot DCM precipitated with

hexane and filtered off providing 04510 g (34) of pure product Identical to the

literature 4

1H NMR (400 MHz DMSO-d6) 1256 (bs 1H COOH) 740 (d J= 8 Hz 1H thiourea-

NH) 736 (s 1H thiourea-NH) 477 (dd J= 3 Hz J= 8Hz 1H Ha) 215 (m 6H) 208

(m 1H Hb) 202 (m 3H) 161 (m 6H) 086 (m 6H isopropyl-Me)

L-(n-butylthiocarbamoyl)-N-valine (29) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1034 (bs 1H COOH) 415 (d J= 3 Hz 1H Ha)

367 (m 2H) 208 (m 1H Hb) 152 (m 2H) 127 (m 2H) 094 - 081 (m 6H

isopropyl-Me) 088 (t J= 7 Hz 3H)

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 18: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S18

L-(phenylthiocarbamoyl)-N-valine (30) was prepared following the same procedures

for 28

1H NMR (400 MHz DMSO-d6) 1059 (bs 1H COOH) 748 (dd J = 7 Hz J = 7 Hz

2H) 743 (d J = 7 Hz 1H) 723 (d J = 7 Hz 2H) 433 (d J= 3 Hz 1H Ha) 219 (m

1H Hb) 104 - 091 (m 6H isopropyl-Me)

General procedures for the hydroformylation reaction

General procedures A stock solution for the hydroformylation experiments was

prepared by charging a flame-dried Schlenk flask with Rh(acac)(CO)2 ligand effectors

and NN-diisopropylethylamine (if stated) internal standard (135-trimethoxylbenzene)

and dried and degassed toluene with standard Schlenk technique or in the Glove-Box

The solution was stirred for 30 minutes and then the 15 mL reaction vials (pre-dried in

oven overnight) equipped with mini Teflon stir bars were charged with proper amount

of substrates followed by the addition of a proper amount of catalyst stock solution in

the Glove-Box The vials were placed in a stainless steel autoclave (250 mL) charged

with an insert suitable for 15 reaction vials for conducting parallel reactions The

autoclave was closed properly and then purged three times with 30 of bar syngas

followed by pressurized at 40 bar of syngas The reaction mixtures were stirred at the

appropriate temperature for the required reaction time Thereafter the pressure was

released and the yield regioselectivity and enantioselectivity were determined by 1H

NMR analysis and GC or HPLC analysis For NMR analysis usually 100 uL reaction

mixture were diluted with a proper amount of CDCl3 For GC analysis usually 50 uL

reaction mixture was dilute to 1 mL with dichloromethane and injected to GC for

measurements with beta DEX 225 column For HPLC analysis usually 30 uL reaction

mixture was evaporated under vacuum and re-dissolved in isopropyl alcohol and n-

heptane and then injected to HPLC for measurements

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 19: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S19

For vinyl acetate vinyl benzoate and vinyl pivalate the enantiomeric ratio was

analyzed by Chiral GC (Supelcorsquos Beta Dex 225)

Hydroformylation of vinyl acetate Initial temperature = 100 oC for 10 min then 4

oCmin to 140 oC then 40 oCmin to 200 oC Retention time tR(R) = 4022 min and tR

(S)= 5277 min6

Hydroformylation of vinyl benzoate Initial temperature= 135 oC for 22 min then 20

oCmin to 220 oC Retention time tR(R) = 14687 min and tR(S) = 15340 min67

Hydroformylation of vinyl pivalate Initial temperature= 77 oC for 22 min then 40

oCmin to 220 oC for 5 min Retention time tR(R)= 11561 min and tR(S)= 1201 min 6

For N-vinyl phthalimide the enantiomeric ratio was analyzed by HPLC (Chiralcel OJ-

H 3 iPrOHn-heptane 08 mLmin λ=220 nm) Retention time tR(major) = 303 min

tR(minor) = 323 min8

Hydroformylation results

Table S1 Evaluation of the effector in succeed groups in the hydroformylation of vinyl

acetatea

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 20: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S20

entry Effector Conv ee bl

1 2 R1R2 = OMe H 72 17(R) gt99

2 3 R1R2 = HBoc 88 43(R) gt99

3 4 R1R2 = HAc 97 60(R) gt99

4 5 R1R2 = HCbz 93 58(R) gt99

5 6 R1R2 = HFmoc 96 57(R) gt99

6 7 R1R2 = HBoc 89 50(R) gt99

7 8 R1R2 = HFmoc 75 41(R) gt99

8 9 R1R2 = MeFmoc 76 54(R) gt99

9 10 R1R2 = H3-

indolyacetyl 55 26(R) gt99

10 11 R1R2 = HCbz 89 49(R) gt99

11 12 R1R2 = HAc 94 62(R) gt99

12 13 R1R2 = HBoc 95 51(R) gt99

13 14 R1R2 = MeBoc 77 30(R) gt99

14 15 R = Boc 92 49(R) gt99

15 16 R = Fmoc 99 49(R) gt99

16 17 R = Cbz 93 54(R) gt99

17 18 R = Boc 95 40(R) gt99

18 19 R = Fmoc 95 51(R) gt99

19 20 R = Ac 87 47(R) gt99

20 21 R = Boc 80 29(R) gt99

21 22 R = H 99 23(R) gt99

22 23 R = Fmoc 99 53(R) gt99

aConditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M vinyl acetate 10 mol effector 8

mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours Conversion and

regioselectivity were determined by 1H NMR analysis ee was determined by GC analysis

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 21: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S21

Table S2 Evaluation of mixtures of effectors of subgroups in the hydroformylation of

vinyl acetate a

entry Sub Effectors Conv ee bl

1 vinylacetate G1(2-6) 80 45(R) gt99

2 vinylacetate G2(7-12) 80 42(R) gt99

3 vinylacetate G3(13-17) 95 51(R) gt99

4 vinylacetate G4(18-23) 95 52(R) gt99

5 vinylacetate G5(31-35) 99 55(R) gt99

6 vinylacetate G6(36-40) 63 34(R) gt99

7 vinylacetate G7(41-44) 75 24(R) gt99

8 vinylacetate G8(45-49) 79 35(R) gt99

9 vinylacetate no 100 1 27

Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M Vinylacetate 2 mol of per

effector 10 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

Conversion and regioselectivity were determined by 1H NMR analysis ee was

determined by GC analysis

Scheme S5 Application of various modified effectors in [Rh][L3] catalyzed asymmetric

hydroformylation Conditions 05 Cat [Rh(acac)(CO)2]L = 113 02 M substrate 10 mol

effector 8 mol DIPEA 1 ml toluene as the solvent 40 bar syngas 40 oC 96 hours

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 22: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S22

Conversion and regioselectivity were determined by 1H NMR analysis ee was determined by

GC and HPLC analysis b Performed at room temperature with 120 hours of reaction time

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 23: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S23

Spectra

Figure S1 1H NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S2 13C NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 24: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S24

Figure S3 13P NMR spectrum of (Bis-3-((48-Di-tert-butyl-210-

dimethoxydibenzo[df][132]dioxaphosphepin-6-yl)oxyl)benzoamide of 11-bis-(7-amino-3-

methyl-1H-indol-2-yl)-propane (L2)

Figure S4 1H NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 25: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S25

Figure S5 1H-1H COSY NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl

phosphito)benzoamide) of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S6 13C NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 26: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S26

Figure S7 31P NMR spectrum of (Bis-(3-((S)-11rsquo-binaphthyl-22-diyl phosphito)benzoamide)

of 11-Bis-(7-amino-3-methyl-1H-indol-2-yl)-propane (L3)

Figure S8 1H NMR spectrum of L-N-trimethylacetyl-Valine (25)

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 27: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S27

Figure S9 1H NMR spectrum of L-(tert-butylcarbamoyl)-N-valine (26)

Figure S10 1H NMR spectrum of effector 1S

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 28: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S28

Figure S11 1H-1H COSY NMR spectrum of effector 1S

Figure S12 13C NMR spectrum of effector 1S

References

1 P Dydio D Lichosyt T Zieliński and J Jurczak Chem Eur J 2012 18

13686ndash13701

2 P Dydio R J Detz and J N H Reek J Am Chem Soc 2013 135 10817ndash

10828

3 P Dydio R J Detz B de Bruin and J N H H Reek J Am Chem Soc

2014 136 8418ndash8429

4 P Dydio C Rubay T Gadzikwa M Lutz and J N H Reek J Am Chem

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029

Page 29: Supporting Information Effector enhanced enantioselective hydroformylation · 2019. 11. 8. · S1 Supporting Information Effector enhanced enantioselective hydroformylation Shao-Tao

S29

Soc 2011 133 17176ndash17179

5 K M Engle D H Wang and J Q Yu J Am Chem Soc 2010 132 14137ndash

14151

6 X Zhang B Cao Y Yan S Yu B Ji and X Zhang Chem Eur J 2010

16 871ndash877

7 K C Miles M L Abrams C R Landis and S S Stahl Org Lett 2016 18

3590ndash3593

8 R I McDonald G W Wong R P Neupane S S Stahl and C R Landis J

Am Chem Soc 2010 132 14027ndash14029


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