Rh(III)-Catalyzed C H Bond Addition/Amine-Mediated ... · S1 Rh(III)-Catalyzed C–H Bond...

S1

Rh(III)-Catalyzed C–H Bond Addition/Amine-Mediated Cyclization of Bis-

Michael Acceptors

Tyler J. Potter and Jonathan A. Ellman*

Yale University Department of Chemistry

225 Prospect Street, New Haven, CT, 06520-8107

[email protected]

Supporting Information

I. General Methods S2

II. Preparation of Substrates S3

III. Rh(III)-Catalyzed Coupling Reactions S7

IV. Diversification Procedures S16

V. Competition Experiment S18

VI. X-Ray Crystallographic Data S20

VII. References S26

VIII. NMR Data S27

S2

I. General Methods

All rhodium reactions were set up inside an inert atmosphere glovebox with a nitrogen atmosphere with O2

and H2O <1 ppm using glassware that was oven-dried at >150 oC for at least 12 h and cooled under inert

atmosphere. 1,4-Dioxane and all other solvents were sparged with argon and purified by elution through a

column of activated alumina under argon before use. Triethylamine was distilled from CaH2 under nitrogen

immediately before use. Benzylamine was distilled from activated zinc under reduced pressure and stored

under nitrogen. Unless otherwise noted, all reagents were purchased from commercial sources and used

without further purification. Products and starting materials were visualized on TLC using UV light or by

staining with KMnO4. Flash-column chromatography was performed either on silica gel (230-400 mesh) or

preparative thin-layer chromatography plates (1 mm SiO2, 20 x 20 cm). NMR characterization was

performed on either a 400, 500, or 600 MHz instrument. Data are reported in the following format: chemical

shift in ppm, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad signal, m = multiplet,

dd = doublet of doublets, etc.), coupling constant J in Hz, and integration. Chloroform-d was used as

received. All spectra were referenced against residual solvent peaks (1H: residual CHCl3 = 7.26 ppm, 13C:

CDCl3 = 77.16 ppm). Partial IR spectra are reported. Melting points are reported uncorrected. High-

resolution mass spectra (HRMS) were obtained using electrospray ionization (ESI) on a time of flight (TOF)

mass spectrometer.

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II. Preparation of Substrates

Catalyst:

[Cp*RhCl2]2 was synthesized according to the published literature procedure.1

C-H bond functionalization substrates:

C-H bond functionalization substrates: 2-(m-tolyl)pyridine2 (2a), 2-(m-tolyl)pyrimidine3 (2c), 1-(m-tolyl)-

1H-pyrazole4 (2d), 1-benzyl-4-(m-tolyl)-1H-1,2,3-triazole5 (2e), N,3-dimethylbenzamide6 (2f),

phenyl(pyrrolidin-1-yl)methanone7 (2g), pyrrolidin-1-yl(m-tolyl)methanone7 (2h), (3-

bromophenyl)(pyrrolidin-1-yl)methanone7 (2i), (4-methoxyphenyl)(pyrrolidin-1-yl)methanone7 (2k), and

(E)-2-(but-2-en-2-yl)pyridine8 (5) were prepared according to previous literature procedures.

Pyrrolidin-1-yl(3-(trifluoromethyl)phenyl)methanone (2j): The title compound was prepared according to

a previously reported general procedure.7 3-trifluoromethylbenzoyl chloride (0.750 mL, 5.00 mmol, 1.00

equiv) was added dropwise to a solution of pyrrolidine (0.450 mL, 5.50 mmol, 1.10 equiv) and Et3N (0.870

mL, 6.25 mmol, 1.25 equiv) in CH2Cl2 (10 mL, [0.5 M]) at room temperature under N2. The reaction mixture

was stirred for 4 h followed by dilution with CH2Cl2 (20 mL). The solution was transferred to a separatory

funnel and was washed with 1M HCl (1 x 30 mL). The organic layer was washed with brine (30 mL), dried

over anhydrous MgSO4, filtered, and concentrated to afford 2j (1.065 g, 88% yield) as a yellow oil, which

was used without further purification. Spectral characterization data matches previously reported data for

the same compound.9

S4

Bis-Michael acceptor substrates:

Ethyl (2E,7E)-9-oxo-9-phenylnona-2,7-dienoate (1e) was prepared according to previously reported

literature procedure.10

Ethyl (E)-4-((4-methyl-N-((E)-4-oxopent-2-en-1-yl)phenyl)sulfonamido)but-2-enoate (1a): To a stirring

solution of ethyl (E)-5-aza-7,7-dimethoxy-5-tosylhept-2-enoate13 (1.00 g, 2.69 mmol, 1.00 equiv) in THF

(40 mL, [0.67 M]) open to air was added 5 M HCl (20 mL). The reaction mixture was heated at 60 oC and

after 30 min there was full consumption of the starting material by TLC. The reaction mixture was cooled

to room temperature and diluted with ethyl acetate (50 mL). The resulting organic layer was washed with

brine (4 x 50 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford

the crude aldehyde, which was used immediately without further purification.

The crude aldehyde was dissolved in CH2Cl2 (10 mL, [0.27 M]) under N2 and 1-

triphenyphosphoranylidene-2-propanone (1.29 g, 4.04 mmol, 1.50 equiv) was added. The reaction mixture

was stirred at room temperature for 16 h, after which the reaction mixture was concentrated under reduced

pressure and the resulting residue was purified by flash chromatography on silica gel (2:1 hexane/ethyl

acetate) to afford 1a (579 mg, 59% yield over 2 steps) as a white solid (mp: 109 – 111 oC). IR (neat): 2987,

1713, 1671, 1660, 1159 cm-1. 1H NMR (500 MHz, Chloroform-d) δ 7.70 (d, J = 8.3 Hz, 2H), 7.33 (d, J =

8.0 Hz, 2H), 6.67 (dt, J = 15.7, 5.9 Hz, 1H), 6.53 (dt, J = 16.0, 5.9 Hz, 1H), 6.07 (d, J = 16.1 Hz, 1H), 5.87

(d, J = 15.7 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.94 (app d, J = 5.7 Hz, 4H), 2.44 (s, 3H), 2.21 (s, 3H), 1.27

(t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ 197.6, 165.5, 144.3, 141.6, 140.7, 136.4, 133.2,

130.1, 127.4, 124.7, 60.8, 48.8, 48.6, 27.4, 21.7, 14.3. HRMS-ESI (m/z): [M+Na]+ calcd for

C18H23NNaO5S+, 388.1189; found, 388.1176.

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Ethyl (E)-4-((4-methyl-N-((E)-4-oxohex-2-en-1-yl)phenyl)sulfonamido)but-2-enoate (1b): To a stirring

solution of ethyl (E)-5-aza-7,7-dimethoxy-5-tosylhept-2-enoate13 (742 mg, 2.00 mmol, 1.00 equiv) in THF

(30 mL, [0.67 M]) open to air was added 5 M HCl (15 mL). The reaction mixture was heated at 60 oC and

after 30 min there was full consumption of the starting material by TLC. The reaction mixture was cooled

to room temperature and diluted with ethyl acetate (50 mL). The resulting organic layer was washed with

brine (4 x 50 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford

the crude aldehyde, which was used immediately without further purification.

The crude aldehyde was dissolved in CH2Cl2 (10 mL, [0.20 M]) under N2 and 1-triphenylphosphanylidene-

2-butanone14 (997 mg, 3.00 mmol, 1.50 equiv) was added. The mixture was stirred at room temperature for

14 h, after which the reaction mixture was concentrated under reduced pressure and the resulting residue

was purified twice by flash chromatography on silica gel (1st: hexane to 2:1 hexane/ethyl acetate gradient,

2nd: hexane to 1:2 hexane/diethyl ether gradient) to afford 1b (276 mg, 38% yield over 2 steps) as a white

solid (mp: 73 – 75 oC). IR (neat): 2981, 2941, 1713, 1675, 1661 cm-1. 1H NMR (500 MHz, Chloroform-d)

δ 7.69 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 7.9 Hz, 2H), 6.71 – 6.62 (m, 1H), 6.57 – 6.48 (m, 1H), 6.11 (d, J =

16.0 Hz, 1H), 5.87 (d, J = 15.7 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.93 (app d, J = 5.8 Hz, 4H), 2.51 (q, J =

7.3 Hz, 2H), 2.43 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.07 (t, J = 7.3 Hz, 3H). 13C NMR (126 MHz, Chloroform-

d) δ 200.0, 165.3, 144.0, 141.4, 139.1, 136.4, 132.0, 130.0, 127.2, 124.5, 60.7, 48.6, 48.4, 33.6, 21.5, 14.2,

7.8. HRMS-ESI (m/z): [M+Na]+ calcd for C19H25NNaO5S+, 402.1346; found, 402.1331.

Ethyl (E)-4-(((E)-4-oxopent-2-en-1-yl)oxy)but-2-enoate (1c): Ozone was bubbled through a solution of

2,5-dihydrofuran (7.01 g, 100 mmol, 10.0 equiv) in CH2Cl2 (100 mL, [1 M in relation to 2,5-dihydrofuran])

at -78 oC until a faint blue color persisted after which ozone was continued to be bubbled through the

solution for an additional 5 min. The solution was then sparged with nitrogen until the blue color faded

after which dimethyl sulfide (8.08 mL, 110 mmol, 11.0 equiv) was added and the solution was placed in a

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0 oC ice bath. After 1 h, (carbethoxymethylene)triphenylphosphorane (3.48 g, 10.0 mmol, 1.00 equiv) was

added, and the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction

mixture was then concentrated under reduced pressure and excess bisaldehyde was removed by silica plug

(2:1 hexane/ethyl acetate) to afford a crude mixture containing the desired aldehyde-ester intermediate (658

mg), which was used without further purification.

The crude aldehyde (658 mg, 3.82 mmol, 1.00 equiv) was dissolved in CH2Cl2 (7.5 mL, [0.5 M]) under N2

and 1-triphenyphosphoranylidene-2-propanone (1.83 g, 5.73 mmol, 1.50 equiv) was added. The mixture

was stirred at room temperature for 16 h, after which the reaction mixture was concentrated under reduced

pressure and the resulting residue was purified by flash chromatography on silica gel (2:1 hexane/ethyl

acetate) to afford 1c (383 mg, 18% over 3 steps) as a clear oil. IR (neat): 2983, 2847, 1716, 1676, 1635 cm-

1. 1H NMR (500 MHz, Chloroform-d) δ 6.94 (dt, J = 15.7, 4.3 Hz, 1H), 6.77 (dt, J = 16.1, 4.4 Hz, 1H), 6.34

(dt, J = 16.1, 2.0 Hz, 1H), 6.10 (dt, J = 15.8, 2.0 Hz, 1H), 4.24 – 4.16 (m, 6H), 2.28 (s, 3H), 1.30 (t, J = 7.1

Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ 198.1, 166.2, 143.5, 142.3, 130.4, 121.7, 69.5, 69.5, 60.6,

27.5, 14.4. HRMS-ESI (m/z): [M+Na]+ calcd for C11H16NaO4+, 235.0941; found, 235.0920.

Ethyl (2E,7E)-9-oxodeca-2,7-dienoate (1d): To a solution of (E)-7-oxooct-5-enal11 (1.00 g, 7.13 mmol, 1.00

equiv) in CH2Cl2 (15 mL, [~0.5 M]) under N2 was added (carbethoxymethylene)triphenylphosphorane (3.73

g, 10.7 mmol, 1.50 equiv). The reaction mixture was stirred at room temperature for 16 h, after which the

reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash

chromatography on silica gel (3:1 hexane/ethyl acetate) to afford 1d (948 mg, 63% yield) as a clear oil.

Spectral characterization data matches previously reported data for the same compound.12

S7

III. Rh(III)-Catalyzed Coupling Reactions

Procedure for the synthesis of the conjugate addition product 3a (Table 1, entry 1):

In a N2-filled glove box, an oven-dried 0.5-2.0 mL Biotage® microwave vial with a triangular stir bar (1 x

0.5 cm) was charged with the bis-Michael acceptor 1a (36.5 mg, 0.10 mmol, 1.0 equiv), 2-(m-tolyl)pyridine

2a (25.4 mg, 0.15 mmol, 1.5 equiv), [Cp*RhCl2]2 (3.1 mg, 0.005 mmol, 0.050 equiv), AgSbF6 (6.9 mg,

0.020 mmol, 0.20 equiv), AcOH (1 mg, 0.02 mmol, 0.2 equiv) and 1,4-dioxane (200 μL, [0.5 M]). The vial

was then sealed and placed in a preheated 60 oC oil bath. After stirring for 20 h, the reaction vial was

removed from the oil bath and cooled to ambient temperature. The reaction mixture was filtered through a

pad of celite eluting with EtOAc, concentrated, and purified by silica gel chromatography (1:1

hexanes/ethyl acetate) to provide the product 3a (32.3 mg, 60% yield) as a clear oil. IR (neat): 2981, 1714,

1339, 1268, 1157 cm-1. 1H NMR (500 MHz, Chloroform-d) δ 8.55 (d, J = 4.8 Hz, 1H), 7.77 (t, J = 7.5 Hz,

1H), 7.57 (d, J = 7.9 Hz, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.28 – 7.17 (m, 5H), 7.11 (s, 1H), 6.41 (dt, J = 15.8,

6.1 Hz, 1H), 5.52 (d, J = 15.7 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.82 – 3.62 (m, 3H), 3.46 (t, J = 12.8 Hz,

1H), 3.20 – 3.06 (m, 2H), 2.88 (dd, J = 17.4, 8.0 Hz, 1H), 2.38 (s, 3H), 2.34 (s, 3H), 2.06 (s, 3H), 1.23 (t, J

= 7.1 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 207.3, 165.4, 160.0, 148.8, 143.6, 141.8, 141.0, 136.7,

136.64, 136.62, 136.2, 131.0, 129.9, 129.7, 127.3, 126.7, 124.6, 123.9, 122.2, 60.5, 53.7, 48.4, 46.5, 34.0,

30.5, 21.6, 21.1, 14.3. HRMS-ESI (m/z): [M+H]+ calcd for C30H35N2O5S+, 535.2261; found, 535.2266.

General procedure for the addition/cyclization sequence:


0.5 cm) was charged with the indicated bis-Michael acceptor (1) (0.20 mmol, 1.0 equiv), the indicated C–

H activation substrate (2) (0.30 mmol, 1.5 equiv), [Cp*RhCl2]2 (6.2 mg, 0.010 mmol, 0.050 equiv), AgSbF6

(13.7 mg, 0.040 mmol, 0.20 equiv), AcOH (2.4 mg, 0.040 mmol, 0.20 equiv) and 1,4-dioxane (400 μL, [0.5

M]). The vial was then sealed and placed in a preheated 60 oC oil bath. After stirring for 20 h, BnNH2 (22

S8

μL, 0.20 mmol, 1.0 equiv) and H2O (20 uL [reaction solvent becomes ~5% H2O in dioxane]) were added

at 60 oC. After stirring for an additional 20 h at 60 oC (40 h total), the reaction vial was removed from the

oil bath and cooled to ambient temperature. The reaction mixture was filtered through a pad of celite eluting

with EtOAc, concentrated, and purified by silica gel chromatography to give the indicated product (4).

(±)-4a: The general procedure was followed using the bis-Michael

acceptor 1a (73.1 mg, 0.200 mmol, 1.00 equiv) and 2-(m-tolyl)pyridine 2a

(50.8 mg, 0.300 mmol, 1.50 equiv). Purification by silica gel

chromatography (1:1 hexanes/ethyl acetate) provided the product 4a (96.0

mg, 90% yield) as a white solid (mp: 83 – 85 oC). IR (neat): 2980, 1728,

1711, 1381, 1184 cm-1. 1H NMR (500 MHz, Chloroform-d) δ 8.71 (d, J =

4.8 Hz, 1H), 7.81 (t, J = 7.7 Hz, 1H), 7.58 (app d, J = 8.1 Hz, 3H), 7.33 – 7.23 (m, 3H), 7.15 (s, 1H), 7.08

(d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 4.12 – 4.04 (m, 3H), 3.82 (d, J = 11.6 Hz, 1H), 3.37 (td, J =

11.4, 4.6 Hz, 1H), 3.08 (dd, J = 11.7, 4.1 Hz, 1H), 2.80 – 2.75 (m, 1H), 2.55 – 2.44 (m, 2H), 2.42 (s, 3H),

2.31 (s, 3H), 2.16 (t, J = 11.5 Hz, 1H), 2.05 (dd, J = 17.5, 3.7 Hz, 1H), 1.96 (s, 3H), 1.23 (t, J = 7.1 Hz,

3H). 13C NMR (126 MHz, Chloroform-d) δ 207.9, 172.3, 159.4, 149.3, 143.3, 141.7, 136.5, 136.3, 135.1,

133.9, 131.1, 129.6, 129.0, 127.6, 125.2, 123.8, 122.0, 60.6, 55.8, 51.9, 50.2, 34.5, 31.9, 31.1, 30.2, 21.4,

20.8, 14.1. HRMS-ESI (m/z): [M+H]+ calcd for C30H35N2O5S+, 535.2261; found, 535.2272.

(±)-4b: A modification of the general procedure was followed. In a N2-

filled glove box, an oven-dried 0.5-2.0 mL Biotage® microwave vial with

a triangular stir bar (1 x 0.5 cm) was charged with the bis-Michael acceptor

1b (75.9 mg, 0.200 mmol, 1.00 equiv), 2-(m-tolyl)pyridine 2a (50.8 mg,

0.300 mmol, 1.50 equiv), [Cp*RhCl2]2 (6.2 mg, 0.010 mmol, 0.050 equiv),

AgSbF6 (13.7 mg, 0.040 mmol, 0.20 equiv), AcOH (4.8 mg, 0.080 mmol,

0.40 equiv) and 1,4-dioxane (400 μL, [0.5 M]). The vial was then sealed and placed in a preheated 60 oC

oil bath. After stirring for 20 h, BnNH2 (22 μL, 0.20 mmol, 1.0 equiv) and H2O (40 uL [reaction solvent

becomes ~10% H2O in dioxane]) were added at 60 oC. After stirring for an additional 20 h at 60 oC (40 h

total), the reaction vial was removed from the oil bath and cooled to ambient temperature. The reaction

mixture was filtered through a pad of celite eluting with EtOAc, concentrated, and purified by silica gel

chromatography (1:1 hexane/ethyl acetate) to provide the product 4b (88.5 mg, 81% yield) as a white solid

(mp: 154 – 155 oC). IR (neat): 2978, 2856, 1728, 1704, 1588 cm-1. 1H NMR (500 MHz, Chloroform-d) δ

8.72 (d, J = 4.8 Hz, 1H), 7.81 (td, J = 7.7, 1.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H),

7.33 – 7.25 (m, 3H), 7.15 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 4.13 – 4.00 (m, 3H),

3.79 (d, J = 11.8 Hz, 1H), 3.40 (td, J = 11.4, 4.6 Hz, 1H), 3.08 (dd, J = 11.7, 4.1 Hz, 1H), 2.77 – 2.71 (m,

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1H), 2.54 – 2.42 (m, 3H), 2.41 (s, 3H), 2.30 (s, 3H), 2.17 – 2.00 (m, 3H), 1.22 (t, J = 7.1 Hz, 3H), 0.82 (t,

J = 7.2 Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ 210.6, 172.5, 159.3, 149.4, 143.4, 141.7, 136.5,

136.3, 134.9, 133.5, 131.1, 129.6, 129.0, 127.6, 125.1, 123.8, 122.0, 60.7, 54.7, 52.0, 50.4, 36.2, 34.3, 32.1,

31.2, 21.5, 20.9, 14.1, 7.4. HRMS-ESI (m/z): [M+H]+ calcd for C31H37N2O5S+, 549.2418; found, 549.2388.

(±)-4c: The general procedure was followed using the bis-Michael

acceptor 1c (42.4 mg, 0.200 mmol, 1.00 equiv) and 2-(m-tolyl)pyridine 2a


chromatography (1:1 hexanes/ethyl acetate) provided the product 4c (52.0

mg, 68% yield) as a tan solid (mp: 86 – 87 oC). IR (neat): 2981, 2913,


4.7 Hz, 1H), 7.80 (td, J = 7.7, 1.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.30 – 7.26 (m, 1H), 7.13 (app s, 3H),

4.07 (q, J = 7.1 Hz, 2H), 4.01 (dd, J = 11.4, 4.5 Hz, 1H), 3.91 (d, J = 11.4 Hz, 1H), 3.61 (d, J = 11.6 Hz,

1H), 3.48 – 3.34 (m, 2H), 3.22 (t, J = 10.9 Hz, 1H), 2.65 – 2.58 (m, 1H), 2.49 (dd, J = 17.0, 9.7 Hz, 1H),

2.32 (s, 3H), 2.10 – 2.03 (m, 1H), 2.03 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, Chloroform-

d) δ 208.4, 172.6, 159.7, 149.2, 141.8, 136.3, 136.1, 134.3, 131.1, 129.1, 125.4, 124.3, 121.9, 73.1, 71.0,

60.5, 55.5, 34.4, 32.6, 31.0, 30.0, 20.9, 14.1. HRMS-ESI (m/z): [M+H]+ calcd for C23H28NO4+, 382.2013;

found, 382.2020.

(±)-4d: The general procedure was followed using the bis-Michael

acceptor 1d (42.1 mg, 0.200 mmol, 1.00 equiv) and 2-(m-tolyl)pyridine 2a


chromatography (3:1 hexanes/ethyl acetate) provided the product 4d (56.6

mg, 75% yield) as a tan solid (mp: 83 – 84 oC). IR (neat): 2985, 2910, 2861,

1734, 1702 cm-1. 1H NMR (400 MHz, Chloroform-d) δ 8.68 (d, J = 4.6 Hz,

1H), 7.82 – 7.69 (m, 2H), 7.30 – 7.22 (m, 1H), 7.10 (app s, 3H), 4.06 (m, 2H), 3.24 (dd, J = 11.8, 3.9 Hz,

1H), 3.10 (td, J = 11.6, 3.7 Hz, 1H), 2.79 – 2.74 (m, 1H), 2.30 (s, 3H), 2.22 – 2.07 (m, 2H), 2.01 (s, 3H),

1.94 – 1.82 (m, 1H), 1.75 – 1.45 (m, 3H), 1.38 – 1.24 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H). 13C NMR (151

MHz, Chloroform-d) δ 210.3, 172.9, 160.1, 149.1, 140.7, 139.9, 135.8, 135.2, 130.8, 129.1, 124.6, 124.5,

121.6, 60.4, 58.2, 35.1, 34.6, 32.4, 32.1, 30.7, 30.3, 20.9, 20.6, 14.2. HRMS-ESI (m/z): [M+H]+ calcd for

C24H30NO3+, 380.2220; found, 380.2246.

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(±)-4e: A modification of the general procedure was followed. In a N2-

filled glove box, an oven-dried 0.5-2.0 mL Biotage® microwave vial with

a triangular stir bar (1 x 0.5 cm) was charged with the bis-Michael acceptor

1e (54.5 mg, 0.200 mmol, 1.00 equiv), 2-(m-tolyl)pyridine 2a (50.8 mg,




oil bath. After stirring for 20 h, BnNH2 (44 μL, 0.40 mmol, 2.0 equiv) was added at 60 oC. After stirring

for an additional 20 h at 60 oC (40 h total), the reaction vial was removed from the oil bath and cooled to

ambient temperature. The reaction mixture was filtered through a pad of celite eluting with EtOAc,

concentrated, and purified by silica gel chromatography (3:1 hexane/ethyl acetate) to provide the product

4e (80.0 mg, 75% yield) as a white solid (mp: 120 – 122 oC). IR (neat): 2918, 2844, 1734, 1472, 1202 cm-

1. 1H NMR (600 MHz, Chloroform-d) δ 8.61 (d, J = 4.8 Hz, 1H), 7.55 – 7.49 (m, 2H), 7.40 – 7.36 (m, 2H),

7.35 – 7.30 (m, 2H), 7.23 (d, J = 8.2 Hz, 1H), 7.19 – 7.15 (m, 1H), 7.11 (s, 1H), 7.09 – 7.02 (m, 5H), 6.60

(d, J = 7.0 Hz, 2H), 4.19 (d, J = 15.2 Hz, 1H), 4.15 (d, J = 15.7 Hz, 1H), 4.11 – 3.98 (m, 2H), 3.39 (td, J =

11.9, 3.7 Hz, 1H), 3.25 (dd, J = 11.7, 3.7 Hz, 1H), 2.73 – 2.67 (m, 1H), 2.60 (dd, J = 15.6, 3.3 Hz, 1H),

2.41 (s, 3H), 2.27 (dd, J = 15.6, 10.3 Hz, 1H), 1.96 (d, J = 12.7 Hz, 1H), 1.69 (d, J = 11.7 Hz, 1H), 1.54 –

1.46 (m, 2H), 1.46 – 1.36 (m, 1H), 1.35 – 1.26 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz,

Chloroform-d) δ 174.0, 172.3, 160.4, 149.1, 141.7, 141.1, 140.6, 139.7, 135.5, 134.7, 131.0, 129.0, 128.5,

128.0, 127.9, 127.4, 125.98, 125.97, 124.9, 124.8, 121.4, 60.3, 56.8, 56.0, 36.4, 36.0, 32.4, 32.1, 30.4, 21.1,

20.8, 14.3. HRMS-ESI (m/z): [M+H]+ calcd for C36H39N2O2+, 531.3006; found, 531.3012.

(±)-4g: The general procedure was followed using the bis-Michael acceptor

1a (73.1 mg, 0.200 mmol, 1.00 equiv) and 2-phenylpyridine 2b (46.6 mg,

0.300 mmol, 1.50 equiv). Purification by silica gel chromatography (2:1

hexanes/ethyl acetate) provided the product 4g (66.0 mg, 63% yield) as a

viscous yellow oil. IR (neat): 2982, 1725, 1708, 1185, 1158 cm-1. 1H NMR

(400 MHz, Chloroform-d) δ 8.72 (d, J = 4.4 Hz, 1H), 7.81 (td, J = 7.7, 1.7

Hz, 1H), 7.58 (app d, J = 8.2 Hz, 3H), 7.36 – 7.23 (m, 6H), 7.14 – 7.09 (m, 1H), 4.17 – 4.03 (m, 3H), 3.82

(dt, J = 11.9, 2.3 Hz, 1H), 3.41 (td, J = 11.4, 4.5 Hz, 1H), 3.10 (dd, J = 11.8, 4.1 Hz, 1H), 2.80 – 2.76 (m,

1H), 2.56 – 2.43 (m, 2H), 2.41 (s, 3H), 2.19 (t, J = 11.3 Hz, 1H), 2.07 – 1.99 (m, 1H), 1.94 (s, 3H), 1.22 (t,

J = 7.1 Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ 208.0, 172.3, 159.3, 149.3, 143.4, 141.9, 138.1,

136.4, 133.6, 130.4, 129.6, 128.3, 127.6, 126.9, 125.2, 123.9, 122.1, 60.7, 55.7, 51.8, 50.2, 34.8, 31.8, 31.0,

30.2, 21.5, 14.1. HRMS-ESI (m/z): [M+H]+ calcd for C29H33N2O5S+, 521.2105; found, 521.2128.

S11

(±)-4h: The general procedure was followed using the bis-Michael

acceptor 1a (73.1 mg, 0.200 mmol, 1.00 equiv) and 2-(m-tolyl)pyrimidine

2c (51.1 mg, 0.300 mmol, 1.50 equiv). Purification by silica gel

chromatography (1:1 hexanes/ethyl acetate) provided the product 4h (93.4



4.8 Hz, 2H), 7.65 – 7.58 (m, 3H), 7.31 – 7.24 (m, 3H), 7.13 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H),

4.38 (dd, J = 11.5, 4.5 Hz, 1H), 4.12 – 4.06 (m, 2H), 3.97 – 3.84 (m, 2H), 3.06 (dd, J = 12.0, 4.1 Hz, 1H),

2.81 – 2.74 (m, 1H), 2.60 (dd, J = 17.5, 9.2 Hz, 1H), 2.54 (d, J = 11.6 Hz, 1H), 2.42 (s, 3H), 2.34 (s, 3H),

2.20 (t, J = 11.2 Hz, 1H), 2.09 (dd, J = 17.6, 2.3 Hz, 1H), 1.90 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR

(126 MHz, Chloroform-d) δ 207.6, 172.3, 167.0, 157.0, 143.3, 139.2, 136.6, 136.2, 134.0, 131.9, 130.1,

129.6, 127.5, 125.8, 118.8, 60.6, 56.1, 51.9, 50.4, 34.4, 32.1, 31.2, 30.1, 21.4, 20.9, 14.1. HRMS-ESI (m/z):

[M+H]+ calcd for C29H34N3O5S+, 536.2214; found, 536.2217.

(±)-4i: The general procedure was followed using the bis-Michael acceptor

1a (73.1 mg, 0.200 mmol, 1.00 equiv) and 1-(m-tolyl)-1H-pyrazole 2d


chromatography (1:1 hexanes/ethyl acetate) provided the product 4i (95.2


1710, 1182, 1165 cm-1. 1H NMR (500 MHz, Chloroform-d) δ 7.82 (s, 1H), 7.69 (s, 1H), 7.58 (d, J = 8.2

Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.13 – 7.04 (m, 3H), 6.46 (t, J = 2.1 Hz, 1H), 4.09 (m, 2H), 3.85 (dd, J =

11.6, 3.3 Hz, 1H), 3.79 (d, J = 11.5 Hz, 1H), 3.09 (td, J = 11.1, 4.5 Hz, 1H), 3.03 – 2.95 (m, 1H), 2.80 –

2.76 (m, 1H), 2.57 (d, J = 11.8 Hz, 1H), 2.47 (dd, J = 17.5, 8.9 Hz, 1H), 2.42 (s, 3H), 2.31 (s, 3H), 2.24 (t,

J = 11.1 Hz, 1H), 2.04 (dd, J = 17.4, 3.4 Hz, 1H), 1.97 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). 13C NMR (151

MHz, Chloroform-d) δ 207.9, 172.2, 143.5, 140.5, 140.2, 137.8, 133.7, 133.5, 131.2, 129.63, 129.60, 128.2,

127.6, 125.8, 106.4, 60.8, 55.4, 51.4, 49.9, 32.6, 31.8, 31.1, 30.1, 21.5, 20.7, 14.1. HRMS-ESI (m/z):

[M+H]+ calcd for C28H34N3O5S+, 524.2214; found, 524.2216.

(±)-4j: The general procedure was followed using the bis-Michael acceptor

1a (73.1 mg, 0.200 mmol, 1.00 equiv) and 1-benzyl-4-(m-tolyl)-1H-1,2,3-

triazole 2e (74.8 mg, 0.300 mmol, 1.50 equiv). Purification by prep plate

(1:2 hexanes/ethyl acetate) followed by purification by silica gel

chromatography (5:1 DCM/MTBE) provided the product 4j (62.0 mg,

50% yield) as a viscous clear oil. IR (neat): 2980, 1727, 1710, 1185, 1157

cm-1. 1H NMR (400 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.46 – 7.25 (m, 6H), 7.26

S12

(d, J = 8.1 Hz, 2H), 7.04 (d, J = 7.9 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 5.69 (d, J = 15.0 Hz, 1H), 5.65 (d, J

= 15.2 Hz, 1H), 4.13 (m, 2H), 3.84 (d, J = 11.9 Hz, 1H), 3.71 (dd, J = 11.9, 3.2 Hz, 1H), 3.51 (td, J = 11.4,

4.3 Hz, 1H), 3.11 (dd, J = 11.7, 4.0 Hz, 1H), 2.81 – 2.78 (m, 1H), 2.54 (d, J = 11.8, 1H), 2.47 (dd, J = 17.6,

8.8 Hz, 1H), 2.40 (s, 3H), 2.29 (s, 3H), 2.14 – 2.04 (m, 2H), 1.96 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR


129.2, 128.7, 128.0, 127.4, 124.9, 122.3, 60.8, 55.7, 54.3, 51.9, 50.4, 34.3, 31.9, 31.1, 30.5, 21.5, 20.8, 14.2.

HRMS-ESI (m/z): [M+H]+ calcd for C34H39N4O5S+, 615.2636; found, 615.2664.

(±)-4k: The general procedure was followed using the bis-Michael

acceptor 1a (73.1 mg, 0.200 mmol, 1.00 equiv) and N,3-

dimethylbenzamide 2f (44.8 mg, 0.300 mmol, 1.50 equiv). Purification by

prep plate (1:2 hexanes/ethyl acetate) followed by purification by silica gel

chromatography (5:1 DCM/MTBE) provided the product 4k (60.0 mg,

58% yield) as a yellow solid (mp: 80 – 83 oC). IR (neat): 3348, 2980, 1729,

1648, 1185 cm-1. 1H NMR (400 MHz, Chloroform-d) δ 7.54 (d, J = 8.2 Hz, 2H), 7.29 – 7.27 (m, 3H), 7.05

(d, J = 8.9 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.87 (d, J = 12.0 Hz, 1H), 3.76 (dd,

J = 11.7, 4.0 Hz, 1H), 3.58 (td, J = 11.4, 4.5 Hz, 1H), 3.17 – 3.09 (m, 1H), 3.03 (d, J = 4.7 Hz, 3H), 2.92 –

2.85 (m, 1H), 2.66 (dd, J = 17.4, 8.0 Hz, 1H), 2.56 (dd, J = 12.2, 1.9 Hz, 1H), 2.41 (s, 3H), 2.33 – 2.21 (m,

1H), 2.26 (s, 3H), 2.10 (t, J = 11.4 Hz, 1H), 2.04 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H). 13C NMR (151 MHz,

Chloroform-d) δ 211.0, 172.0, 169.9, 143.7, 137.92 137.3, 133.2, 133.0, 130.6, 129.7, 129.68, 127.59,

125.1, 60.9, 56.9, 52.2, 50.7, 34.0, 32.0, 31.4, 30.3, 26.5, 21.5, 20.8, 14.1. HRMS-ESI (m/z): [M+H]+ calcd

for C27H35N2O6S+, 515.2210; found, 515.2230.

(±)-4l: The general procedure was followed using the bis-Michael

acceptor 1a (73.1 mg, 0.200 mmol, 1.00 equiv) and phenyl(pyrrolidin-1-

yl)methanone 2g (52.6 mg, 0.300 mmol, 1.50 equiv). Purification by silica

gel chromatography (5:1 DCM/MTBE) provided the product 4l (70.3 mg,

65% yield) as a white solid (mp: 172 – 174 oC). IR (neat): 2975, 1716,

1707, 1619, 1185 cm-1. 1H NMR (500 MHz, Chloroform-d) δ 7.61 (d, J

= 8.1 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 7.27 – 7.17 (m, 3H), 7.13 (br d, J = 7.4 Hz, 1H), 4.11 (m, 2H), 4.07

– 3.99 (m, 1H), 3.83 (d, J = 11.9 Hz, 1H), 3.76 – 3.60 (m, 2H), 3.44 – 3.31 (m, 2H), 3.22 – 3.12 (m, 2H),

2.83 – 2.79 (m, 1H), 2.71 – 2.59 (m, 2H), 2.40 (s, 3H), 2.24 (m, 2H), 2.04 (s, 3H), 2.02 – 1.88 (m, 4H), 1.25

(t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ 208.4, 172.3, 168.8, 143.4, 138.7, 137.1, 133.6,

129.6, 129.0, 128.2, 127.7, 127.0, 126.7, 60.7, 54.9, 51.2, 50.1, 48.9, 45.6, 35.9, 31.8, 31.4, 30.4, 26.1, 24.6,

21.5, 14.1. HRMS-ESI (m/z): [M+H]+ calcd for C29H37N2O6S+, 541.2367; found, 541.2389.

S13

(±)-4m: The general procedure was followed using the bis-Michael

acceptor 1a (73.1 mg, 0.200 mmol, 1.00 equiv) and (4-

methoxyphenyl)(pyrrolidin-1-yl)methanone 2k (61.6 mg, 0.300 mmol,

1.50 equiv). Purification by silica gel chromatography (5:1 DCM/MTBE)

provided the product 4m (62.1 mg, 54% yield) as a tan solid (mp: 203 –

204 oC). IR (neat): 2928, 2843, 1732, 1711, 1614, 1605 cm-1. 1H NMR

(500 MHz, Chloroform-d) δ 7.61 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.3 Hz, 1H),

6.74 – 6.67 (m, 2H), 4.10 (m, 2H), 4.00 – 3.93 (m, 1H), 3.78 (app d, J = 9.6 Hz, 1H), 3.76 (s, 3H), 3.72 –

3.57 (m, 2H), 3.42 – 3.36 (m, 2H), 3.21 – 3.10 (m, 2H), 2.80 – 2.77 (m, 1H), 2.67 – 2.62 (m, 2H), 2.41 (s,

3H), 2.36 – 2.26 (m, 1H), 2.22 (dd, J = 17.3, 4.3 Hz, 1H), 2.05 (s, 3H), 2.02 – 1.88 (m, 4H), 1.25 (t, J = 7.1

Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ 208.4, 172.3, 168.9, 159.8, 143.4, 139.3, 133.5, 129.6,

129.1, 128.2, 127.6, 126.8, 111.0, 60.7, 55.3, 54.8, 50.8, 50.0, 49.1, 45.7, 35.7, 31.7, 31.5, 30.4, 26.2, 24.7,

21.5, 14.1. HRMS-ESI (m/z): [M+Na]+ calcd for C30H38N2NaO7S+, 593.2292; found, 593.2281.

(±)-4n: The general procedure was followed using the bis-Michael

acceptor 1a (73.1 mg, 0.200 mmol, 1.00 equiv) and pyrrolidin-1-yl(m-

tolyl)methanone 2h (56.8 mg, 0.300 mmol, 1.50 equiv). Purification by

silica gel chromatography (5:1 DCM/MTBE) provided the product 4n

(82.6 mg, 74% yield) as a white solid (mp: 186 – 187 oC). IR (neat): 2981,

1729, 1709, 1619, 1607 cm-1. 1H NMR (500 MHz, Chloroform-d) δ 7.61

(d, J = 8.1 Hz, 2H), 7.27 (d, J = 7.8 Hz, 2H), 7.06 – 6.97 (m, 3H), 4.15 – 4.08 (m, 2H), 4.05 – 3.96 (m, 1H),

3.83 (d, J = 12.0 Hz, 1H), 3.76 – 3.60 (m, 2H), 3.44 – 3.36 (m, 1H), 3.30 (td, J = 11.1, 4.4 Hz, 1H), 3.21 –

3.13 (m, 2H), 2.84 – 2.78 (m, 1H), 2.71 – 2.57 (m, 2H), 2.41 (s, 3H), 2.28 (s, 3H), 2.26 – 2.14 (m, 2H), 2.05

(s, 3H), 2.03 – 1.89 (m, 4H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 208.4, 172.3,

168.9, 143.3, 138.5, 136.7, 133.89, 133.85, 129.62, 129.55, 127.6, 127.3, 126.4, 60.7, 54.9, 51.2, 50.1, 48.8,

45.6, 35.6, 31.9, 31.5, 30.3, 26.1, 24.6, 21.4, 20.8, 14.1. HRMS-ESI (m/z): [M+H]+ calcd for C30H39N2O6S+,

555.2523; found, 555.2516.

(±)-4o: The general procedure was followed using the bis-Michael

acceptor 1a (73.1 mg, 0.200 mmol, 1.00 equiv) and (3-

bromophenyl)(pyrrolidin-1-yl)methanone 2i (76.2 mg, 0.300 mmol, 1.50

equiv). Purification by silica gel chromatography (5:1 DCM/MTBE)

provided the product 4o (80.9 mg, 65% yield) as a white solid (mp: 103 –

104 oC). IR (neat): 2974, 1729, 1709, 1624, 1185 cm-1. 1H NMR (400

MHz, Chloroform-d) δ 7.60 (d, J = 8.4 Hz, 2H), 7.38 – 7.33 (m, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.01 – 6.99

S14

(m, 1H), 4.14 – 4.09 (m, 2H), 4.05 – 3.95 (m, 1H), 3.82 (d, J = 11.3 Hz, 1H), 3.76 – 3.59 (m, 2H), 3.48 –

3.40 (m, 1H), 3.30 (td, J = 10.9, 4.5 Hz, 1H), 3.24 – 3.08 (m, 2H), 2.86 – 2.79 (m, 1H), 2.70 – 2.55 (m,

2H), 2.41 (s, 3H), 2.25 – 2.11 (m, 2H), 2.05 (s, 3H), 2.03 – 1.91 (m, 4H), 1.26 (t, J = 7.2, 3H). 13C NMR


120.6, 60.8, 54.9, 50.9, 50.1, 48.9, 45.7, 35.4, 31.7, 31.4, 30.2, 26.1, 24.6, 21.5, 14.1. HRMS-ESI (m/z):

[M+H]+ calcd for C29H36BrN2O6S+, 619.1472; found, 619.1489.

(±)-4p: The general procedure was followed using the bis-Michael

acceptor 1a (73.1 mg, 0.200 mmol, 1.00 equiv) and pyrrolidin-1-yl(3-

(trifluoromethyl)phenyl)methanone 2j (73.0 mg, 0.300 mmol, 1.50

equiv). Purification by silica gel chromatography (5:1 DCM/MTBE)

provided the product 4p (70.1 mg, 58% yield) as a white solid (mp: 92 –

94 oC). IR (neat): 2977, 1731, 1710, 1628, 1155 cm-1. 1H NMR (500 MHz,

Chloroform-d) δ 7.62 (d, J = 8.5 Hz, 2H), 7.52 – 7.47 (m, 2H), 7.31 – 7.22 (m, 3H), 4.13 (m, 2H), 4.08 –

4.00 (m, 1H), 3.86 (d, J = 11.8 Hz, 1H), 3.78 – 3.62 (m, 2H), 3.48 – 3.37 (m, 2H), 3.23 – 3.14 (m, 2H), 2.89

– 2.83 (m, 1H), 2.71 – 2.61 (m, 2H), 2.42 (s, 3H), 2.28 – 2.11 (m, 2H), 2.07 (s, 3H), 2.05 – 1.90 (m, 4H),

1.26 (t, J = 7.3 Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ 208.0, 172.1, 167.2, 143.6, 141.7, 139.4,

133.5, 129.7, 129.6, 129.2 (q, J = 32.5 Hz), 127.6, 125.7, 123.7, 123.6 (q, J = 270.4 Hz), 60.8, 55.0, 50.9,

50.0, 48.9, 45.8, 35.9, 31.7, 31.3, 30.0, 26.2, 24.6, 21.5, 14.1. 19F NMR (471 MHz, Chloroform-d) δ -62.7.

HRMS-ESI (m/z): [M+H]+ calcd for C30H36F3N2O6S+, 609.2241; found, 609.2241.

(±)-6: A modification of the general procedure was followed. In a N2-filled

glove box, an oven-dried 0.5-2.0 mL Biotage® microwave vial with a

triangular stir bar (1 x 0.5 cm) was charged with the bis-Michael acceptor 1a

(146 mg, 0.400 mmol, 1.00 equiv), (E)-2-(but-2-en-2-yl)pyridine 5 (107 mg,




oil bath. After stirring for 20 h, BnNH2 (44 μL, 0.40 mmol, 1.0 equiv) and H2O (80 uL [reaction solvent

becomes ~10% of H2O in dioxane]) were added at 60 oC. After stirring for an additional 20 h at 60 oC (40

h total), the reaction vial was removed from the oil bath and cooled to ambient temperature. The reaction

mixture was filtered through a pad of celite eluting with EtOAc, concentrated, and purified by silica gel

chromatography (1:1 hexane/ethyl acetate) to provide the product 6 (131 mg, 66% yield) as a white solid

(mp: 152 – 154 oC). IR (neat): 2985, 2930, 1731, 1710, 1585 cm-1. 1H NMR (600 MHz, Chloroform-d) δ

8.60 (d, J = 4.5 Hz, 1H), 7.72 (td, J = 7.7, 1.9 Hz, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 7.8 Hz, 1H),

S15

7.29 (d, J = 8.0 Hz, 2H), 7.20 – 7.17 (m, 1H), 4.07 (m, 2H), 3.76 – 3.67 (m, 2H), 2.80 (td, J = 11.4, 4.6 Hz,

1H), 2.76 – 2.71 (m, 1H), 2.70 – 2.64 (m, 1H), 2.43 (s, 3H), 2.37 – 2.29 (m, 2H), 2.13 – 2.06 (m, 1H), 2.11

(s, 3H), 1.97 – 1.92 (m, 1H), 1.95 (s, 3H), 1.55 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz,

Chloroform-d) δ 207.9, 172.4, 161.7, 149.4, 143.3, 136.3, 135.6, 133.6, 129.6, 128.9, 127.6, 122.7, 121.6,

60.7, 53.7, 50.1, 48.5, 36.5, 31.6, 31.0, 29.6, 21.5, 20.1, 14.1. HRMS-ESI (m/z): [M+H]+ calcd for

C27H35N2O5S+, 499.2261; found, 499.2247.

S16

IV. Diversification Procedures

A previously reported general procedure was followed.15 Alkene substrate 6 (75 mg, 0.15 mmol, 1 equiv)

and dry pyridine (36 μL, 0.45 mmol, 3 equiv) were dissolved in dry CH2Cl2 (1.5 mL, [0.1 M]) in an oven-

dried 2-5 mL Biotage® microwave vial. The solution was cooled to -78 oC, and ozone was gently bubbled

through the solution for 3 min. After 3 min, there was full consumption of starting material by TLC and

the reaction solution was purged with O2 for 1 min. The reaction mixture was then allowed to warm to

room temperature, concentrated under a stream of N2, and purified immediately by silica gel

chromatography (2:1 hexane/ethyl acetate) to provide the product 7 (39 mg, 63% yield) as an amorphous

opaque white solid. IR (neat): 2925, 2852, 1730, 1708, 1186 cm-1. 1H NMR (600 MHz, Chloroform-d) δ

7.59 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 4.17 – 4.09 (m, 2H), 3.98 (dd, J = 11.3, 4.5 Hz, 1H),

3.79 (dt, J = 11.9, 2.3 Hz, 1H), 3.17 (td, J = 11.4, 4.4 Hz, 1H), 2.92 – 2.82 (m, 2H), 2.64 (dd, J = 17.3, 9.3

Hz, 1H), 2.43 (s, 3H), 2.37 (d, J = 11.9 Hz, 1H), 2.30 (s, 3H), 2.13 (s, 3H), 2.06 – 1.95 (m, 2H), 1.26 (t, J

= 7.2 Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ 208.2, 208.1, 171.9, 144.1, 132.6, 129.9, 127.5,

60.9, 53.6, 50.1, 47.1, 45.4, 31.5, 30.9, 30.1, 28.4, 21.5, 14.1. HRMS-ESI (m/z): [M+H]+ calcd for

C20H28NO6S+, 410.1632; found, 410.1605.

To a solution of 1,4-diketone 7 (25.0 mg, 0.0611 mmol, 1.00 equiv) in toluene (0.60 mL, [~0.10 M]) in an

oven-dried 0.5-2.0 mL Biotage® microwave vial with a triangular stir bar (1 x 0.5 cm) was added one 3 Å

molecular sieve followed by p-TsOH•H2O (12.8 mg, 0.0672 mmol, 1.10 equiv). The vial was then purged

with N2, sealed, and placed in a preheated 110 oC oil bath. The reaction mixture went from a clear

solution to a dark purple color after about 1 min. The reaction was monitored by TLC and within 15 min

there was full consumption of the starting material. After 15 min, the solution was allowed to cool to

room temperature and was diluted with NaHCO3 (2 mL) and EtOAc (2 mL). The layers were separated

and the aqueous layer was extracted with EtOAc (3 x 1 mL). The combined organic layer was washed

with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified

S17

by silica gel chromatography (5:1 hexane/ethyl acetate) to provide the product 8 (19.0 mg, 80% yield) as

a thick clear oil. IR (neat): 2920, 1728, 1373, 1350, 1159 cm-1. 1H NMR (600 MHz, Chloroform-d) δ 7.70

(d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 4.42 (d, J = 13.5 Hz, 1H), 4.21 – 4.13 (m, 2H), 3.77 (dd, J =

12.2, 2.8 Hz, 1H), 3.49 (d, J = 13.5 Hz, 1H), 3.24 – 3.19 (m, 1H), 2.75 (dd, J = 16.7, 9.6 Hz, 1H), 2.68

(dd, J = 12.2, 3.6 Hz, 1H), 2.48 – 2.41 (m, 1H), 2.43 (s, 3H), 2.13 (s, 3H), 2.10 (s, 3H), 1.28 (t, J = 7.1

Hz, 3H). 13C NMR (151 MHz, Chloroform-d) δ 172.2, 144.1, 143.6, 142.5, 133.6, 129.7, 127.6, 116.3,

111.6, 60.6, 48.5, 42.3, 37.7, 28.2, 21.5, 14.2, 11.8, 11.7. HRMS-ESI (m/z): [M+H]+ calcd for

C20H26NO5S+, 392.1526; found, 392.1503.

A previously reported procedure was modified.16 1,4-diketone 7 (20.0 mg, 0.0488 mmol, 1.00 equiv) and

BnNH2 (15.7 mg, 0.147 mmol, 3.0 equiv) were dissolved in a 6:1 mixture of MeOH/AcOH (0.25 mL,

[~0.20 M]) in an oven-dried 0.5-2.0 mL Biotage® microwave vial with a triangular stir bar (1 x 0.5 cm).

The vial was then purged with N2, sealed, and placed in a preheated 65 oC oil bath. After stirring for 18 h,

the solution was allowed to cool to room temperature and was diluted with water (1 mL) and EtOAc (1

mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 1 mL). The

combined organic layer was dried over Na2SO4, and concentrated under reduced pressure. To remove

baseline impurities, the crude residue was purified using a small silica plug eluting with 2:1 hexane/ethyl

acetate to provide the product 9 (21.3 mg, 91% yield) as a clear oil. IR (neat): 2924, 1727, 1391, 1347,

1162 cm-1. 1H NMR (500 MHz, Chloroform-d) δ 7.73 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.30 –

7.26 (m, 2H), 7.22 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 7.4 Hz, 2H), 4.94 (s, 2H), 4.54 (d, J = 13.0 Hz, 1H),

4.23 – 4.09 (m, 2H), 3.95 (d, J = 11.9 Hz, 1H), 3.56 (d, J = 13.0 Hz, 1H), 3.31 – 3.24 (m, 1H), 2.84 (dd, J

= 16.6, 10.0 Hz, 1H), 2.70 (dd, J = 12.1, 3.4 Hz, 1H), 2.48 – 2.38 (m, 1H), 2.43 (s, 3H), 2.00 (s, 3H), 1.96

(s, 3H), 1.28 (t, J = 7.2 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 172.7, 143.2, 138.2, 134.1, 129.5,

128.7, 127.7, 127.1, 125.5, 121.8, 120.4, 115.0, 110.0, 60.3, 49.0, 46.5, 43.6, 38.6, 29.3, 21.4, 14.2, 9.83,

9.77. HRMS-ESI (m/z): [M+H]+ calcd for C27H33N2O4S+, 481.2156; found, 481.2149.

S18

V. Competition Experiment


0.5 cm) was charged with the bis-Michael acceptor (36.5 mg, 0.10 mmol, 1.0 equiv), 2-phenylpyridine

(11.6 mg, 0.075 mmol, 0.75 equiv), 2-phenylpyridine-d5 (12.0 mg, 0.075 mmol, 0.75 equiv), [Cp*RhCl2]2

(3.1 mg, 0.005 mmol, 0.050 equiv), AgSbF6 (6.9 mg, 0.020 mmol, 0.20 equiv), AcOH (1 mg, 0.02 mmol,

0.2 equiv) and 1,4-dioxane (200 μL, [0.5 M]). The vial was then sealed and placed in a preheated 60 oC oil

bath. After stirring for 1 h, the reaction vial was removed from the oil bath and cooled to ambient

temperature. The reaction mixture was filtered through a pad of celite eluting with EtOAc, concentrated,

and analyzed by 1H NMR and LC-MS. The conjugate addition product was observed in 24% yield as

determined by 1H NMR spectroscopic analysis relative to SiMe3Ph as an external standard. LC-MS analysis

of the crude reaction mixture showed extensive H/D scrambling in the remaining 2-phenylpyridine starting

materials and extensive H/D scrambling in the product (expanded traces included below).

Expanded LC-MS trace of a 1:1 mixture of proteo and deutero 2-phenylpyridine starting materials

S19

Expanded LC-MS trace of concentrated reaction mixture after 1 hour reaction time. Shows extensive

H/D scrambling of remaining 2-phenylpyridine starting material.

Expanded LC-MS trace of concentrated reaction mixture after 1 hour reaction time. Shows extensive

H/D scrambling of the product.

S20

VI. X-Ray Crystallographic Data

Experimental

Single crystals of 4n were obtained by slow layer diffusion of pentane (2 mL) floated on a concentrated

solution of 4n (~10 mg) in dichloromethane (0.25 mL) in a NMR tube over the course of 3 days.

Room temperature diffraction data (ω-scans) were collected on a Rigaku MicroMax-007HF diffractometer

coupled to a Saturn994+ CCD detector with Cu Kα (λ = 1.54178 Å) for the structure of 007-16028. The

diffraction images were processed and scaled using the Rigaku CrystalClear software (CrystalClear and

CrystalStructure; Rigaku/MSC: The Woodlands, TX, 2005). This data was collected at room temperature.

Many crystals were tried at several temperatures (-180, -80, and -50 degrees Celsius); all crystals cracked

under the nitrogen cold-stream. The structure was solved with SHELXT and was refined against F2 on all

data by full-matrix least squares with SHELXL (Sheldrick, G. M. Acta Cryst. 2008, A64, 112–122). All

non-hydrogen atoms were refined anisotropically. Hydrogen atoms were included in the model at

geometrically calculated positions and refined using a riding model. The isotropic displacement parameters

of all hydrogen atoms were fixed to 1.2 times the U value of the atoms to which they are linked (1.5 times

for methyl groups). The ester group with atoms O5, O6, C28, C29, and C30 is disordered over two positions.

The atoms that have been modeled in two positions are distinguished by the suffixes "a" and "b". A free

variable was used to refine the site occupancies of the two positions. The occupancies converges at values

of 0.23(1) and 0.77(1) for "a" and "b", respectively. The tensor direction of the ellipsoids was expected to

be similar within the two models and a rigid bond restraint was applied to reflect this fact. The hydrogen

atoms for the disordered ester were placed in expected positions that complement the disorder in position

and occupancy. The full numbering scheme of compound 007-16028 can be found in the full details of the

X-ray structure determination (CIF), which is included as Supporting Information. CCDC number

XXXXXX (007-16028) contains the supplementary crystallographic data for this paper. These data can be

obtained free of charge from The Cambridge Crystallographic Data Center via

www.ccdc.cam.ac.uk/data_request/cif.

Figure S1. The complete numbering scheme of 007-16028 with 50% thermal ellipsoid probability

levels. The hydrogen atoms are shown as circles for clarity.

S21

Table S1. Crystal data and structure refinement for 007-16028.

Identification code 007-16028

Empirical formula C30 H38 N2 O6 S

Formula weight 554.68

Temperature 298(2) K

Wavelength 1.54178 Å

Crystal system Monoclinic

Space group P 21/n

Unit cell dimensions a = 12.6105(9) Å O

b = 14.0740(10) A O

c = 17.2452(12) Å O

Volume 2966.0(4) Å3

Z 4

Density (calculated) 1.242 Mg/m3

Absorption coefficient 1.330 mm-1

F(000) 1184

Crystal size 0.220 x 0.210 x 0.100 mm3

Crystal color and habit Colorless Prism

Diffractometer Rigaku Saturn 944+ CCD

Theta range for data collection 3.919 to 66.584∞.

Index ranges -15<=h<=15, -16<=k<=16, -20<=l<=20

Reflections collected 103343

Independent reflections 5239 [R(int) = 0.0310]

Observed reflections (I > 2sigma(I)) 4254

Completeness to theta = 66.584∞ 100.0 %

S22

Absorption correction Semi-empirical from equivalents

Max. and min. transmission 1.000 and 0.894

Solution method SHELXT-2014/5 (Sheldrick, 2014)

Refinement method SHELXL-2014/7 (Sheldrick, 2014)

Data / restraints / parameters 5239 / 30 / 383

Goodness-of-fit on F2 1.095

Final R indices [I>2sigma(I)] R1 = 0.0444, wR2 = 0.1400

R indices (all data) R1 = 0.0525, wR2 = 0.1468

Extinction coefficient n/a

Largest diff. peak and hole 0.221 and -0.422 e.Å-3

S23

Table S2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103)

for 007-16028. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor.

________________________________________________________________________________

x y z U(eq)

________________________________________________________________________________

S(1) 4636(1) 3073(1) 5966(1) 79(1)

O(1) 5601(1) 3522(2) 5852(1) 108(1)

O(2) 4619(2) 2078(1) 6101(1) 101(1)

O(3) 3133(1) 1278(1) 8077(1) 80(1)

O(4) 3918(2) 4249(1) 9347(1) 99(1)

O(5A) 6487(10) 6007(6) 8351(14) 146(8)

O(5B) 6862(4) 5529(6) 7844(2) 180(3)

O(6A) 7525(10) 4798(9) 8731(11) 91(3)

O(6B) 7369(3) 4930(3) 9042(2) 86(1)

N(1) 4342(1) 3586(1) 6739(1) 68(1)

N(2) 3162(2) 1642(1) 9350(1) 77(1)

C(1) 4531(2) 4615(1) 6835(1) 71(1)

C(2) 4664(1) 4871(1) 7707(1) 64(1)

C(3) 3612(1) 4595(1) 7955(1) 58(1)

C(4) 3294(1) 3551(1) 7779(1) 56(1)

C(5) 3303(2) 3290(1) 6917(1) 63(1)

C(6) 3556(2) 3320(1) 5133(1) 69(1)

C(7) 2686(2) 2700(2) 4926(1) 79(1)

C(8) 1845(2) 2886(2) 4273(1) 85(1)

C(9) 1846(2) 3666(2) 3793(1) 79(1)

S24

C(10) 2701(2) 4292(2) 4020(1) 85(1)

C(11) 3548(2) 4134(2) 4682(1) 80(1)

C(12) 961(2) 3798(2) 3037(2) 114(1)

C(13) 2163(1) 3336(1) 7900(1) 56(1)

C(14) 1297(2) 3954(1) 7617(1) 69(1)

C(15) 261(2) 3761(2) 7705(1) 75(1)

C(16) 34(2) 2953(1) 8078(1) 69(1)

C(17) 892(2) 2338(1) 8367(1) 67(1)

C(18) 1944(2) 2508(1) 8281(1) 57(1)

C(19) -1104(2) 2754(2) 8167(2) 98(1)

C(20) 2806(2) 1767(1) 8563(1) 63(1)

C(21) 2925(2) 2251(2) 9983(1) 88(1)

C(22) 3740(4) 1974(3) 10700(2) 170(2)

C(23) 4451(3) 1271(3) 10524(2) 135(1)

C(24) 4023(2) 953(2) 9687(2) 94(1)

C(25) 3717(2) 4840(2) 8829(1) 73(1)

C(26) 3581(3) 5854(2) 9018(2) 126(1)

C(27) 5699(2) 4429(2) 8246(1) 77(1)

C(28) 6670(2) 5065(2) 8357(1) 87(1)

C(29A) 8503(17) 5220(20) 9064(16) 134(9)

C(29B) 8354(4) 5554(4) 9214(4) 87(1)

C(30) 8764(2) 5511(2) 10057(2) 114(1)

________________________________________________________________________________

S25

Figure S2. Another perspective of the 4n crystal structure showing the indicated relative stereochemistry.

The hydrogen atoms are omitted for clarity.

S26

VII. References

1) Fujita, K.; Takahashi, Y.; Owaki, M.; Yamamoto, K.; Yamaguchi, R. Org. Lett. 2004, 6, 2785.

2) Liu, C.; Yang, W. Chem. Commun. 2009, 6267.

3) Zheng, X.; Song, B.; Xu, B. Eur. J. Org. Chem. 2010, 4376-4380.

4) Liu, P. M.; Frost, C. G. Org. Lett. 2013, 15, 5862.

5) Gower, M. L.; Crowley, J. D. Dalton Trans. 2010, 39, 2371.

6) Ackermann, L.; Lygin, A. V.; Hofmann, N. Angew. Chem. Int. Ed. 2011, 50, 6379.

7) Hesp, K. D.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2012, 14, 2304.

8) Yoshikai, N.; Yamakawa, T.; Seto, Y. Synlett 2015, 26, 340.

9) Kim, M.; Sharma, S.; Mishra, N. K.; Han, S.; Park, J.; Kim, M.; Shin, Y.; Kwak, J. H.; Han, S.

H.; Kim, I. S. Chem. Commun. 2014, 50, 11303.

10) Aroyan, C. E.; Dermenci, A.; Miller, S. J. J. Org. Chem. 2010, 75, 5784.

11) Yan, L.-H.; Dagorn, F.; Gravel, E.; Séon-Méniel, B.; Poupon, E. Tetrahedron 2012, 68, 6276.

12) Pandey, G.; Hajra, S.; Ghorai, M. K.; Jumar, K. R. J. Am. Chem. Soc. 1997, 119, 8777.

13) Suero, R.; Gorgojo, J. M.; Aurrecoechea, J. M. Tetrahedron 2002, 58, 6211.

14) Manley, D. W.; McBurney, R. T.; Miller, P.; Walton, J. C.; Mills, A.; O'Rourke, C. J. Org. Chem.

2014, 79, 1386.

15) Willand-Charnley, R.; Fisher, T. J.; Johnson, B. M.; Dussault, P. H. Org. Lett. 2012, 14, 2242.

16) Zhou, H.; Aguilar, A.; Chen, J.; Bai, L.; Liu, L.; Meagher, J. L.; Yang, C. Y.; McEachern, D.;

Cong, X.; Stuckey, J. A.; Wang, S. J. Med. Chem. 2012, 55, 6149.

S27

VIII. NMR Data

1a

S28

1a

S29

1b

S30

1b

S31

1c

S32

1c

S33

3a

S34

3a

S35

4a

S36

4a

S37

4b

S38

4b

S39

4c

S40

4c

S41

4d

S42

4d

S43

4e

S44

4e

S45

4g

S46

4g

S47

4h

S48

4h

S49

4i

S50

4i

S51

4j

S52

4j

S53

4k

S54

4k

S55

4l

S56

4l

S57

4m

S58

4m

S59

4n

S60

4n

S61

4o

S62

4o

S63

4p

S64

4p

S65

4p

S66

6

S67

6

S68

7

S69

7

S70

8

S71

8

S72

9

S73

9

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