Chapter 2
71
2.1 Introduction
Asymmetric cyanation of carbonyl compounds is one of the most important C–C bond
forming reactions in organic chemistry.1
Chiral cyanohydrins are bifunctional compounds which
can be conveniently transformed to produce a number of biologically important compounds
including -hydroxy acids, esters, -hydroxy aldehydes, ketones, -amino acids2 and -
aminoalcohols.2-3
Due to the potential application of chiral cyanohydrins, in the last couple of
decades there have been spurt of excellent reports on enantioselective cyanation of carbonyl
compounds employing enzymes,3,4
synthetic peptides,3,4
organo-catalysts3 and complexes of V,
Mn, Ti, Al and lanthanide metal ions5-23
as catalysts under homogenous and heterogeneous6
conditions with various cyanide sources noticeable among them are HCN,2 NaCN,
22,24 KCN,
5c,7
trimethylsilyl cyanide (TMSCN),5a,11,25
ethyl cyanoformate5f,9a,20,26
acyl cyanide,9 acetone
cyanohydrin14
etc. Among all metal complexes Ti-salen system play vital role for cyanation
reaction. In the mechanistic studies, it has been established that for monomeric Ti-salen complex
the key transition state is bimetallic in nature, where both titanium ions take part in the catalysis
in simultaneous activation of the aldehyde and cyanide.5,23
Similar mechanism was also
visualized for monomeric V-salen complex.5,7
It is proposed that in solution, two monomeric
Ti/V-salen complexes by intermolecular association form dimeric µ-oxo species in the presence
of stoichiometric amount of water. In order to maximize the amount of bimetallic complex in
solution, we conceptualized a macrocyclic framework having two salen units covalently linked
through a flexible linker. Accordingly, in the present chapter we have synthesized chiral V(V)
dimeric macrocyclic salen complexes 1a, 1b where two salen units linked appropriately in a
macrocycle whose structure is somewhat akin to Jacobsen’s macrocyclic catalyst27
and can act
co-operatively28
within an enzyme-like chiral cavity for their use as catalysts for enantioselective
cyanation of aldehydes with KCN/NaCN and ethyl cyanoformate as cyanide sources. For the
sake of comparison, we have also synthesized monomeric salen complexes 1c, 1d in a
macrocyclic framework. For linker we used polyether motif (crown ether like) with a purpose of
activation of KCN and NaCN by trapping K+ and Na
+ ions respectively.
29 A support of this
concept was provided by Evans and Truesdale30
wherein crown ether complex of alkali metal
cyanide was found to be effective catalytic agent for the cyanation reaction. Belokon et al., also
demonstrated encouraging role of KCN/18-crown-6 complex as a co-catalyst in asymmetric
addition of achiral cyanoformates to aldehydes.31
Ding group22
reported exceptionally efficient
Chapter 2
72
Ti based chiral catalysts for enantioselective cyanation of aldehydes with TMSCN and NaCN.
Structurally these catalysts are open ended bimetallic Ti-salen complexes, where the two salen
units were linked with various linkers. Although, full characterization data for the corresponding
ligands were given, the synthesis or synthetic procedure for these ligands and their complexes
was not provided.23
Nevertheless, among all these complexes, the complex having two salen
units were oriented at 180o to one another gave best catalytic performance.
23 The chiral
macrocyclic V(V) catalysts synthesized for the present study have indeed demonstrated excellent
performance (albeit among reported vanadium based catalysts) with KCN and ethyl
cyanoformate as cyanide sources in the enantioselective cyanation of various aldehydes to give
O-protected cyanohydrins/ cyanohydrins carbonate in quantitative yields with high chiral
induction. Moreover, the V(V)macrocyclic salen complex 1b demonstrated excellent
recyclability. We have also tested structurally similar but relatively rigid macrocyclic salen
ligands 1e and 1f32
in V(V) catalyzed asymmetric cyanation of benzaldehyde which showed
relatively inferior performance.
2.2 Experimental methods
2.2.1 Materials and Methods
Vanadyl sulfate hydrate (Loba chemie, India), KCN (Merck), NaCN (Merck), ethyl
cyanoformate, benzaldehyde, 2-methoxy benzaldehyde, 3-methoxy benzaldehyde, 4-methoxy
benzaldehyde, 4-chlorobenzaldehyde, 4-flurobenzaldehyde, 2-flurobenzaldehyde,4-
bromobenzaldehyde, 2-naphthaldehyde, 1-naphthaldehyde, 2-benzyloxy benzaldehyde,
hydrocinnamaldehyde, hexanal, crotonaldehyde, 2-tert-butyl phenol, 2,4-di-tert-butyl phenol
were purchased from Aldrich Chemicals whereas 2-methyl benzaldehyde, 3-methyl
benzaldehyde and 4-methyl benzaldehyde were purchased from Merck and were used as
received. 3-tert-butyl salicylaldehyde, 3,5-di-tert-butyl salicylaldehyde and 4-chloromethyl-3-
tert-butyl salicylaldehyde were synthesized by the reported method.25
The 1R,2R-(-)-diamino
cyclohexane was resolved from the technical grade racemic trans 1,2 diamino cyclohexane by
the method as described in the literature. 25
All the solvents were dried by standard procedures,
distilled and stored under nitrogen. Microanalysis of the products was carried out on a Perkin
Elmer 2400 CHNS analyzer. The 1H NMR and
13C NMR spectra were recorded on Bruker 200
MHzor 500 MHz instruments at ambient temperature. The chemical shifts are reported in ppm
Chapter 2
73
relative to TMS(δ = 0.00) for 1H NMR and relative to the central CDCl3 resonance (δ = 77.0) for
13C NMR. FT-IR spectra were recorded on Perkin Elmer Spectrum GX spectrophotometer in
KBr window. TOF mass of the catalysts and intermediates were determined on a Micromass Q-
TOF-micro instrument where as the MALDI-TOF analysis were recorded on Voyager-DETM
STR Biospectrometry workstation, equipped with nitrogen laser (337 nm). The purity of the
solvents and aldehydes and the analysis of the cyanohydrin products were determined by gas
chromatography (GC) using a Shimadzu GC 14B instrument with a stainless-steel column (2m
long, 3mm inner diameter, 4mm outer diameter) packed with 5% SE30 (mesh size 60–80) and
equipped with an FID detector. Ultrapure nitrogen was the carrier gas (rate 30 ml/min). Injection
port and detector temperature were kept at 200 oC. Synthetic standards of the products were used
to determine the conversions by comparing the peak height and area. Flash chromatography (FC)
was carried out using neutral alumina (Grade-1). Enantiomeric excesses (ee) were determined by
HPLC (Shimadzu SCL-10AVP and Shimadzu CBM-20A) using Daicel Chiralpak OD or AD
column with 2-propanol/hexane as eluent and gas chromatography using a Shimadzu GC 2010
instrument with a Supelco Astec Chiral DEXTM
G-TA column. Optical rotations of chiral
complexes and their ligand precursors were recorded on an automatic Polarimeter (Digipol 781,
Rudolph) instrument. The following abbreviations were used to designate chemical shift
multiplicities: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad, coupling constants
are given in Hertz (Hz). NMR data of known compounds is in aggrement with literature values.
Optical rotations are reported as follow: [α]Dt (cin g per 100 mL, solvent).
2.2.2 Synthesis of chiral salen ligands (1’) (Scheme 2.1)
The synthesis of chiral ligands and its precursor is described as follows.
2.2.2.1 Synthesis of 2
Sodium hydride (60% dispersed in oil) (5.5 g, 133.2 mmol) was washed three times (3 x
50 mL) with dry THF in three neck round bottom flask under nitrogen. Trigol (5 g, 33.3 mmol)
was added along with 50 mL dry THF and stirred for 1 h resulted a white curdy mixture. 3-tert-
butyl-5(chloro methyl)-2-hydroxy benzaldehyde (15 g, 66.6 mmol) was added slowly into the
reaction mixture and stirred at room temperature for 6-8 h. After completion of the reaction THF
was removed under reduced pressure. The reddish black residue was extracted with
Chapter 2
74
dichloromethane (200 mL) and water (100 mL). The organic layer was separated and was
washed successively with 1(N) HCl and saturated solution of NaHCO3. The organic layer was
further washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure followed by purification by silica gel chromatography (100-200 mesh), (30%
EtOAc/Hexane) Yellowish viscous liquid; (yield 50%) [Found: C, 67.88; H, 7.96.C30H42O8
calcd. C, 67.90; H, 7.98%]; Rf (30% EtOAc/Hexane) 0.45;FT-IR (KBr): 2928, 1964, 1732,
1645, 1446, 1384, 1323, 520, 1093, 1032, 933, 878, 770, 711 cm–1
; 1H NMR (500 MHz, CDCl3):
δ=1.40 (18H, s, C(CH3)3), 3.65-3.70 (12H, m, CH2OCH2), 4.50(4H, s, OCH2Ar), 7.39 (2H, s,),
7.47 (2H, s,), 9.85 (2H, s, CHO), 11.76(2H, s, OH) ppm;13
C NMR (125 MHz, CDCl3): δ=196.8,
160.5, 138.1, 133.8, 130.9, 128.6, 119.0, 77.0, 72.4, 70.3, 69.2, 34.6, 28.9 ppm; MS (ESI) m/z
found 553.6 [M+Na]+.
2.2.2.2 Synthesis of 3
Sodium hydride (60% dispersed in oil) (6 g, 144.8 mmol) was washed three times (3 x 50
mL) with dry THF in three neck round bottom flask under nitrogen. 1,3 phenylenedimethanol (5
g, 36.2 mmol) was added along with 50 mL dry THF and stirred for 1 h resulted a white curdy
mixture. 3-tert-butyl-5(chloro methyl)-2-hydroxy benzaldehyde (16.4 g, 72.4 mmol) was added
slowly into the reaction mixture and stirred at room temperature for 6-8 h. After completion of
the reaction THF was removed under reduced pressure. The reddish black residue was extracted
with dichloromethane (200 mL) and water (100 mL). The organic layer was separated and was
washed successively with 1(N) HCl and saturated solution of NaHCO3. The organic layer was
further washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under
reduced pressure followed by purification by silica gel chromatography (100-200 mesh), (30%
EtOAc : Hexane). Yellowish viscous liquid, yield 55%,. [Found: C, 74.08; H, 7.34C32H38O6
calcd. C, 74.08; H, 7.34%]; Rf (30% EtOAc/Hexane) 0.53;FT-IR (KBr): 3274, 1725, 1646,
1441, 1155, 1080, 881, 709, 537 cm-1
; 1H NMR (500 MHz, CDCl3): δ=1.41 (18H, s, C(CH3)3),
4.51 (4H,s, CH2Ar), 4.50(4H, s, CH2Ar), 7.40-7.33 (6H,m, ), 7.50 (2H, s,J =1.4HZ, ), 9.85 (2H,
s, CHO), 11.78 (2H, s, OH) ppm;13
C NMR (125 MHz, CDCl3): δ=197.1, 161.1, 138.8, 134.2,
131.3, 129.3, 128.9, 127.4, 120.7, 72.0, 35.2,29.5ppm;MS (ESI) m/z found 541 [M+Na]+.
Chapter 2
75
2.2.2.3 Synthesis of 1′a
A solution of 2 (0.53 g,1.1 mmol) in dry THF (1.2 mL) was added to 1R, 2R-(+)-1,2-
diphenylethane-1,2-diamine (0.25 g,1.2 mmol) in dry (0.6 mL) THF in a single neck 50 mL
round bottom flask and was stirred at room temperature. After 2 h solvent was removed under
reduced pressure. The bright yellow solid product was extracted with dichloromethane (50 mL)
and water (50 mL). Organic layer was washed with brine and finally dried over anhydrous
Na2SO4. Dichloromethane was removed under reduced pressure followed by purification by
silica gel chromatography (100-200 mesh), (60% EtOAc/Hexane) to yield yellowish solid
product (94% yield). Melting point: 95°C; [Found: C, 74.72; H, 7.68; N, 3.93C88H108N4O12
calcd. C, 74.76; H, 7.70; N, 3.96%]; Rf (60% EtOAc/Hexane) 0.40; [α]D29
= +305.3o (c = 0.108,
CHCl3); FT-IR (KBr): 3495, 2952, 2866, 2361, 1625, 1448, 1386, 1358, 1320, 1264, 1209,
1151, 1100, 1031, 930, 871, 803, 770, 573 cm–1
; 1H NMR (200 MHz, CDCl3): δ= 1.40 (36H, s,),
3.53-3.63 (24H, m,), 4.37 (8H, s,), 4.71 (4H, s,), 6.97 (4H, s,), 7.19-7.29 (24H, m,), 8.32 (4H, s,),
13.78 (4H, br,) ppm; 13
C NMR (125 MHz, CDCl3): δ=166.7, 159.9, 139.5, 137.3, 129.8, 128.3,
128.1,127.6,118.1, 80.0, 73.1, 70.6, 69.1, 34.8, 29.3ppm; MALDI-TOF: m/z found 1414.19
[M+H]+.
2.2.2.4 Synthesis of 1′b
A solution of 2 (0.53 g,1.1 mmol) in dry THF (1.2 mL) was added to 1R,2R-(-)-1,2-
diaminocyclohexane (0.13 g,1.2 mmol) in dry (0.6 mL) THF in a single neck 50 mL round
bottom flask and was stirred at room temperature. After 2 h solvent was removed under reduced
pressure. The bright yellow solid product was extracted with dichloromethane (50 mL) and water
(50 mL). Organic layer was washed with brine and finally dried over anhydrous Na2SO4.
Dichloromethane was removed under reduced pressure followed by purification by silica gel
chromatography (100-200 mesh), (60% EtOAc/Hexane) to yield yellowish solid product (yield
96%) Melting point: 76°C; [Found:C, 71.04; H, 8.63; N, 4.57.C72H104N4O12 calcd. C, 71.02; H,
8.61; N, 4.6%]; Rf (60% EtOAc/Hexane) 0.32; [α]D30
= –165.7o (c = 0.052, CH2Cl2); FT-IR
(KBr): 3424, 2928, 2858, 2356, 1615, 1537, 1440, 1387, 1313, 1239, 1096, 940, 866, 785, 671,
569, 420 cm–1
; 1H NMR (500 MHz, CDCl3): δ= 1.38 (36H, s,),1.67–1.93 (16H, m,), 3.32 (4H,
m,), 3.55 (8H, t, J = 5,), 3.61 (16H, t, J =7,), 4.37 (8H, s,), 6.97 (4H, s,), 7.20 (4H, s,), 8.26 (4H,
Chapter 2
76
s,), 13.86 (4H, br,) ppm ;13
C NMR (125 MHz, CDCl3): δ=167.0, 161.6, 138.8, 131.2, 128.7,
119.8, 79.0,74.8, 74.0, 72.2, 70.7, 34.7, 31.0, 25.0, ppm; MALDI-TOF: m/z found 1218.19
[M+H]+.
2.2.2.5 Synthesis of 1′c
A solution of 1R, 2R-(+)-1,2-diphenylethane-1,2-diamine (0.25 g,1.2 mmol) in dry (5
mL) was added drop wise to dialdehyde 2 (0.5 g, 1.1 mmol) in dry MeOH (10 mL) in a single
neck 50 mL round bottom flask at 0 oC and after complete addition stirred at room temperature.
After 12 h solvent was removed under reduced pressure. The bright yellow solid product was
extracted with dichloromethane (50 mL) and water (50 mL). Organic layer was washed with
brine and finally dried over anhydrous Na2SO4. Dichloromethane was removed under reduced
pressure followed by purification by silica gel chromatography (100-200 mesh), (20%
EtOAc/Hexane) to yield yellowish solid product (85%yield); Melting point: 98 oC;[Found:C,
74.73; H, 7.68; N, 3.95C44H54N2O6 calcd. C, 74.76; H, 7.70; N, 3.96%]; Rf (25%
EtOAc/Hexane) 0.56; [α]D29
= +136.2o (c = 0.206, CHCl3); IR (KBr): 3439, 2926, 2860, 1616,
1553, 1443, 1267, 1094, 845, 726, 585, 464 cm–1
; 1H NMR (200 MHz, CDCl3): δ= 1.46 (18H,
s,), 3.30-3.36 (4H, m,), 3.57-3.68 (8H, m,), 4.19 (2H, d, J = 10 Hz,), 4.47 (2H, d, J = 10 Hz,),
4.56 (2H, s,), 6.72 (2H, d, J = 1.8 Hz,), 7.18-7.30 (12H, m,), 8.24 (2H, s,), 13.86 (2H, br,) ppm;
13C NMR (125 MHz, CDCl3): δ=166.8, 160.1, 139.8, 137.4, 129.2, 128.4, 128.3, 127.5, 118.3,
78.6, 72.5, 70.8, 69.0 ppm; MS (ESI): m/z found 708.45 [M+H]+.
2.2.2.6 Synthesis of 1′d
A solution of 1R,2R-(-)-1,2-diaminocyclohexane (0.13 g,1.2 mmol) in dry (5 mL) was
added drop wise to dialdehyde 2 (0.5 g, 1.1 mmol) in dry MeOH (10 mL) in a single neck 50
mL round bottom flask at 0 oC and after complete addition stirred at room temperature. After 12
h solvent was removed under reduced pressure. The bright yellow solid product was extracted
with dichloromethane (50 mL) and water (50 mL). Organic layer was washed with brine and
finally dried over anhydrous Na2SO4. Dichloromethane was removed under reduced pressure
followed by purification by silica gel chromatography (100-200 mesh), (20% EtOAc/Hexane) to
yield yellowish solid product ( yield 85%) Melting point: 104 °C; [Found:C, 71.0; H, 8.58; N,
4.58.C36H52N2O6 calcd. C, 71.02; H, 8.61; N, 4.6%]; Rf (20% EtOAc/Hexane) 0.56;[α]D30
= –
Chapter 2
77
201.0o
(c = 0.052, CH2Cl2); FT-IR (KBr): 3421, 2950, 2866, 2359, 1619, 1558, 1438, 1389,
1331, 1259, 1209, 1108, 970, 841, 768, 732, 666, 594 cm–1
; 1H NMR (500 MHz, CDCl3):
δ=1.44 (18H, s, C(CH3)3),1.73–1.91 (8H, m,), 3.23-3.25 (2H, m,), 3.31-3.33 (4H, m,), 3.51-3.62
(8H, m,), 4.19 (2H, d, J = 11 Hz,), 4.43 (2H, d, J = 11 Hz,), 6.72 (2H, s,), 7.27 (2H, s,), 8.07 (2H,
s,), 11.78 (2H, br,) ppm; 13
C NMR (125 MHz, CDCl3): δ=166.2, 160.0, 137.4, 129.8, 127.3,
118.3, 76.4, 72.3, 70.7, 69.2, 68.5, 34.8, 32.7, 29.4, 24.3 ppm; MS (ESI) m/z found 610.2
[M+H]+.
2.2.2.7 Synthesis of 1′e
A solution of 3 (0.60 g, 1.1 mmol) in dry MeOH (10 ml) was added to a solution of (1R,
2R)-(-)-1,2-diaminocyclohexane (0.131 g, 1.2 mmol; in 15 ml dry MeOH at ambient temperature
(25-30oC) and the resulting mass was stirred for 12 h . The solvent from the reaction mixture was
removed under reduced pressure. The bright yellow solid product thus obtained was taken in
dichloromethane (40 ml) and the organic layer was washed with water (2 x 40 ml), brine (40 ml)
and was dried over anhydrous Na2SO4. filtered and concentrated under reduced pressure
followed by purification by silica gel chromatography (100-200 mesh), (30% EtOAc/Hexane)
light yellow powder (Yield: 86%); Melting point: 135°C; [Found:C, 76.44; H, 8.08; N,
4.71C38H48N2O4 calcd. C, 76.48; H, 8.11; N, 4.69 %]; Rf (30% EtOAc/Hexane) 0.45; [α]D27
= –
139.5o (c = 0.8, CHCl3);FT-IR (KBr): 3436, 2930, 2859, 1629, 1443, 1267, 1159, 1079, 874,
754, 663, 421 cm-1
; 1H NMR (500 MHz, CD2Cl2): δ=1.36 (18H,s,), 1.71-1.94 (8H, m,), 3.32
(2H, m,), 4.35 (4H, s,), 4.44 (4H, s,), 7.01 (2H, s,), 7.30-7.21 (6H, m,), 8.29 (2H, s,), 13.90 (2H,
s,) ppm; 13
C NMR (125 MHz, CDCl3): δ=165.35, 160.03, 138.61, 137.31, 129.41, 128.37,
127.13, 126.95, 118.3, 72.19, 71.88, 34.75, 33.02, 29.39, 24.26 ppm; MS (ESI): m/z found
597.4[M+H]+.
2.2.2.8 Synthesis of 1′f
The ligand was prepared from 1R, 2R-(+)-1, 2-diphenylethane-1, 2-diamine according to
the synthesis of 1′b. Purification was done by silica gel chromatography (100-200 mesh), (55%
EtOAc/Hexane) to yield a light yellow powder (85%yield); Melting point: 142 °C; [Found:C,
79.48; H, 7.23; N, 4.01C46H50N2O4 calcd. C, 79.51; H, 7.25; N, 4.03%]; Rf (55%
EtOAc/Hexane) 0.36; [α]D27
= +19.4o (c = 0.8, CHCl3); FT-IR (KBr): 3434, 2954, 2863, 1626,
Chapter 2
78
1442, 1266, 1207, 1157, 1078, 1028, 874, 772, 699, 518, 421 cm-1
; 1H NMR (500 MHz,
CD2Cl2): δ =1.39 (18H, s,), 4.35 (4H, s,), 4.43 (4H, s,), 4.77 (2H, s,), 7.0 (2H, s,), 7.29-7.2 (16H,
m,), 8.33 (2H, s,), 13.84 (2H, s,) ppm; 13
C NMR (125 MHz, CDCl3): δ=167.3, 160.2, 139.6,
139.9, 137.6, 130.3, 130.0, 128.7, 128.4, 127.9, 127.4, 127.2, 118.5, 80.0, 72.4, 72.2, 35.1, 29.5,
ppm; MS (ESI): m/z found 695.32[M+H]+.
2.2.3 Synthesis of complex 1a
The ligand 1′a (0.5 mmol) was dissolved in ethanol/CH2Cl2 (3:2, 15 mL), to which an
aqueous solution of vanadyl sulfate hydrate (0.009 g, 0.5 mmol in 2 mL water) was added drop
wise under an inert atmosphere at room temperature. The resulting solution was refluxed for 4 h
and then cooled to room temperature with stirring for 2 h while opening the side arm of the
reaction flask. The solvent was removed under reduced pressure and the residue was dissolved in
CH2Cl2 (10 mL), washed with water (3 x 5 mL) and then with brine. The organic layer was dried
with anhydrous Na2SO4, filtered and evaporated to give the solid VV complex 1a (yield 64%).
[Found:C, 60.37; H, 6.48; N, 3.07; S, 3.51 C92H118N4O24S2V2 calcd. C, 60.38; H, 6.50; N, 3.06;
S, 3.50%]; [α]D29
= +764.4o (c = 0.012, CHCl3); FT-IR (KBr): 2956, 2872, 2365, 1632, 1453,
1390, 1360, 1323, 1270, 1211, 1155, 1035, 932, 875, 810, 778, 585 cm–1
; 1H NMR (200 MHz,
CDCl3): δ= 0.90-0.94 (6H,t, J= 8 Hz, )1.43 (36H, s, ), 3.59-3.72 (28H, m,), 4.53 (8H, s,), 4.83
(4H, s,), 7.12 (4H, s,), 7.23-7.35 (24H, m,), 8.38 (4H, s,) ppm; MALDI-TOF: m/z found
1678.62[C88H108N4O16V2]+4
.
2.2.4 Synthesis of complex 1b
The catalyst was prepared from 1′b according to the synthesis of 1a with 65% yield;
[Found:C, 74.72; H, 7.68; N, 3.93; S, C76H110N4O22S2V2.2H2O calcd. C, 74.76; H, 7.70; N,
3.96%]; [α]D31
= –264.9o (c = 0.01, CH2Cl2); FT-IR (KBr): 2931, 2861, 1628, 1598, 1443,
1387, 1358, 1320, 1267, 1208, 1159, 1099, 936, 868, 775, 665, 561, 517 cm–1
; 1H NMR (200
MHz, CDCl3): δ=0.92-0.96 (6H, t, J=8 Hz,), 1.42 (36H, s,), 1.74–1.95 (20H, m,), 3.63-3.68 (8H,
t, J=10 Hz,), 3.74-3.80 (16H, t, J=12 Hz,), 4.47 (8H, s,), 7.13-7.14 (4H, d, J=2 Hz,), 7.28-7.29
(4H, d, J=2 Hz,), 8.33 (4H, s,) ppm; MALDI-TOF: m/z found 1382.81
[C72H100N4O16V2.2H2O]+4
; ICP: Found: 7.34 mg/100mg calcd. 7.36 mg/100mg.
Chapter 2
79
2.2.5 Synthesis of 1c
The catalyst was prepared from 1′c according to the synthesis of 1a with 70% yield
[Found: C, 60.36; H, 6.52; N, 3.05; S, 3.48 C46H59N2O12SV2 calcd. C, 60.38; H, 6.50; N, 3.06, S,
3.50%]; [α]D29
= +845o (c = 0.015, CHCl3); IR (KBr): 2930, 2865, 1625, 1448, 1275, 1098,
870, 735, 590 cm–1
; 1H NMR (200 MHz, CDCl3): δ= 1.25 (3H, t, J= 4.4 Hz, ), 1.48 (18H, s,),
3.52-3.78 (14H, m,), 4.36-4.40 (4H, m,), 4.6 (2H, s,), 7.15 (2H, d, J = 2 Hz,), 7.23-7.35 (12H,
m,), 8.53 (2H, s,) ppm; MS (ESI): m/z found 789.3 [C44H54N2O8SV]+.
2.2.6 Synthesis of complex 1d
The catalyst was prepared from 1′d according to the synthesis of 1a with 70% yield.
[Found:C, 55.83; H, 7.08; N, 3.45; S, 3.91 C38H55N2O11SV.H2O calcd. C, 55.87; H, 7.03; N,
3.43; S, 3.93%]; [α]D31
= –1266.8o (c = 0.015, CH2Cl2);FT-IR (KBr): 2957, 2914, 2870, 2361,
1627, 1445, 1388, 1363, 1266, 1217, 1162, 1057, 1029, 949, 877, 799, 770, 647, 627, 566, 525,
cm–1
; 1H NMR (200 MHz, CDCl3): δ= 1.26 (3H, t, J= 4.6 Hz,), 1.50 (18H, s,), 1.61–2.37 (8H,
m,), 3.59-3.68 (16H, m,), 4.49-4.53 (4H, m,), 7.60 (2H, s,), 7.63 (2H, s,), 8.54 (1H, br,), 8.70
(1H, br,) ppm; MS (ESI): m/z found 691.29 [C36H50N2O7V.H2O]+2
.
2.2.7 Synthesis of 1e
The catalyst was prepared from 1′b according to the synthesis of 1a with 65% yield;
[Found:C, 60.89; H, 6.75; N, 3.56; S, 4.07 C40H53N2O9SV calcd. C, 60.90; H, 6.77; N, 3.55; S,
4.06 %]; [α]D27
= –658.5o (c = 0.016, CHCl3);FT-IR (KBr): 2936, 2862, 1637, 1447, 1270, 1165,
1085, 890, 772, 670 cm-1
; 1H NMR (200 MHz, CD2Cl2): δ=0.98-1.2 (3H, t, J= 8 Hz, ), 1.39
(18H,s,), 1.75-2.08 (8H, m,), 3.42 (4H, m,), 4.40 (4H, s,), 4.56 (4H, s,), 7.12 (2H, s,), 7.28-7.34
(6H, m,), 8.43 (2H, s,) ppm; MS (ESI): m/z found 788.28[C40H53N2O5V]+.
2.2.8 Synthesis of 1f
The catalyst was prepared from 1′b according to the synthesis of 1a with 65% yield
[Found:C, 65.01; H, 6.23; N, 3.17; S, 3,61 C48H55N2O9SV calcd. C, 65.0; H, 6.25; N, 3.16; S,
3.62%]; [α]D27
= +278o (c = 0.015, CHCl3); FT-IR (KBr): 2960, 2867, 1638, 1445, 1270, 1214,
1161, 1082, 1032, 877, 785, 710, 522 cm-1
; 1H NMR (200 MHz, CD2Cl2): δ =0.93-0.97 (3H, t,
J= 7.8 Hz, ), 1.45 (18H, s,), 3.53-3.59 (2H, q, J = 8 Hz, ), 4.41 (4H, s,), 4.50 (4H, s,), 4.85 (2H,
Chapter 2
80
s,), 7.12 (2H, s,), 7.28-7.37 (16H, m,), 8.47 (2H, s,) ppm; MS (ESI): m/z found 761.3
[C46H50N2O5SV]+.
Scheme 2.1 Synthesis of the macrocyclic catalysts (i) NaH, trigol, dry THF, N2 atm. RT, 6-8 h,
yield 55%. (ii) NaH, 1,3-phenylenedimethanol, dry THF, N2 atm. RT, 6-8 h, yield 50%. (iii) 5,
dry methanol, RT, 12 h, yield 85-88% (iv) 6, dry methanol, RT, 12h, yield 85-88%. (v) 5, dry
THF, RT, 2 h,yield 96%. (vi) 6, dry THF, RT, 2 h. (vii) vanadyl sulphate, dry ethanol, H2O, N2
atm. reflux 6 h, followed by auto oxidation, yield 65-70%.
Chapter 2
81
2.2.9 General procedure for 1a-1f catalyzed asymmetric O-acetylcyanation of aldehyde
Caution! KCN/NaCN must be used carefully in well-ventilated hood due to its high
toxicity. Catalyst (0.012 mmol) was dissolved in CH2Cl2 (1.5 mL) and the solution was cooled to
-200C. t-BuOH (2.09 mmol), H2O (1.11 mmol), aldehyde (1.2 mmol) and Ac2O (4.8 mmol) and
CH2Cl2 (0.5 mL) were added to the solution in that order. The addition of KCN or NaCN (2.4
mmol), taken in a Schlenk tube, was done slowly during 2 h, followed by addition of CH2Cl2 (0.5
mL). After the reaction was completed, the reaction mass was filtered by passing through a pad
of celite and washed with water (3 x 15 mL) followed by brine and the organic layer was
separated and dried with anhydrous Na2SO4. The solution was filtered, evaporated under reduced
pressure at ambient temperature and the O-acetylcyanohydrin product was purified by flash
column chromatography on silica gel (eluted with hexane:ethylacetate = 95:5). The enantiomeric
excess of O-acetylcyanohydrin was determined by HPLC and GC analysis.
2.2.10 General procedure for 1b catalyzed asymmetric O-acetylcyanation of aldehyde
Catalyst 1b (0.012 mmol) was dissolved in CH2Cl2 (1.5 mL) and the solution was cooled
to -20 0C. aldehyde (1.2 mmol) and 2,6-lutidine (4.8 mmol) were added to the solution in that
order. The addition of ethyl cyanoformate (2.4 mmol), was added slowly during 2 h followed by
addition of CH2Cl2 (0.5 mL). After the reaction was completed, the reaction mass was filtered by
passing through a pad of celite and washed with water (3 x 15 mL) followed by brine and the
organic layer was separated and dried with anhydrous Na2SO4. The solution was filtered,
evaporated under reduced pressure at ambient temperature and the product was purified by flash
column chromatography on silica gel (eluted with hexane:ethylacetate = 95:5). The enantiomeric
excess of cyanohydrin was determined by HPLC analysis.
2.2.11Characterization data of product
Chapter 2
82
[α]D30
= −30.5o (c =1, CH2Cl2);
1H NMR (200 MHz, CDCl3): δ= 2.11 (3H,s), 6.38 (1H,s), 7.40–
7.52 (5H,m) ppm; 13
C NMR (50 MHz, CDCl3): δ= 169.4, 132.3, 130.8, 129.7, 128.3, 116.7,
63.3, 20.8 ppm; TOF–MS (ESI+): m/z found 176.2 [M+H]+requires C10H9NO2 176.06
[M+H]+.The enantiomeric excess was determined by HPLC with an OD column at 264 nm
(Hexane: Isopropanol = 99:1, flow rate 0.8 mL/min), tR = 18.9 min (minor); tR = 20.3 min
(major)
[α]30
D= −26.22 (c =1, CH2Cl2); 1HNMR (200 MHz, CDCl3): δ= 2.17 (3H,s), 2.43 (3H, s), 6.51
(1H,s), 7.23–7.58 (4H,m) ppm; 13
C NMR (50 MHz, CDCl3): δ= 169.0, 138.2, 132.0, 131.1,
130.8, 129.2, 127.5, 113.2, 61.7, 21.0,19.5, ppm; TOF–MS (ESI+): m/z found191.03 [M+H]+
requires [C11H11NO2] 189.08 [M]+. The enantiomeric excess was determined by HPLC with an
OD column at 264nm (Hexane : Isopropanol = 99:1, flow rate 0.8 mL/min), tR = 26.2 min
(major).
[α]D30
= -57.8o(c = 0.037, CH2Cl2);
1HNMR (200 MHz, CDCl3): δ= 2.20 (3H, s,), 2.41 (3H, s,),
6.34 (1H, s,), 7.25–7.67 (4H, m,) ppm; 13
C NMR (50 MHz, CDCl3): δ= 166.2, 136.9, 133.4,
133.1, 130.9, 128.8, 127.0, 113.2, 62.7, 21.5, 20.2 ppm; TOF–MS (ESI+): m/z found191.02
[M+H]+requires [C11H11NO2] 189.21 [M]
+; The enantiomeric exess was determined by HPLC
with an OD column at 264nm (Hexane: Isopropanol = 99:1, flow rate 0.8 mL/min), tR = 31.7 min
(minor); tR = 35.8 min (major).
Chapter 2
83
[α]30
D = -23.1o(c = 1, CH2Cl2);
2-81HNMR (200 MHz, CDCl3): δ= 2.19 (3H, s,), 2.40 (3H, s,),
6.29 (1H, s,), 7.12–7.28 (4H, m,) ppm; 13
C NMR (50 MHz, CDCl3): δ= 169.2, 138.5, 132.2,
131.2, 130.9, 129.3, 127.5, 113.2, 62.1, 19.6, 21.3 ppm; TOF–MS (ESI+): m/z found191.02
[M+H]+ requires [C11H11NO2] 189.21 [M]
+; The enantiomeric excess was determined by GC
with Supelco Astec Chiral DEXTM
G-TA 30 M X 0.25mm column, injector : 200oC, detector :
200oC, column temperature 110
oC, tR = 8.6 min (major); tR = 8.9min (minor).
[α]D30
= −25.6o (c = 1, CH2Cl2);
2-81HNMR (200 MHz, CDCl3): δ= 2.13 (3H, s,), 3.85 (3H, s,),
6.68 (1H, s,), 6.91–7.57 (4H, m,) ppm; 13
C NMR (50 MHz, CDCl3): δ= 169.3, 157.2, 132.3,
129.1, 121.1, 116.7, 111.7, 68.6, 56.2, 20.8, ppm; TOF–MS (ESI+): m/z found 206.5
[M+H]+requires [C11H11NO3] 206.21 [M+H]
+; The enantiomeric excess was determined by
HPLC with an OD column at 264nm (Hexane: Isopropanol = 99:1, flow rate 0.8 mL/min), tR =
19.6 min (major); tR = 22.3 min (minor).
[α]D30
= −23.1o (c = 1, CH2Cl2);
2-81HNMR (200 MHz, CDCl3): δ= 2.16 (3H,s,), 3.83 (3H, s,),
6.37 (1H, s,), 6.96–7.39 (4H, m,) ppm; 13
C NMR (50 MHz, CDCl3): δ= 169.5 160.8, 133.7,
130.9, 120.5, 116.6, 113.9, 63.3, 56.1, 21.0 ppm; TOF–MS (ESI+): m/z found 206.3 [M+H]+
requires [C11H11NO3] 206.21 [M+H]+; The enantiomeric excess was determined by HPLC with
Chapter 2
84
an OD column at 235nm (Hexane: Isopropanol = 99:1, flow rate 0.8 mL/min), tR = 11.0 min
(minor); tR = 18.6 min (major).
[α]D27
= −24.4o (c = 1, CH2Cl2);
2-81HNMR (200 MHz, CDCl3): δ= 2.14 (3H,s), 3.83 (3H,s), 6.35
(1H,s), 6.94 (2H, d, J = 8.75 Hz); 7.44 (2H, d, J = 8.90) ppm; 13
C NMR (50 MHz, CDCl3): δ=
169.7, 161.9, 132.6, 130.3, 115.3, 115.1, 63.3, 56.1, 21.5 ppm; TOF–MS (ESI+): m/z found
205.18 [M]+ requires [C11H11NO3] 205.21 [M]
+; The enantiomeric excess was determined by
HPLC with an OD column at 215nm (Hexane: Isopropanol = 99:1, flow rate 0.8 mL/min), tR =
10.9 min (major); tR = 13.8 min (minor).
[α]D28
= -19.5o
(c = 0.130, CH2Cl2); 1H NMR (200 MHz, CDCl3): δ= 2.15 (3H, s,), 6.40 (1H,s),
7.18-7.62 (4H,m) ppm; 13
C NMR (50 MHz, CDCl3): δ= 169.5, 160.9, 130.7, 129.4, 117.3, 116.4,
68.7, 21.0, ppm; TOF–MS (ESI+): m/zfound 194.2 [M+H]+ requires [C10H8NO2F] 193.17
[M+H]+; The enantiomeric excess was determined by HPLC with an AD column at 247nm
(Hexane: Isopropanol = 99:1, flow rate 0.8 mL/min), tR = 15.3 min (major).
[α]D30
= −12.20 (c = 1, CH2Cl2);2-81
H NMR (200 MHz, CDCl3): δ= 2.15 (3H, s), 6.25 (1H,s),
7.37–7.42 (2H, d, J = 8.70), 7.44–7.49 (2H, d, J = 8.56) ppm; 13
C NMR (50 MHz, CDCl3): δ=
169.2, 132.9, 130.8, 129.9, 129.7, 116.7, 62.6, 20.8 ppm; TOF–MS (ESI+): m/z found 211.20
[M+H]+ requires [C10H8NO2Cl] 209.63 [M]
+; The enantiomeric excess was determined by HPLC
Chapter 2
85
with an OD column at 264nm (Hexane: Isopropanol = 99:1, flow rate 0.8 mL/min), tR = 25.4 min
(minor); tR = 30.4 min (major).
[α]D30
= +13.3o
(c = 0.165, CHCl3); 1H NMR (200 MHz, CDCl3): δ= 2.12 (3H,s), 5.14 (2H,s),
6.73 (1H,s), 6.98-7.02 (3H,m), 7.023-7.551 (6H,m) ppm; 13
C NMR (50 MHz, CDCl3): δ= 166.3,
155.9, 131.3, 128.6, 128.1, 127.2, 121.2, 112.6, 70.5, 58.4, 21.8 ppm; TOF–MS (ESI+):
m/zfound282.15 [M+H]+ requires [C17H15NO3] 282.31 [M+H]
+; The enantiomeric excess was
determined by HPLC with an OD column at 264nm (Hexane: Isopropanol = 99:1, flow rate 0.8
mL/min), tR = 29.1 min (major); tR = 37.4 min (minor).
1HNMR (200 MHz, CDCl3): δ= 2.21 (s, 3H), 6.57 (s, 1H), 7.47–7.67 (m, 3H), 7.95-8.047 (m,
4H) ppm; 13
C NMR (50 MHz, CDCl3): δ= 20.4, 61.3, 116.1, 122.6, 125.1, 126.6, 127.6, 129.2,
131.5, 134.0, 168.9 ppm; [α]D29
= + 20.8o(c= 0.152, isopropanol); TOF–MS(ESI+): m/zcalcd. for
[C14H11NO2] 225.08, found226.11 [M]+; The enantiomeric excess was determined by HPLC with
an OD column at 264nm (Hexane: Isopropanol = 99:1, flow rate 0.8 mL/min), tR= 40.0 min
(major).
1HNMR (200 MHz, CDCl3): δ= 2.21 (s, 3H), 6.57 (s, 1H), 7.53-7.58(m, 4H), 7.847-7.881 (m,
3H), 7.899-8.015 (m, 3H) ppm; 13
C NMR (50 MHz, CDCl3): δ= 20.3, 63.0, 116.1, 124.2, 127.8,
128.6, 129.4, 132.9, 133.9, 168.8 ppm; [α]D28
= +28.6o (c= 0.094, isopropanol); TOF–MS(ESI+):
Chapter 2
86
m/zcalcd. for [C14H11NO2] 225.08, found225.1 [M]+; The enantiomeric excess was determined
by HPLC with an OD column at 264nm (Hexane: Isopropanol = 99: 1, flow rate 0.8 mL/min),
tR= 30.0min (major).
1HNMR(500 MHz, CDCl3): δ= 2.10-2.15 (m, 2H),2.22 (s, 3H), 5.12 (t, J = 6.0, 1H), 7.17-7.33
(m, 5H) ppm; 13
C NMR (125 MHz, CDCl3): δ= 20.4, 30.8, 34.7, 64.0, 116.5, 126.9, 128.5,
129.1, 139.0, 167.6 ppm; [α]D30
= -26.2o (c= 0.046, CH2Cl2); TOF–MS(ESI+): m/zcalcd. for
[C12H13NO2] 203.24, found204.56 [M+H]; The enantiomeric excess was determined by HPLC
with an OD column at 220nm (Hexane: Isopropanol = 99: 1, flow rate 0.8 mL/min), t R = 32.9
(minor); tR = 39.5 (major).
1H NMR (200 MHz, CDCl3): δ= 1.81 (d, J = 2.6, 3H), 2.22 (s, 3H), 5.60-5.68(m, 2H), 6.14-6.23
(m, 1H) ppm; 13
C NMR (50 MHz, CDCl3): δ= 17.7, 20.5, 65.3, 115.7, 121.1, 136.5, 166.4 ppm;
[α]D29
= -29.9o(c = 0.063, CH2Cl2); TOF–MS (ESI+): m/zcalcd. for [C7H9NO2] 139.15, found
140.31 [M+H]; The enantiomeric excess was determined by GC with Supelco Astec Chiral
DEXTM
G-TA 30 M X 0.25mm column, injector : 200oC, detector : 200
oC, column temperature
70-140oC programme rate 2
oC/min, tR = 20.9 min (minor); tR = 21.6 min (major).
[α]D30
= -30.5o(c = 0.063, CH2Cl2);
1H NMR (200 MHz, CDCl3): (200 MHz, CDCl3): δ= 0.85
(3H, t, J = 6.5 Hz), 1.36-1.54 (6H,m),1.85 (2H,m), 2.20 (3H,s), 5.12(1H, t, J = 6.6 Hz) ppm; 13
C
NMR (50 MHz, CDCl3): δ= 165.7, 115.1, 64.2, 28.6, 24.4, 23.1, 20.4, 14.5ppm; TOF–MS
(ESI+): m/zfound 170.10 [M+H]+ requires [C9H15NO2] 170.22 [M+H]
+; The enantiomeric excess
Chapter 2
87
was determined by GC with Supelco Astec Chiral DEXTM
G-TA 30 M X 0.25mm column,
injector : 200oC, detector : 200
oC, column temperature 70-140
oC programme rate 2
oC/min, tR =
13.6 min (minor); tR = 21.6 min (major).
. 1
HNMR = 1.32 (t, J = 7.5, 3H), 4.25-4.30 (m, 2H), 6.26 (s, 1H), 7.43-7.54 (m, 5H)ppm.
13CNMR 14.21, 65.73, 66.48, 115.93, 127.99, 129.38, 130.74, 131.37, 153.53; The enantiomeric
excess was determined by HPLC with an OD column at 232 nm (Hexane: Isopropanol = 99:1,
flow rate 1 mL/min), tR = 16.26 min (minor); tR = 20.27 min (major).
1H NMR = 1.33 (t, J = 7.5, 3H), 2.44 (s, 3H), 4.25-4.31 (m, 2H), 6.38(s, 1H), 7.23-7.37(m,
3H), 7.55(d, J =8, 1H)ppm. 13
C NMR = 14.27, 19.06, 64.72, 65.75, 115.83, 126.93, 128.75,
129.55, 130.83, 131.48, 136.90, 153.61ppm. The enantiomeric excess was determined by HPLC
with an OD column at 264 nm (Hexane: Isopropanol = 99:1, flow rate 1 mL/min), tR = 16.1 min
(minor); tR = 20.6 min (major).
1H NMR = 1.33 (t, J = 7, 3H), 2.38 (s, 3H), 4.24-4.30 (m, 2H), 6.22(s, 1H), 7.26-7.34(m,
4H)ppm. 13
C NMR = 14.24, 21.24, 65.70, 66.53, 116.02, 125.09, 128.57, 129.26, 131.26,
131.51, 139.40, 153.57ppm. D25
= - 9.2 (c = 1.0, CHCl3). The enantiomeric excess was
determined by HPLC with an OD column at 264 nm (Hexane: Isopropanol = 99:1, flow rate 1
mL/min), tR = 16.8 min (minor); tR = 22.7 min (major).
Chapter 2
88
1H NMR = 1.33 (t, J = 7, 3H), 2.38 (s, 3H), 4.28 (q, J = 6.5, 2H), 6.22 (s, 1H), 7.24-7.26 (m,
2H), 7.42-7.43 (m, 2H) ppm.13
C NMR = 14.32, 21.53, 66.48, 65.73, 116.10, 128.12, 130.10,
141.14, 153.65ppm. The enantiomeric excess was determined by HPLC with an OD column at
264 nm (Hexane: Isopropanol = 99:1, flow rate 1 mL/min), tR = 18.8 min (minor); tR = 21.3 min
(major).
1H NMR = 1.32 (t, J = 7, 3H), 3.86 (s, 3H), 4.26-4.29 (m, 2H), 6.58 (s, 1H), 6.94(d, J = 8, 1H),
7.00-7.03 (m, 1H), 7.40-7.4(m, 1H), 7.55(dd, J = 2, 6, 1H)ppm. 13
C NMR =14.28, 55.90, 61.85,
65.57, 111.25, 116.10, 119.60, 121.09, 128.09, 132.21, 153.66, 156.89ppm. D25
+2.0 (c = 1.0,
CHCl3) HPLC analysis: The enantiomeric excess was determined by HPLC with an OD-H
column at 220 nm (Hexane: Isopropanol = 99:1, flow rate 1 mL/min), tR = 22.7 min (minor); tR =
38.3 min (major).CHIRALCEL OD-H column, hexane/isopropanol 99:1, flow rate 1 ml/ min,
wavelength 220 nm.
1H NMR = 1.33 (t, J = 7, 3H), 3.82 (s, 3H), 4.26-4.29 (m, 2H), 6.23 (s, 1H), 6.97-7.11(m, 3H),
7.33-7.36(m, 1H)ppm. 13
C NMR =14.12, 55.44, 65.65, 66.24, 113.12, 115.80, 116.38, 119.97,
130.39, 132.55, 153.41, 160.13ppm. D25
-9.6 (c = 2.0, CHCl3) 84% ee HPLC analysis: The
enantiomeric excess was determined by HPLC with an OD-H column at 220 nm (Hexane:
Isopropanol = 99:1, flow rate 1 mL/min), tR = 14.1 min (minor); tR = 18.6 min
Chapter 2
89
(major).CHIRALCEL OD-H column, hexane/isopropanol 99:1, flow rate 1 ml/ min, wavelength
225 nm.
1H NMR = 1.25 (t, J = 7, 3H), 3.75 (s, 3H), 4.18-4.21 (m, 2H), 6.13 (s, 1H), 6.88 (d, J =8.5,
2H), 7.40 (d, J = 8.5, 2H)ppm. 13
C NMR = 14.23, 55.54, 65.60, 66.26, 114.69, 116.13, 123.44,
129.85, 153.58, 161.44ppm. The enantiomeric excess was determined by HPLC with an OD-H
column at 220 nm (Hexane: Isopropanol = 99:1, flow rate 1 mL/min), tR = 7.0 min (minor); tR =
7.8 min (major).CHIRALCEL OD-H column, hexane/isopropanol 99:1, flow rate 1 ml/ min,
wavelength 274 nm.
1H NMR = 1.33 (t, J = 7, 3H), 4.28 (q, J = 7.5, 2H), 6.25 (s, 1H), 7.13-7.16( m, 2H), 7.53-7.55
(m, 2H)ppm.13
C NMR =14.23, 65.72, 66.12, 115.43, 129.66, 130.10, 137.97, 153.39ppm.
D25
- 20.1 (c = 2, CHCl3). HPLC with CHIRALCEL OD column at 205nm (Hexane:
Isopropanol = 99:1, flow rate 1 mL/min), tR = 15.8 min (minor); tR = 20.1 min (major).
1H NMR = 1.31 (t, J = 7, 3H), 4.22-4.30 (m, 2H), 6.20 (s, 1H), 7.40 (d, J = 8.5, 2H), 7.57 (d, J
= 8.5, 2H)ppm.13
C NMR =14.24, 65.78, 65.92, 115.52, 125.21, 129.60, 130.40, 132.63,
Chapter 2
90
153.38ppm. D25
= + 9.0 (c = 1.35, CHCl3). The enantiomeric excess was determined by HPLC
with an OD column at 254nm (Hexane: Isopropanol = 99:1, flow rate 0.8 mL/min), tR = 25.1 min
(minor); tR = 29.8 min (major).
1H NMR d = 1.34 (t, J = 7.5,3H), 4.28-4.33(m, 2H), 6.43 (s, 1H), 7.25 (s, 1H), 7.54-7.59 (m,
3H), 7.86-8.04 (m, 3H) ppm. 13CNMR d = 14.32, 65.87, 66.77, 116.00, 124.37, 127.29, 127.86,
128.03, 128.29, 128.63, 129.69,133.01, 134.18, 153.68ppm. D25
= + 19.32 ( c = 1.0, CHCl3)
95% ee ). The enantiomeric excess was determined by HPLC with an OD column at 254nm
(Hexane: Isopropanol = 99:1, flow rate 0.8 mL/min), tR = 41.3 min (minor); tR = 43.5 min
(major).
1HNMR(CDCl3 ) δ = 0.87-0.90 (m, 3H), 1.31-1.32 (m, 7H), 1.46-1.54 (m, 2H), 1.89-1.94 (m,
2H), 4.23-4.37(m, 2H), 5.18 (t J = 6.7 Hz, 1H). D25
=-54.0( C = 2.0, CHCl3) 81% . The
enantiomeric excess was determined by GC with Supelco Astec Chiral DEXTM
G-TA 30 M X
0.25mm column, injector : 200oC, detector : 200
oC, column temperature 70-140
oC programme
rate 2oC/min, tR = 27.1 min (minor); tR = 27.6 min (major).
2.2.12 Large scale asymmetric O-acetylcyanation of benzaldehyde with KCN catalyzed by
1b
The O-acetylcyanation of benzaldehyde at relatively higher scale (50 mmol) was
conducted in exactly same manner as described in section 4.1 except that the quantities of other
ingredients were scaled for 50 mmol of benzaldehyde in 15 mL DCM.
Chapter 2
91
2.2.13 Reuse of catalyst 1b in asymmetric O-acetylcyanation of benzaldehyde with KCN
For catalyst recycle experiments the general procedure for O-acetylcyanation of
benzaldehyde with KCN as described in section 2.2.9 was followed at ca. 3 time scale. After the
reaction was completed, the reaction mass was filtered by passing through a pad of celite and
washed with water (3 x 30 mL) followed by brine and the organic layer was separated and dried
over anhydrous Na2SO4. The solution was filtered, evaporated under reduced pressure at ambient
temperature. The catalyst was extracted with hexane to isolate the product. The remaining solid
was further washed with hexane (5 mL), dried under reduced pressure for 12 h and was used as
recovered catalyst 1b for recycle experiments.
2.3 Results and Discussion
Chiral macrocyclic ligands 1′a-1′f were synthesized as depicted in Scheme-1.
Dialdehydes 2 and 3, were synthesized in moderate yields by the reaction of 3-t-Bu-5-
chloromethyl-2-hydroxy benzaldehyde with trigol and 1,3-phenylenedimethanol respectively in
dry THF containing sodium hydride. The macrocyclic chiral salen ligands 1’c, 1’d, 1’e, 1’f were
synthesized by reacting stoichiometric amount of dialdehydes A and B with(1R,2R)-(-)-
diaminocyclohexane / (1R,2R)-(+)-1,2-diphenylethylenediamine respectively in methanol for 12
h in quantitative yield. However, the macrocyclic dimeric ligands 1′a and 1’b were obtained by
the reaction of chiral diamines5,6 with dialdehydes 2,3i n dry THF in 2 h. V(V)-complexes 1a-1f
were synthesized by the reaction of corresponding macrocyclic ligands 1′a-1′f with vanadyl
sulphate followed by auto-oxidation (Scheme 2.1).
All the monomeric and dimeric ligands 1’a-1’f used in the present study were isolated in
pure form by column chromatography and their characterization was accomplished by elemental
analysis, MALDI-TOF, 1H and
13C NMR. An attempt is also made to correlate catalyst structure
vis-à-vis catalytic performance in view of experimental results. MS and MALDI-TOF data for
ligands 1′a-f gave molecular peaks that correspond to the proposed structures. In the case of
dimeric complexes, ICP analysis of V in 1b demonstrated complete metallation of the ligand 1’b.
MS spectral analysis of monomer 1′d showed base peak at 610.1 (M+H), which matched well
with its molecular weight, while the base peak at 1218.2 (M+H) in MALDI-TOF spectra
correspond to dimer 1′b. 1H NMR spectroscopy of the ligands (Figure 2.1) 1′b and 1′d has
clearly differentiated the two ligands. A peak for -HC=N- appeared at 8.00 ppm in the case of
Chapter 2
92
1′d, whereas for ligand 1′b it was at 8.27 ppm. However, major difference in the 1H NMR
spectra of 1′d and 1′b noticed for the protons of –O-CH2-CH2-O- spacer groups and -O-CH2-
attached with the benzene ring. While the 1H NMR spectrum for 1′b gave singlet at 4.37 ppm for
-O-CH2, these protons appeared as double doublet (4.17-4.47 ppm) with geminal coupling of 12
Hz. Similarly, in 1′b protons for –O-CH2-CH2-O- appeared as two triplets (3.54-3.55 ppm and
3.60-3.63 ppm) but these were multiplet (3.30-3.35 ppm and 3.55-3.69 ppm) in the case of 1′d.
These changes in 1H NMR of the ligand 1′d can be attributed to its rigid skeleton, which restrict
flipping bonds of -O-CH2- and –O-CH2-CH2-O-, thereby making these protons chemically
different, whereas the skeleton of 1′b is flexible.
Figure 2.11H NMR spectrum comparision between ligands 1′d and 1′b. (a) NMR spectra of the
ligand 1’b where as (b) the NMR spectra of the ligand 1’d.
The macrocyclic salen ligands used in the present study were designed with the
expectation that crown ether like motif may act to trap for alkali metal ions30
and therefore can
facilitate the activation of KCN in cyanation reactions. To examine the concept experimentally,
cyanation of benzaldehyde was carried out in presence and absence of dibenzo-18-crown-6 using
earlier reported dimeric V(V) salen complex25c
as catalyst and KCN as cyanide source under
identical condition. However, the catalytic reaction in the presence of crown ether yielded the
ppm (t1)3.04.05.06.07.08.0
8.3
4.4
(a)
8.0
4.4
4.3
4.2
4.1
(b)
Chapter 2
93
cyanohydrin product in a very low ee (20%) possibly due to the enhanced background reaction.
This is to be noted that conducting the cyanation of benzaldehyde with dibenzo-18-crown-6
alone and in combination with ligand 1’d/1’b yielded racemic benzocyanohydrin.
In order to understand the role of polyether functionality in catalytic reaction KCN was
added to the CDCl3+CD3OD solution of 1’b, the signals of polyether ethylene proton signals
shifted downfield (ca. 35 Hz) as a result of binding of K+ to the oxygen atoms. Similar trend was
also observed (Figure 2.2) in 13
C spectra of 1’b with downfield shift of ca. 22 Hz for polyether
ethylene carbons. All the spectra on this aspect are given in Figure 2.3.
Figure 2.2 Partial 1H NMR (500MHz) spectra of (a) ligand 1’b, (b) ligand 1’b + KCN. in CDCl3
+ CD3CN .
Figure 2.3 Partial 13
C NMR (125MHz) spectra of (a) ligand 1’b, (b) ligand 1’b + KCN. in
CDCl3 + CD3CN .
ppm (t1)3.504.00
(a)
ppm (t1)3.504.00
(b)
ppm (t1)10203040506070
(b)
(a)
Chapter 2
94
These results indicate that polyether (crown ether like) functionality activate
KCN/NaCN, thereby, facilitate the catalytic cyanation reaction faster (TOF 19.8 h-1
as compare
to reported5 ~9.6). With this backdrop, our initial experiments were conducted with macrocyclic
monomeric vanadium complex 1d and dimeric complex 1b to catalyze asymmetric cyanation of
benzaldehyde with KCN in the presence of acetic anhydride. At first, the effect of loading of the
catalysts 1d and 1b in CH2Cl2 was carried out at 25 oC (Table 2.1, entries 1-4 and 9-12). The
data revealed that 5 mol% monomeric complex 1d gave best results in terms of yield (99%) and
enantio-induction (ee, 45%; entry 3) for the product cyanohydrin. On the other hand, the dimeric
complex 1b (having 2 salen units) with a loading of 1 mol% was found to be the best (yield,
99%; ee, 63%, entry 10). Therefore, 5 mol% of 1d (entries 5-8) and1 mol % of 1b (entries 13-16)
were used to optimize the reaction temperature. Accordingly, this reaction was conducted at
temperatures 0, -10, -20 and -30 oC, where -20
oC was found to be most suitable reaction
temperature for both the catalysts 1d and 1b (Table 2.1, entries 7, 15). We next screened the
monomeric catalysts 1c, 1e and 1f (5 mol%) and dimeric complex 1a (1 mol%) for asymmetric
cyanation of benzaldehyde as model substrate with KCN as source of cyanide in CH2Cl2 at -20
oC. The data clearly show that complex1b is better catalyst in terms of product yield and
enantioselectivity (Figure 2.4).
In homogenous catalysis the nature of solvent plays an important role on the activity and
enantioselectivity of the catalyst. It is reported in literature5 that protic solvents also play a role in
cyanation reaction. A proton source as an additive (1-2 equivalents of water and tert-butanol
with respect to catalyst) was found to have positive impact on reactivity and to some extent
enantioselectivity of the catalyst with CH2Cl2 as main solvent. However, when the asymmetric
cyanation reaction was conducted solely in protic solvents like methanol, ethanol and tert-
butanol there was a drastic decrease in enantioselectivity though these reactions more rapid
(Table 2.2, entries 3,4,9, 10 ). A possible explanation for this effect can be attributed to the
release of HCN by the reaction of protic solvent with KCN, which in turn enhances the racemic
background reaction. Other aprotic solvents, for example THF, toluene, and acetonitrile (in the
presence of water and tert-butanol as an additive) were relatively less effective than CH2Cl2 in
terms of yield and enantioselectivity.
Chapter 2
95
Table 2.1. Catalyst loading and temperature variations in the asymmetric O-acetylcyanation of
benzaldehydea
Entry Catalyst Temp.
(oC)
Catalyst
loading
(mol%)
Time
(h)
Yieldb
(%)
ee c
(%)
1 1d 25 2 7 92 40
2 1d 25 1 7 91 32
3 1d 25 5 6 99 45
4 1d 25 10 8 96 46
5 1d 0 5 12 96 68
6 1d -10 5 12 96 75
7 1d -20 5 12 97 83
8 1d -30 5 15 96 83
9 1b 25 2 3 99 62
10 1b 25 1 4 99 63
11 1b 25 0.5 6 95 60
12 1b 25 5 3 96 62
13 1b 0 1 5 99 81
14 1b -10 1 5 99 86
15 1b -20 1 5 99 92
16 1b -30 1 6 98 92 aReaction conditions: catalyst 1dor 1b, benzaldehyde (1.2 mmol), KCN (2.4 mmol), H2O (1.11 mmol), t-BuOH
(2.09 mmol), acetic anhydride (4.8 mmol) in DCM (2 mL). b Isolated yield.
c Ees were determined by HPLC on chiral OD column. The absolute configuration (S) was established by
comparison of the optical rotation values with that in the literature.25
These data on catalyst loading of 1d and 1b under similar reaction parameters strongly
suggest that the two salen units in the catalysts have some cooperative role to play.5
Chapter 2
96
Figure 2.4 Screening of catalysts activity towards asymmetric O-acetylcyanation of
benzaldehyde with KCN. Reaction conditions: catalyst mononuclear (1c,1d, 1e,1f 5 mol%) or
dinuclear (1a,1b 1 mol%), benzaldehyde (1.2 mmol), KCN (2.4 mmol), H2O (1.11 mmol), t-
BuOH (2.09 mmol), acetic anhydride (4.8 mmol) in DCM (2 mL).
Catalysts 1d and 1b enabled asymmetric cyanation reaction of a variety of aromatic and
aliphatic aldehydes as substrates with KCN as cyanide source at the best reaction conditions
given in Table 2.3 (entries 6 and 12). In general, substrates irrespective of electron donating or
withdrawing group on benzene ring attached to aldehyde functional group gave the products with
very good to excellent ee in 5-6 h with the catalyst 1b and 10-12 h with 1d. However, aldehyde
group directly appended to an aliphatic carbon gave the products in high yield but with moderate
to good ee (entries 13-15). Over all the catalyst 1b gave better performance than catalyst 1d in
terms of product yield and ee, therefore, the catalyst 1b was further explored for cyanation of
aldehydes (2a-q) using NaCN as cyanide source at the most suitable reaction conditions as given
in entry 12 of Table 2.3.
0
10
20
30
40
50
60
70
80
90
100
1a 1b 1c 1d 1e 1f
conv.(%)
ee (%)
Chapter 2
97
Table 2.2. Screening of the solvents in the asymmetric O-acetylcyanation of benzaldehydea
Entry Catalyst Solvent
(2mL)
Time
(h)
Yieldb
(%)
eec
(%)
1 1d THF 16 63 51
2 1d Toluene 12 85 58
3 1d MeOH 6 90 40
4 1d t-BuOH 6 90 45
5 1d Acetonitrile 12 58 49
6 1d Dichloromethane 12 97 83
7 1b THF 16 62 59
8 1b Toluene 12 82 65
9 1b MeOH 5 92 45
10 1b t-BuOH 5 90 50
11 1b Acetonitrile 12 62 50
12 1b Dichloromethane 5 99 92 aReaction conditions: catalyst 1d (5 mol%) or 1b (1 mol%), benzaldehyde (1.2 mmol), KCN (2.4 mmol), H2O
(1.11 mmol), t-BuOH (2.09 mmol), acetic anhydride (4.8 mmol) at -20 oC.
bIsolated yield.
cEes were determined by HPLC on chiral OD column. The absolute configuration (S) was established by
comparison of the optical rotation values with that in the literature.25
Table 2.3 Substrate scope of catalytic asymmetric O-acetylcyanation of aldehydesa
Chapter 2
98
Entry Substrate Catalyst 1d Catalyst 1b
Yieldb
(%)
Eec
(%)
Yieldb
(%)
eec
(%)
1 7a 97 83 99 (98)e 92 (90)
2 7b 98 89 98 (99) >99 (96)
3 7c 97 82 95 (95) 91(88)
4 7d 95 81 95 (93) 90 (89)
5 7e 96 86 95 (96) 97 (95)
6 7f 95 84 99 (99) 96 (95)
7 7g 94 82 97 (94) 96 (94)
8 7h 99 87 97 (96) >99 (97)
9 7j 98 84 97 (94) 92 (90)
10 7l 98 78 97 (96) 89 (85)
11 7m 99 85 99 (99) >99 (97)
12 7n 99 89 99(99) >99(98)
13 7o 98 65 96 (95) 78 (76)
14 7p 98 82 98 (98) 89(85)
15 7q 98 53d 99(97) 73
d (72)
aReaction conditions: catalyst 1d (5 mol%) or 1b (1 mol%), dichloromethane (2 mL), aldehyde (1.2 mmol),
KCN (2.4 mmol), H2O (1.11 mmol), t-BuOH (2.09 mmol), acetic anhydride (4.8 mmol) at -20 oC in 5-6 h.
b Isolated yield.
cEes were determined by HPLC on chiral OD or AD column.The absolute configuration (S) was established
by comparison of the optical rotation values with that in the literature.25
dEe was determined by GC on chiral GTA column.
e Data in the parentheses are with NaCN as a cyanide source.
2.3 Scope of organic cyanide source.
After successfully demonstrating the utility of catalysts 1d and 1b for the asymmetric
cyanation of various aldehydes with inorganic cyanide source, we explored the usefulness of 1b
(1 mol%) with organic cyanide source ethyl cyanoformate for asymmetric cyanation of
benzaldehyde as representative substrate (Table 2.4). It is known in the literature that a base as
an additive9,26
or a built-in basic site in the catalyst is vital to activate ethyl cyanoformate. In
view of the above we screened several organic and inorganic bases as co-catalyst (5 mol%) with
1b for the cyanation of benzaldehyde with ethyl cyanoformate in CH2Cl2 (entries 1-10). Very
good to excellent yield of cyanohydrins carbonate was achieved with the use of all the bases
Chapter 2
99
except for imidazole and 2-methyl imidazole where 50-60% yield was obtained in 48 h (entries 1
and 2). The use of triethylamine as a co-catalyst accelerated the cyano ethoxycarobonylation
reaction tremendously so that the reaction was over in 4 h giving the product in >99% yield
however, the reaction took non-enantioselective route (ee, 10%; entry 4). Among all the co-
catalysts used in the present study, 2,6-lutidine gave 97% product yield with moderate ee (64%).
Therefore, our subsequent studies for asymmetric cyano ethoxycarobonylation were carried out
with chiral V(V) macrocyclic salen complex 1b as catalyst and 2,6-lutidine as co-catalyst.
Further, in order to get the optimal reaction condition we carried out asymmetric cyano
ethoxycarobonylation of benzaldehyde at different temperatures, catalyst loading and co-catalyst
loading and the results are summarized in Table 2.5. At first, the catalyst loading was varied
over a range of 0.25 to 2.5 mol% keeping the co-catalyst loading at 5- 10 mol% at 25 oC to -40
oC (Table 2.5). It is evident from the results that only 0.5 mol% catalyst-loading and 5 mol% co-
catalyst is optimum (entry 7) at -20 oC.
Table 2.4 Catalyst loading and temperature variations in the synthesis of asymmetric
cyanohydrins carbonates of benzaldehydea
Entry Cocatalyst Time
(h)
Yieldb
(%)
eec
(%)
1 Imidazole 48 50 30
2 N-methylimidazole 48 60 33
3 N,N- diisopropyl amine 18 97 55
4 Triethylamine 4 >99 10
5 Pyridine 16 92 45
6 2,6-lutidine 8 97 64
7 Al2O3 48 84 35
8 Hydrotalcite 48 82 30
9 DMAP 12 95 32
10 DBU 16 88 50 aReaction conditions: catalyst 1b (0.5 mol%), benzaldehyde (1.2 mmol), EtCOOCN (1.8 mmol), additive (5
mol%) in 0.8 mL DCM (0.8 mL) at RT. bIsolated yield.
cees were determined by HPLC on chiral OD column.The absolute configuration (S) was established by comparison
of the optical rotation values with that in the literature.26
Chapter 2
100
Table 2.5 Catalyst loading and temperature variations in the synthesis of asymmetric
cyanohydrins carbonates of benzaldehyde.a
Entry Catalyst
loading
(mol%)
Cocatalyst
loading
(mol%)
Temp
(oC)
Time
(h)
Yieldb
(%)
Eec
(%)
1 2.5 5 25 8 97 64
2 1 5 25 8 97 64
3 0.5 5 25 8 97 67
4 0.25 5 25 14 93 60
5 0.5 10 25 6 98 58
6 0.5 5 0 10 96 87
7 0.5 5 -20 12 96 95
8 0.5 5 -40 18 90 95 aReaction conditions: chiral ligand 1b (0.5 mol%), benzaldehyde (1.2 mmol), 2,6-lutidine (0.13 mmol), ethyl
cyanoformate (1.8 mmol) in 0.8 mL DCM. bIsolated yield.
cees were determined by HPLC on chiral OD column.
Table 2.6 Screening of solvents for the synthesis of asymmetric cyanohydrins carbonate of
benzaldehyde with catalyst in 1b.
a
Entry Solvent Time
(h)
Yieldc
(%)
eed
(%)
1 Toluene 18 90 85
2 Toluene + isopropyl
alcoholb
12 92 82
3 Dichloromethane 12 96 95
4 Dichloromethane +
isopropyl alcoholb
10 98 80
5 THF 30 80 65
Chapter 2
101
a Reaction conditions: chiral ligand 1b (0.5 mol%), benzaldehyde (1.2 mmol), 2,6-lutidine (0.13 mmol),
ethylcyanoformate (1.8 mmol) at -20 oC.
bToluene or dichloromethane 0.5mL and isopropyl alcohol 0.3 mL.
c Isolated yield.
dees were determined by HPLC on chiral OD column.
Under the optimized reaction conditions the scope of this protocol for the cyano
ethoxycarobonylation reaction was further extended to a variety of aromatic and aliphatic
aldehydes using chiral V(V) salen complex as catalyst in the presence of 2,6-lutidine as co-
catalyst in dichloromethane at -20 oC. Data in Table 2.7 shows overall good to excellent isolated
yields (90-97%) and enantiomeric excess (85-97%). In the case of hexanal as aliphatic aldehyde
the product ethyl cyanohydrins carbonate was obtained in 81% ee and 88% isolated yield in 15 h
(entry 11).
Table 2.7 Substrate scope of catalytic asymmetric cyanohydrin carbonatesa of aldehydes with
1b under optimum reaction conditions
Entry Substrate Time
(h)
Yieldb
(%)
eec
(%)
1 7a 12 96 95
2 7b 12 97 93
3 7c 15 94 85
4 7d 12 97 96
5 7e 16 95 92
6 7f 18 90 87
7 7g 12 96 97
8 7i 16 95 93
9 7k 18 93 91
10 7n 12 95 95
11 7q 15 88 81d
Chapter 2
102
aReaction conditions: chiral ligand 1b (0.5 mol%), benzaldehyde (1.2 mmol),
ethyl cyanoformate (1.8 mmol), 2,6-lutidine (5 mol%) at -20 oC in 0.8 mL
DCM.
b Isolated yield.
c eeswere determined by HPLC on chiral OD, OD-H columns.
dee was determined by chiral GC using chiral GTA column
2.4 Reuse of complex 1b
Cyanide sources KCN and ethyl cyanoformate were used with catalyst 1b for reuse
experiments6,25
by using benzaldehyde (3.06 mmol) as model substrate in the manner described
earlier (see experimental section). In both the cases after the completion of the catalytic reaction,
the catalysts were retrieved quantitatively and reused five times with retention of
enantioselectivity. However, during catalyst recovery process there was some physical loss of the
catalyst. Since in each reuse experiment, the amount of substrate was kept constant, there was a
change in substrate to catalyst ratio which was responsible for longer reaction time in subsequent
catalytic runs (Table 2.8). As there were no changes in the ee of the product up to the 5 recycle
experiments conducted, it can be safely presumed that the catalyst structure remained unchanged.
This was further substantiated by the FT-IR of the recovered catalyst 1bwhich matched well with
the fresh catalyst.
Table 2.8 Reuse of catalysts 1b for O-acetylcyanationa and synthesis of asymmetric
cyanohydrin carbonateb of benzaldehyde
Rune
1 2 3 4 5 6
Yieldc(%) 95 (99) 95 (99) 94(98) 94(97) 93(97) 92(96)
Eed(%) 95 (92) 95 (92) 95 (92) 95 (92) 95 (92) 95 (92)
aReaction conditions: chiral catalyst1b (0.5 mol%),benzaldehyde (3.06 mmol), 2,6-lutidine (5 mol%) ethyl
cyanoformate (4.59 mmol) at -20 oC in DCM (0.8 mL).
Chapter 2
103
b catalyst 1b (1 mol%), benzaldehyde (3.06 mmol), KCN (6.12 mmol), H2O (2.22 mmol), t-BuOH (4.18 mmol),
acetic anhydride (12.24 mmol) at -20 oC in DCM (2 mL).
c Isolated yield.
dThe ees were determined by using chiralpak HPLC OD column.
e Data in parenthesis correspond to KCN as cyanide source.
2.5 Conclusion
This work has uncovered a new class of chiral macrocyclic V(V)salen complexes as
efficient, recyclable and scalable catalysts for asymmetric addition of KCN/NaCN and ethyl
cyanoformate to aldehydes. Particularly, catalyst 1b with flexible polyether linkage (a crown
ether like motif) work in cooperation to afford corresponding enantioenriched cyanohydrin
derivatives (yields up to 99%) at -20 oC. Synthetic procedure for the preparation of pre-catalysts
(corresponding macrocyclic ligands) once established was very convenient and reproducible to
get desired monomeric and dimeric ligands in reasonably high yield. Multi-gram level catalytic
runs demonstrated no change in the performance of these catalysts suggest that the present
protocol for asymmetric cyanation reaction is scalable.
Chapter 2
104
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