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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