Enantioselective cyanoformylation of aldehydes catalyzed with solid base mediated chiral V(V) salen complexes

Article abstract of DOI:10.1002/chir.20719

Polymeric and monomeric V(V) chiral salen complexes-catalyzed enantioselective ethyl cyanoformylation of aldehydes using ethyl cyanoformate as a source of cyanide was accomplished in the presence of several basic cocatalysts viz., NaOH, KOH, basic Al

Full text of DOI:10.1002/chir.20719

CHIRALITY 22:153–158 (2010)
Enantioselective Cyanoformylation of Aldehydes Catalyzed with
Solid Base Mediated Chiral V(V) Salen Complexes
*
NOOR-UL H. KHAN, SANTOSH AGRAWAL, RUKHSANA I. KURESHY, SAYED H. R. ABDI,
KAVITA PATHAK, AND HARI C. BAJAJ
Discipline of Inorganic Materials and Catalysis, Central Salt and Marine Chemicals Research Institute (CSMCRI),
Bhavnagar, Gujarat, India
ABSTRACT
Polymeric and monomeric V(V) chiral salen complexes-catalyzed enan-
tioselective ethyl cyanoformylation of aldehydes using ethyl cyanoformate as a source
of cyanide was accomplished in the presence of several basic cocatalysts viz., NaOH,
KOH, basic Al2O3 and hydrotalcite. Excellent yield (>95%) of chiral ethyl cyanohydrin-
carbonate with high enantioselectivity up to 94% was achieved in 24–36 h when hydrotal-
cite was used as an additive. The polymeric catalyst 1 is more reactive than the mono-
meric catalyst 2 to produce chiral ethyl cyanohydrincarbonate in high optical purity.
The chiral polymeric catalyst 1 and cocatalysts hydrotalcite and basic alumina used
in this study were recoverable and recyclable several times with retention of its
C
VV
performance. Chirality 22:153–158, 2010.
2009 Wiley-Liss, Inc.
KEY WORDS: cyanoformylation; V(V) salen complex; solid base; enantioselective;
aldehydes
INTRODUCTION
cyanoformylation of aldehydes in isopropanol:chloroform
mixture as solvent at 2208C to give the products in excel-
lent yields (up to 99%) and with high enantioselectivities
(up to 91% ee). Recently, we have reported monomeric
V(V) salen complex as a catalyst for the enantioselective
cyanoformylation of aldehydes in the presence of imidaz-
ole as cocatalyst to give products in excellent yield (up to
97%) and enantioselectivity (up to 96% ee).58 Among all the
catalytic systems reported for cyanoformylation of alde-
hydes hitherto none had reported the recyclablity of the
essentially expensive catalyst which is desirable from eco-
nomic point of view. In view of our on going interest in
asymmetric cyanation reaction as well as making the cata-
lyst recyclable,59–63 we present here the use of V(V) poly-
meric and monomeric salen complexes 1 and 2 as effi-
cient catalysts for the enantioselective cyanation of alde-
hydes using ethylcyanoformate as a source of cyanide in
combination with hydrotalcite as cocatalyst. Excellent
yield (95%) and ee (94%) was achieved for the ethyl cyano-
carbonate of 2-benzyloxybenzaldehyde with the added
advantage of several times re-cyclablity of polymeric com-
plex 1 with HT and alumina.
Optically pure cyanohydrins play an important role in or-
ganic synthesis for the preparation of various versatile syn-
thetic building blocks for pharmaceuticals, agrochemicals,
insecticides,1–7 and chiral auxiliaries.8–13 Over the last two
decades, attempts were made to achieve chirally pure cya-
nohydrins of aldehydes through chiral catalytic route14–35
with different sources of cyanide viz., trimethylsilyl cya-
nide (TMSCN), hydrogen cyanide, and KCN. Among dif-
ferent catalysts used V(V) salen complex has revealed re-
markable results in terms of enantio-induction for O-tri-
methylsilyl cyanohydrins with TMSCN18–21 as a cyanide
source. However, the product O-trimethylsilyl cyanohy-
drins are less stable and can readily undergo hydrolysis to
give cyanohydrins that are prone to racemization. As a
result, currently, other sources of cyanide such as acetyl
cyanide, cyanoformate esters (ROCOCN), diethyl cyano-
phosphonate, and benzoyl cyanide have been explored to
prepare optically pure cyanohydrins with different catalytic
systems.36–57 Belokon et al.,40 has reported the ethyl cya-
noformylation of aldehydes using Ti(IV) salen complex (5
mol %) as catalyst at 2408C giving the product in high
yield with excellent enantiomeric excess (ee) in 6–48 h.
Later, Moberg and coworkers48 have significantly reduced
the time (4–12 h) for this reaction in the presence of vari-
ous Lewis bases as co-catalyst best among which was
found to be triethylamine. Feng and coworkers56 under-
took cyanoethoxycarbonylation of aldehydes catalyzed by
heterobimetallic aluminum lithium bis(binaphthoxide) and
cinchonine to give the product in excellent yield (up to
99%) with moderate to high enantioselectivity (up to 95%
ee) in short time. Feng et al. also reported the use of
Additional Supporting Information may be found in the online version of
this article.
Contract grant sponsor: DST and CSIR Network Project on Catalysis.
Contract grant sponsor: CSIR.
*Correspondence to: Noor-Ul H. Khan, Discipline of Inorganic Materials
and Catalysis, Central Salt and Marine Chemicals Research Institute
(CSMCRI), G. B. Marg, Bhavnagar 364 002, Gujarat, India.
E-mail: khan2593@yahoo.co.in
Received for publication 21 October 2008; Accepted 5 February 2009
DOI: 10.1002/chir.20719
Published online 22 April 2009 in Wiley InterScience
salen-Ti(OiPr)4 complex as catalyst in the enantioselective (www.interscience.wiley.com).
C
VV
2009 Wiley-Liss, Inc.

154
KHAN ET AL.
Synthesis of Complex 2
EXPERIMENTAL
Materials and Methods
The complex 2 was synthesized by the reported proce-
dure.19 The solution of (1R, 2R)-N,N0-bis[3, 5-di(tetr-butyl)-
salicyliden] cyclohexane-1, 2-diamine (2.7 mmol, 1.5 g) in
THF (20 ml) and vanadyl sulfate hydrate (2.7 mmol, 0.69
g) in hot ethanol (30 ml) were mixed. The resulting solu-
tion were refluxed for 2 h under inert atmosphere and
then cooled to room temperature with an extended stirring
for 12 h while opening the side arm of the reaction flask.
Solvent was completely evaporated and the residue was
dissolved in CH2Cl2 (15 ml), washed with water (3 3 5
ml) and finally with brine. The organic layer was dried
over anhydrous Na2SO4, the complex was purified by col-
umn chromatography as a dark green solid.
Vanadyl sulfate hydrate (Loba Chemie, India), Hydrotal-
cite {Mg6Al2(CO3)(OH)16ꢀ4H2O}, benzaldehyde, 4-methox-
ybenzaldehyde, 3-methoxybenzaldehyde, 2-methoxyben-
zaldehyde, 4-chlorobenzaldehyde, 4-bromobenzaldehyde,
4-fluorobenzaldehyde, crotonaldehyde, isovaraldehyde,
hexanal, 3-methyle-2-butenal, 2-ethoxybenzaldehyde, 2-
benzyloxybenzaldehyde, and ethylcyanoformate were pur-
chased from Aldrich Chemicals and were used as
received. 2-Methylbenzaldehyde, 3-methylbenzaldehyde,
and 4-methylbenzaldehyde were from Merck chemicals
where as basic Al2O3, NaOH, and KOH were from s. d.
Fine-Chemicals Limited, Mumbai (India). All the solvents
were distilled and dried by standard procedures64 and
stored under nitrogen. The synthesis and characterization
of poly [(R,R)-N,N0-bis-{3-(1,1-dimethylethyl)-5-methylene
salicylidene} cyclohexane-1,2-diamine] and its precursors
was carried out as described in Ref. 65.
Typical Experimental Procedure for the Enantioselective
Cyanoformylation of Aldehydes
A solution of V(V) salen complexes 1/2 (0.015 mmol) and
appropriate aldehyde (0.62 mmol) in dry CH2Cl2 (0.8 ml) was
stirred for 10 min at room temperature under N2 atmosphere.
To this solution, hydrotalcite/basic alumina (25 mg) was
added and the solution was cooled to 158C. To this cooled so-
lution, ethyl cyanoformate (77 ll, 0.78 mmol) was added
drop-wise over a period of 5 min. The reaction was monitored
on TLC. After completion of the reaction, the product was
purified by flash column chromatography on a silica gel col-
umn (eluent, hexane/ethyl acetate 5 90:10). The purified
products were characterized by 1H and 13C NMR which
were in agreement with the reported values (see supporting
information).42–57
Instrumentation
Microanalysis of the complex was done on CHNS ana-
lyzer, Perkin Elmer model 2400. NMR spectra were
obtained with a Bruker F113V spectrometer (500 MHz
1
and 125 MHz for H and 13C, respectively) and are refer-
enced internally with TMS. FTIR spectra were recorded
on Perkin Elmer Spectrum GX spectrophotometer in KBr
window. High-resolution mass spectra were obtained with
a LC-MS (Q-TOF) LC (Waters), MS (Micromass) instru-
ments. For the product purification, flash chromatography
was performed using silica gel 100–200 mesh purchased
from s. d. Fine-Chemicals Limited, Mumbai (India). The
product formation and quantification was determined on
capillary GC column SPB-5 (60 m) using Shimadzu 2010
with respect to internal standard (n-tridecane). Enantio-
meric excess were determined by HPLC (Shimadzu SCL-
10AVP) using Daicel Chiralpak OD and OD-H chiral col-
umns with 2-propanol/hexane as eluent. HPLC traces
were compared with racemic samples and GC analysis
CHIRALDEX G-TA (30 m, 0.25 mm) column. Optical rota-
tions were measured with a Digipol 781 Automatic Polar-
imeter, Rudolph Instrument.
RESULTS AND DISCUSSION
Chiral vanadium salen complexes 1 and 2 were synthe-
sized by the reaction of poly[(R,R)-N,N0-bis-{3-(1,1-di-
methylethyl)-5-methylene salicylidene} cyclohexane 1,2-
diamine]/(1R, 2R)-N,N0-bis[3, 5-di(tert-butyl)salicylidene]
cyclohexane-1, 2-diamine with vanadyl sulfate hydrate fol-
lowed by auto-oxidation by the reported method (see Fig.
1).19,59,60 Earlier, we58 and others46,48,49 have reported that
the presence of a cocatalyst greatly influence the chiral
metal complexes catalyzed enantioselective addition of eth-
ylcyanoformate to aldehydes. The cocatalysts used so far
for this reaction are essentially organic bases and are non-
recoverable after the catalytic run is over. We explored
Synthesis of Complex 1
The complex 1 was synthesized by the reported proce- here the use of solid base like hydrotalcite and alumina as
dure.59,60 The solution of poly[(R,R)-N,N0-bis-{3-(1,1-di- recoverable cocatalysts. Simultaneously we also used poly-
methylethyl)-5-methylene salicylidene} cyclohexane 1,2- meric V(V) salen complex as an active and recoverable cat-
diamine] (0.799 g, 1.79 mmol) was dissolved in mixed sol- alyst for the ethylcyanoformylation of aldehydes.
vent ethanol:CH2Cl2 (3:2, 15 ml) to which an aqueous solu-
Feasibility of the enantioselective cyanoformylation reac-
tion of vanadyl sulfate hydrate (0.453 g, 1.79 mmol in 2 ml tion using benzaldehyde as a model substrate with poly-
water) was added drop-wise under an inert atmosphere at meric V(V) salen complex 1 (2.5 mol %) as catalyst and vari-
room temperature. The resulting solution was refluxed for ous inorganic bases as cocatalyst at 0–258C was systemati-
4 h and then cooled to room temperature with an extended cally studied and the data are presented in Figure 2 and
stirring for 12 h while opening the side arm of the reaction Table 1. Both hydrotalcite and basic alumina were effective
flask for aerial oxidation. Solvent was completely evapo- cocatalysts; however, former was better (Table 1, Entries 1
rated and the residue was dissolved in CH2Cl2 (10 ml), and 2). The use of NaOH and KOH (Table 1, Entries 3 and
washed with water (3 3 5 ml) and finally with brine. The or- 4) as cocatalyst hasten the reaction (8–9 h) but the reaction
ganic layer was dried over anhydrous Na2SO4, filtered, and took racemic pathway (ee, 3–20%), due to the fact that alkali
evaporated to give dark green polymeric V(V) complex.
alone (Entry 5) is an active achiral catalyst for this reaction.
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE CYANOFORMYLATION OF ALDEHYDES
155
Fig. 2. Optimized reaction condition.
suggest that catalyst 1 loading 2.5 mol % and 25 mg of
hydrotalcite at 158C is optimum for this reaction.
Under the optimized reaction conditions as described
earlier (Table 1, Entry 1), we extended this protocol of
ethyl cyanoformylation reaction to a variety of aromatic and
aliphatic aldehydes using the complex 1 as catalyst. The
data in Table 2 is an indicative of applicability of this proto-
col over a range of substrates where good to excellent iso-
lated yield (88–95%) and ee (75–94%) for the products were
achieved in 21–30 h (Entries 1–24). Surprisingly, electronic
and steric factors for different substituents on the aromatic
Fig. 1. Structure of complexes 1 and 2.
In the absence of any cocatalyst, the catalyst 1 failed to cata-
lyze this reaction (Entry 8). Investigation of reaction parame-
ters viz., catalyst and hydrotalcite loading, and temperature
TABLE 1. Optimization of reaction condition for the enantioselective addition of ethyl cyanoformate to benzaldehyde in
presence of polymeric V(V) salen complex 1a
Entry
Catalyst (mol %)
Cocatalyst
Time (h)
Temp. (8C)
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
2.5
2.5
2.5
2.5
–
–
–
2.5
5
1
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
HT (25 mg)
Al2O3 (25 mg)
NaOH (5 mg)
KOH (7 mg)
KOH (7 mg)
Al2O3 (50 mg)
HT (50 mg)
–
HT (25 mg)
HT (25 mg)
HT (50 mg)
HT (75 mg)
HT (15 mg)
HT (10 mg)
Al2O3 (50 mg)
Al2O3 (15 mg)
Al2O3 (10 mg)
HT (25 mg)
HT (25 mg)
24
24
8
9
9
15
15
15
15
15
25
15
25
15
15
15
15
15
15
15
15
15
25
0
94
93
96
97
98
20
Trace
–
90
75
94
94
75
68
97
92
82
89
88
75
03
20
Racemic
–
30
30
48
30
30
24
24
36
48
18
36
48
24
48
–
–
87
72
87
86
82
79
50
83
81
75
Trace
–
aAll reaction carried out at 0–258C using catalyst 1 (indicated amount), benzaldehyde (0.62 mmol), ethyl cyanoformate (1.24 mmol), and cocatalyst
(indicted amount) in dry DCM (0.8 ml).
bIsolated yield.
cee was determined using chiracel OD column.
Chirality DOI 10.1002/chir

156
KHAN ET AL.
TABLE 2. Enantioselective addition of ethyl cyanoformate
to various aldehydes using V(V) salen complex 1and 2 with
HT as a cocatalysta
TABLE 3. Data for the enantioselective addition of ethyl
cyanoformate to benzaldehyde using recycle polymeric
V(V) salen complex 1 with recycle HT and basic
Al2O3 as a cocatalyst
Run
1
2
3
4
Time (h)
Yield (%)a
ee (%)c
24
28
92 (90)
88 (72)
30
92 (91)
87 (74)
30
89 (88)
86 (71)
94 (93)b
88 (75)
Time
(h)
Yield
(%)b
ee
Entry
Substrate
(%)c
aIsolated Yield.
bThe data in the parenthesis given for basic Al2O3 as a cocatalyst.
cThe ee was determined by using chiralpak HPLC OD column.
1 (2)d Benzaldehyde
3 (4)
5 (6)
7 (8)
9 (10) 2-Methoxybenzaldehyde
11 (12) 3-Methoxybenzaldehyde
13 (14) 4-Methoxybenzaldehyde
15 (16) 2-Ethoxy benzaldehyde
17 (18) 2-Benzyloxybenzaldehyde
19 (20) 4-Fluorobenzaldehyde
21 (22) 4-Chlorobenzaldehyde
23 (24) 4-Bromobenzaldehyde
25 (26) Hexanal
24 (30) 94 (93) 88 (87)
30 (36) 91 (90) 81 (80)
24 (36) 93 (91) 83 (81)
24 (28) 91 (89) 80 (78)
24 (36) 92 (89) 91 (90)
24 (36) 89 (87) 84 (82)
24 (36) 90 (89) 83 (79)
24 (36) 90 (87) 84 (81)
24 (30) 92 (91) 94 (92)
24 (24) 95 (93) 90 (88)
24 (30) 88 (89) 75 (71)
24 (30) 89 (90) 85 (86)
21 (30) 93 (91) 81 (80)
2-Methylbenzaldehyde
3-Methylbenzaldehyde
4-Methylbenzaldehyde
substrate did not have noticeable effect on the yield and
selectivity of the products. Similarly, aliphatic substrates
were also ethyl cyanoformylated with similar yield and
enantioselectivity (Table 2, Entries 25–31). We also
extended this cyanoformylation protocol to these sub-
strates using monomeric V(V) salen complex 2 as catalyst
which showed comparable yields and enantioselectivities.
However, the reaction took longer time when compared
with the use of polymeric V(V) salen complex 1 as catalyst
(Table 2, Entries 2, 4, 6, 8, 10, 12, 14, 16, 18, 22, 24, 26, 28,
30, 32). Moreover, in the case of monomeric complex 2,
the catalyst was not recoverable though the hydrotalcite
was recovered and recycled at the end of the catalytic run,
whereas in the case of polymeric catalyst both catalyst and
hydrotalcite were recoverable and recyclable. The
enhanced reactivity in the case of polymeric complex as
against monomeric complex may be attributed to the
27 (28) 3-Methyl-2-butenealdehyde 24 (36) 91 (89) 83 (82)
29 (30) Crotonaldehyde
31 (32) Isovaraldehyde
24 (36) 88 (87) 77 (75)
21 (30) 90 (92) 86 (85)
aAll reaction carried out at 158C using catalyst 1 and 2 (2.5 mol %), alde-
hyde (0.62 mmol), ethyl cyanoformate (1.24 mmol), and HT (25 mg) in
dry DCM (0.8 ml).
bIsolated yield.
cee determined by chiral HPLC and GC.
dThe data in parentheses given for complex 2.
Scheme 1. Probable mechanism of cyanoethylation of aldehydes.
Chirality DOI 10.1002/chir

ENANTIOSELECTIVE CYANOFORMYLATION OF ALDEHYDES
157
2. Thierry RJA, Lisa AC, Michael N. Asymmetric catalysis of carbon-car-
bon bond-forming reactions using metal(salen) complexes. Synlett
2005;12:1828–1847.
increase reactive sites which may be working in co-opera-
tion.59,60,63 In all the catalytic runs, the (R)- form of V(V)
salen complexes 1 and 2 as catalysts resulted in to (S)
enantiomer of the product ethyl cyanohydrincarbonates.
To assess the recyclability of the polymeric complex 1,
the catalytic runs for the ethyl cyanoformylation of benzal-
dehyde was taken as representative test run using hydro-
talcite/basic alumina as cocatalysts under the reaction
condition mentioned in Entries 1 and 2 (Table 1). Conse-
quently, after the first catalytic runs excess amount of hex-
ane was added to each reaction mixture and the resulting
solids were collected by filtration. The recovered solids
were thoroughly washed with hexane and vacuum dried
before reuse. The recovered solids containing both the
catalyst 1 and the cocatalysts hydrotalcite/basic alumina
were used as such in the manner same as fresh catalyst in
the ethyl cyanoformylation of benzaldehyde which showed
similar activity and enantioselectivity in the recycle experi-
ments (Table 3, Runs 2–4) though there was some
increase in reaction time. The recyclability of this catalytic
system has clear edge over previously reported polymeric
V(V) salen complexes.17,59,60
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On the basis of the product distribution, a probable
mechanism of cyanoformylation of aldehydes is proposed
(Scheme 1). In view of high chiral induction in the pro-
duct, it would be appropriate to consider that the substrate
is activated by the way of its interaction with the acidic
metal site of the chiral complex. Concomitantly, the solid
base activates the source of cyanide. In a concerted man-
ner, then nucleophilic attack of CN took place while the
ethylformyl group moves to the aldehydic oxygen to pro-
duce the desired product in high chiral purity.58
14. Belokon YN, Gutnov AV, Moskalenko MA, Yashkina LV, Lesovoy
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M, Timofeeva GI, Yashkina LV. The asymmetric addition of trimethyl-
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CONCLUSION
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In conclusion, a highly efficient enantioselective ethyl
cyanoformylation of various aromatic and aliphatic alde-
hydes was carried out by using V(V) chiral polymeric and
monomeric salen complexes 1 and 2, respectively, as cata-
lysts with ethyl cyanoformate as a source of cyanide in the
presence of several cocatalysts. Excellent yield (95%) and
enantioselectivity up to 94% for the product ethyl cyanohy-
drincarbonate was achieved when hydrotalcite was used
as cocatalyst. The chiral polymeric catalyst 1 and solid
base used as cocatalysts were recyclable several times
with retention of their performances.
18. Belokon YN, North M, Maleev VI, Voskoboev NV, Moskalenko MA,
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Chirality DOI 10.1002/chir