Enantioselective O-acetylcyanation/cyanoformylation of aldehydes using catalysts with built-in crown ether-like motif in chiral macrocyclic V(V) salen complexes

Article abstract of DOI:10.1016/j.tet.2011.07.005

Chiral macrocyclic V(V) salen complexes 1a-f derived from macrocyclic ligands obtained by the reaction of 1R,2R-(-) diaminocyclohexane/(1R,2R)-(+)-1, 2-diphenylethylenediamine with bis-aldehydes 2 and 3 were synthesized and used as efficient catalysts in asymmetric cyanation reactions. The V(V) catalysts demonstrated excellent performance (product yields and ees up to 99%) with potassium cyanide (KCN) and sodium cyanide (NaCN). The catalytic system also performed very well with a safer source of cyanide-ethyl cyanoformate to give cyanohydrin carbonates in excellent yield and ee (up to 97%). The V(V) macrocyclic salen complex 1b retained its performance at multi-gram level and was conveniently recycled for a number of times.

Full text of DOI:10.1016/j.tet.2011.07.005

Tetrahedron 67 (2011) 7073e7080
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Tetrahedron
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Enantioselective O-acetylcyanation/cyanoformylation of aldehydes using catalysts
with built-in crown ether-like motif in chiral macrocyclic V(V) salen complexes
*
Noor-ul H. Khan , Arghya Sadhukhan, Nabin C. Maity, Rukhsana I. Kureshy, Sayed H.R. Abdi, S. Saravanan,
Hari C. Bajaj
Discipline of Inorganic Materials and Catalysis, Central Salt and Marine Chemicals Research Institute (CSMCRI), Council of Scientific and Industrial Research (CSIR),
G. B. Marg, Bhavnagar 364 002, Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 May 2011
Received in revised form 30 June 2011
Accepted 1 July 2011
Available online 6 July 2011
Chiral macrocyclic V(V) salen complexes 1aef derived from macrocyclic ligands obtained by the reaction
of 1R,2R-(ꢀ) diaminocyclohexane/(1R,2R)-(þ)-1,2-diphenylethylenediamine with bis-aldehydes 2 and 3
were synthesized and used as efficient catalysts in asymmetric cyanation reactions. The V(V) catalysts
demonstrated excellent performance (product yields and ees up to 99%) with potassium cyanide (KCN)
and sodium cyanide (NaCN). The catalytic system also performed very well with a safer source of
cyanide-ethyl cyanoformate to give cyanohydrin carbonates in excellent yield and ee (up to 97%). The
V(V) macrocyclic salen complex 1b retained its performance at multi-gram level and was conveniently
recycled for a number of times.
Keywords:
Asymmetric O-acetylcyanohydrin
Cyanohydrin carbonate
Macrocyclic salen V(V) complexes
Aldehydes
Ó 2011 Elsevier Ltd. All rights reserved.
Enantioselective
1. Introduction
visualized for mononuclear Vesalen complex.5,7 It is proposed that
in solution, two mononuclear Ti/Vesalen complexes form dinuclear
Asymmetric cyanation of carbonyl compounds to form cyano-
hydrins is one of the most important CeC bond forming reactions in
organic chemistry.1 Chiral cyanohydrins being bifunctional, can be
conveniently transformed to produce a number of biologically
m-oxo species in the presence of stoichiometric amount of water by
intermolecular association. 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 manuscript we are
reporting the synthesis of chiral V(V) dinuclear macrocyclic salen
complexes 1a, 1b where two salen units linked appropriately in
a macrocycle whose structure is somewhat akin to Jacobsen’s
macrocyclic catalyst26 and can act co-operatively27 within an
enzyme-like chiral cavity. These complexes were used 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 mononuclear 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 Kþ and Naþ ions, respectively.28 A support of this concept
was provided by Evans and Truesdale29 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.30
While we were preparing this manuscript Ding group21 reported
exceptionally efficient Ti based chiral catalysts for the enantiose-
lective cyanation of aldehydes with TMSCN and NaCN. Structurally
important compounds including
a
-hydroxy acids, esters,
a-hydroxy
aldehydes, ketones,
a
-amino acids2 and
b
-aminoalcohols.2,3 Driven
by the potential application of chiral cyanohydrins, the last couple
of decades have seen spurt of excellent reports on enantioselective
cyanation of carbonyl compounds. Typically for this reaction en-
zymes,3,4 synthetic peptides,3,4 organo-catalysts3 and complexes of
V, Mn, Ti, Al and lanthanide metal ions5e22 have been used as
catalysts under homogenous and heterogeneous6 condition. As far
as the source of cyanide is concerned, HCN,2 NaCN,21,23 KCN,5c,7
trimethylsilyl cyanide (TMSCN),5a,10,24 ethyl cyanoformate5f,8a,19,25
acyl cyanide8 and acetone cyanohydrin13 have been frequently
employed. From mechanistic studies, it has been established that
for mononuclear Tiesalen complexes the key transition state is
bimetallic in nature. According to this transition state both the
titanium ions simultaneously activate the aldehyde and the cya-
nide5,22 (Fig. 1s, Supplementary data). Similar mechanism was also
* Corresponding author. Fax: þ91 0278 2566970; e-mail address: khan251293@
yahoo.in (N.-ul H. Khan).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.005

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N.-ul H. Khan et al. / Tetrahedron 67 (2011) 7073e7080
these catalysts are open ended bimetallic Tiesalen complexes,
where the two salen units were linked with various linkers. Al-
though, full characterization data for the corresponding ligands
were given, the synthesis or synthetic procedure for these ligands
and their complexes was not provided.22 Nevertheless, among all
these complexes, the complex having two salen units that are ori-
entated 180ꢁ to one another gave best catalytic performance.22 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 cyano-
formate as cyanide sources in the enantioselective cyanation of
various aldehydes to give O-protected cyanohydrins/cyanohydrins
carbonate in quantitative yields with high chiral induction. More-
over, the V(V) macrocyclic salen complex 1b demonstrated excel-
lent recyclability. We have also tested structurally similar but
relatively rigid macrocyclic salen ligands 1e and 1f31 in V(V) cata-
lyzed asymmetric cyanation of benzaldehyde, which showed rela-
tively inferior performance.
attract alkali metal ions29 and therefore can facilitate the activation
of KCN in cyanation reactions. To examine the concept experi-
mentally, cyanation of benzaldehyde was carried out in the pres-
ence and absence of dibenzo-18-crown-6 using earlier reported
dinuclear V(V) salen complex24c (Fig. 2s, supplementary data) as
catalyst and KCN as cyanide source under identical condition.
However, the catalytic reaction in the presence of crown ether
yielded the 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 10d/10b yielded ra-
cemic benzocyanohydrin.
In order to understand the role of polyether functionality in
catalytic reaction KCN was added to the CDCl3þCD3OD solution of
10b, the signals of polyether ethylene proton signals shifted
downfield (ca. 35 Hz) as a result of binding of Kþ to the oxygen
13
atoms. Similar trend was also observed in C spectra of 10b with
downfield shift of ca. 22 Hz for polyether ethylene carbons. All the
spectra on this aspect are given in Supplementary data. These re-
sults indicate that polyether (crown ether like) functionality acti-
vate KCN/NaCN, thereby, facilitate the catalytic cyanation reaction
(TOF 19.8 hꢀ1 as compared to reported5 w9.6).
2. Results and discussion
Chiral macrocyclic ligands 10aef 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 benz-
aldehyde with trigol and 1,3-phenylenedimethanol, respectively in
dry THF containing sodium hydride. The macrocyclic chiral salen
ligands 10c, 10d, 10e, 10f were synthesized by reacting stoichio-
metric amount of dialdehydes 2 and 3 with (1R,2R)-(ꢀ)-dia-
minocyclohexane 5/(1R,2R)-(þ)-1,2-diphenylethylenediamine 6,
respectively in methanol for 12 in quantitative yield. However, the
macrocyclic dinuclear ligands 10a and 10b were obtained by the
reaction of chiral diamines 5, 6 with dialdehydes 2, 3 in dry THF in
2 h. V(V)-complexes 10aef were synthesized by the reaction of
corresponding macrocyclic ligands 10ae10f with vanadyl sulfate
followed by auto-oxidation (Scheme 1).
With this backdrop, our initial experiments were conducted
with macrocyclic mononuclear vanadium complex 1d and dinu-
clear complex 1b to catalyze asymmetric cyanation of benzalde-
hyde 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 ꢁC (Table 1, entries 1e4 and 9e12). The data revealed that
5 mol % mononuclear complex 1d gave best results in terms of yield
(99%) and enantio-induction (ee, 45%; entry 3) for the product cy-
anohydrin. On the other hand, the dinuclear complex 1b (having
two 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
5e8) and 1 mol % of 1b (entries 13e16) were used to optimize the
reaction temperature. Accordingly, this reaction was conducted at
temperatures 0, ꢀ10, ꢀ20 and ꢀ30 ꢁC, where ꢀ20 ꢁC was found to
be most suitable reaction temperature for both the catalysts 1d and
1b (Table 1, entries 7, 15). We next screened the mononuclear cat-
alysts 1c, 1e and 1f (5 mol %) and dinuclear complex 1a (1 mol %) for
asymmetric cyanation of benzaldehyde as model substrate with
KCN as source of cyanide in CH2Cl2 at ꢀ20 ꢁC. The data clearly show
that complex 1b is better catalyst in terms of product yield and
enantioselectivity (Fig. 1). For the sake of comparison the asym-
metric cyanation of benzaldehyde with KCN was carried out by the
catalysts 1d and 1b having similar metal loadings in CH2Cl2
at ꢀ20 ꢁC. Accordingly, 2 mol % of 1d (conversion, 44%; ee, 59%) and
1 mol % of 1b (conversion, 99%; ee, 92%) were taken to catalyze this
reaction under identical reaction conditions for 5 h.
All the mononuclear and dinuclear ligands 10aef used in the
present study were isolated in pure form by column chromatog-
raphy and their characterization was accomplished by elemental
analysis, MALDI-TOF, 1H and 13C NMR. An attempt is also made to
ꢀ
correlate catalyst structure vis-a-vis catalytic performance in view
of experimental results. MS and MALDI-TOF data for ligands 10aef
gave molecular peaks that correspond to the proposed structures.
In the case of dinuclear complexes, ICP analysis of V in 1b dem-
onstrated complete metallation of the ligand 10b.
MS spectral analysis of mononuclear 10d showed base peak at
610.2 [Mþ2H], which matched well with its calculated molecular
weight (610.3 [Mþ2H]), while the base peak at 1218.1 (Mþ2H)
(calculated molecular weight,1218.7 [Mþ2H]) in MALDI-TOF spectra
(Please see Supplementary data) correspond to ligand 10b. 1H NMR
spectroscopy of the ligands 10b and 10d has clearly differentiated the
two ligands (Please see Supplementary data). A peak for eHC]Ne
appeared at 8.00 ppm in the case of 10d, whereas for ligand 10b it was
at 8.27 ppm. However, major difference in the 1H NMR spectra of 10d
and 10b noticed for the protons of eOeCH2eCH2eOe spacer groups
and eOeCH2e attached with the benzene ring. While the 1H NMR
spectrum for 10b gave singlet at 4.37 ppm for eOeCH2, these protons
appeared as double doublet (4.17e4.47 ppm) with geminal coupling
of 12 Hz. Similarly, in 10b protons for eOeCH2eCH2eOe appeared as
two triplets (3.54e3.55 ppm and 3.60e3.63 ppm) but these were
multiplet (3.30e3.35 ppm and 3.55e3.69 ppm) in the case of 10d.
These data on catalyst loading of 1d and 1b under similar re-
action parameters strongly suggest that the two salen units in the
catalysts have some cooperative role to play.5
In homogenous catalysis the nature of solvent plays an impor-
tant role on the activity and enantioselectivity of the catalyst. It is
reported in literature5 that protic solvents play an important role in
cyanation reaction. A proton source as an additive (1e2 equiv 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 sol-
vents like methanol, ethanol and tert-butanol there was a drastic
decrease in enantioselectivity though these reactions were much
faster (Table 2, entries 3, 4, 9, 10).
1
These changes in H NMR of the ligand 10d can be attributed to
its rigid skeleton, which restrict flipping bonds of eOeCH2e
and eOeCH2eCH2eOe, thereby making these protons chemically
different, whereas the skeleton of 10b is flexible.
The macrocyclic salen ligands used in the present study were
designed with the expectation that crown ether-like motif may
This effect can be attributed to the release of HCN by the re-
action of protic solvent with KCN, which in turn enhances the ra-
cemic background reaction. Other aprotic solvents, for example,
THF, toluene and acetonitrile (in the presence of water and tert-

N.-ul H. Khan et al. / Tetrahedron 67 (2011) 7073e7080
7075
Scheme 1. Synthesis of the macrocyclic catalysts. (i) NaH, trigol, dry THF, N2 atm rt, 6e8 h, yield 55%. (ii) NaH, 1,3-phenylenedimethanol, dry THF, N2 atm rt, 6e8 h, yield 50%. (iii) 5,
dry methanol, rt, 12 h, yield 85e88% (iv) 6, dry methanol, rt, 12 h, yield 85e88% (v) 5, dry THF, rt, 2 h, yield 96% (vi) 6, dry THF, rt, 2 h (vii) vanadyl sulfate, dry ethanol, H2O, N2 atm
reflux 6 h, followed by auto-oxidation, yield 65e70%.
butanol as an additive) were relatively less effective than CH2Cl2
both in terms of yield and enantioselectivity.
Catalysts 1d and 1b enabled asymmetric cyanation reaction of
a variety of aromatic and aliphatic aldehydes as substrates with
KCN as cyanide source (Table 3) at the best reaction conditions
given in Table 2 (entries 6 and 12). In general, substrates irre-
spective of electron donating or withdrawing group on benzene
ring attached to aldehyde functional group gave the products with
very good to excellent ee in 5e6 h with the catalyst 1b and 10e12 h
with 1d.

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N.-ul H. Khan et al. / Tetrahedron 67 (2011) 7073e7080
Table 1
Table 2
Catalyst loading and temperature variations in the asymmetric O-acetylcyanation of
Screening of the solvents in the asymmetric O-acetylcyanation of benzaldehydea
benzaldehydea
H
OCOC
3
O
H
OCOC
3
Catalyst 1d or 1b
N
C
O
K N
C
Catalyst
or
1d 1b
H
N
C
+
,
,
u
H
O
-
t B
H
2O
K N
C
H
BuOH,
-
H O,
2
t
Acetic anhydride,
Acetic anhydride,
CH2Cl2 , N2 atm.
solvent, -20 o C,
N2 atm.
Entry Catalyst Temp (ꢁC) Catalyst loading Time (h) Yieldb (%) ee (%)c
(mol %)
Entry
Catalyst
Solvent (2 mL)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1d
1d
1d
1d
1d
1d
1b
1b
1b
1b
1b
1b
THF
Toluene
MeOH
t-BuOH
Acetonitrile
Dichloromethane
THF
Toluene
MeOH
16
12
6
63
85
90
90
58
97
62
82
92
90
62
99
51
58
40
45
49
83
59
65
45
50
50
92
1
2
3
4
5
6
7
8
1d
1d
1d
1d
1d
1d
1d
1d
1b
1b
1b
1b
1b
1b
1b
1b
1d
25
25
25
25
0
ꢀ10
ꢀ20
ꢀ30
25
25
25
25
0
ꢀ10
ꢀ20
ꢀ30
ꢀ20
2
1
5
10
5
5
5
5
2
1
7
7
6
92
91
99
96
96
96
97
96
99
99
95
96
99
99
99
98
44
40
32
45
46
68
75
83
83
62
63
60
62
81
86
92
92
59
6
8
12
12
16
12
5
5
12
5
12
12
12
15
3
4
6
3
5
5
5
6
5
9
9
10
11
12
t-BuOH
Acetonitrile
Dichloromethane
10
11
12
13
14
15
16
17
0.5
5
1
1
1
1
2
a
Reaction 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 anhy-
dride (4.8 mmol) at ꢀ20 ꢁC.
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
a
literature.24
Reaction conditions: catalyst 1d or 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
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 4). It is known in the literature that a base as an additive8,25
or a built-in basic site in the catalyst is vital to activate ethyl
cyanoformate.
(S) was established by comparison of the optical rotation values with that in the
literature.24
In view of the above we screened several organic and inorganic
bases as co-catalyst (5 mol %) with 1b for the cyanation of benz-
aldehyde with ethyl cyanoformate in CH2Cl2 (entries 1e10). Very
good to excellent yield of cyanohydrins carbonate was achieved
with the use of all the bases except for imidazole and 2-methyl
imidazole where 50e60% yield was obtained in 48 h (entries 1
and 2). The use of triethylamine as a co-catalyst accelerated the
ethyl cyanoformylation reaction tremendously (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 ethyl cyano-
formylation were carried out with chiral V(V) macrocyclic salen
complex 1b as catalyst and 2,6-lutidine as a co-catalyst. Further, in
order to get the optimal reaction condition we carried out asym-
metric ethyl cyanoformylation of benzaldehyde at different tem-
peratures, catalyst loading and co-catalyst loading and the results
are summarized in Table 5. At first, the catalyst loading was varied
over a range of 0.25e2.5 mol % keeping the co-catalyst loading at
5e10 mol % at 25 ꢁC to ꢀ40 ꢁC (Table 5). It is evident from the re-
sults that only 0.5 mol % catalyst loading and 5 mol % co-catalyst is
optimum (entry 7) at ꢀ20 ꢁC. Further, it is observed for most
enantioselective reactions that on decreasing the reaction tem-
perature there is an improvement in enantioselectivity. Therefore,
we carried out cyanoformylation reaction at ꢀ40 ꢁC as well, which
showed no improvement in the enantioselectivity moreover, there
was concomitant decrease in the yield of the product (entry 8). On
the other hand, raising the temperature from ꢀ20 ꢁC to 0 ꢁC the ee
of cyanohydrins carbonate was dropped significantly (entry 6).
Fig. 1. Screening of catalysts activity towards asymmetric O-acetylcyanation of benz-
aldehyde 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).
However, aldehyde group directly appended to an aliphatic
carbon gave the products in high yield but with moderate to good
ee (entries 13e15). 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 (7aeq)
using NaCN as cyanide source at the most suitable reaction condi-
tions as given in entry 12 of Table 3. Both the cyanide sources KCN
and NaCN gave comparable results, therefore data on NaCN with
catalyst 1d were not included in Table 3.
2.1. Scope of organic cyanide source
After successfully demonstrating the utility of catalysts 1d and
1b for the asymmetric cyanation of various aldehydes with

N.-ul H. Khan et al. / Tetrahedron 67 (2011) 7073e7080
7077
Table 3
Substrate scope of catalytic asymmetric O-acetylcyanation of aldehydesa
H
C
O
CHO
H
C
O
H
H
C O
C
O
CHO
CHO
H
H
C O
C
O
F
Me
Me
O
Me
Me
O
e
OM
Me
F
7i
a
7
c
7
7
g
7h
7b
e
7
7f
7d
H
C
O
CHO
CHO
CHO
H
C
O
O
CHO
CH2Ph
H
C
O
H
C
O
r
B
l
C
m
7
o
7
7
q
n
7
7
p
7
j
7k
7l
Catalyst 1d (5mol%) or 1b (1mol%), H
2O,
O
H
OCOC
3
t-BuOH,
K N
C
R
H
Acetic anhydride, -20oC, CH Cl , N2 atm.
R
N
C
7
2
2
Entry
Substrate
Catalyst 1d
Catalyst 1b
Yieldb (%)
eec (%)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
7j
97
98
97
95
96
95
94
99
98
98
99
99
98
98
98
83
89
82
81
86
84
82
87
84
78
85
89
65
82
53d
99 (98)
98 (99)
95 (95)
95 (93)
95 (96)
99 (99)
97 (94)
97 (96)
97 (94)
97 (96)
99 (99)
99 (99)
96 (95)
98 (98)
99 (97)
92 (90)
>99 (96)
91 (88)
90 (89)
97 (95)
96 (95)
96 (94)
>99 (97)
92 (90)
89 (85)
>99 (97)
>99 (98)
78 (76)
89 (85)
73d (72)
9
10
11
12
13
14
15
7l
7m
7n
7o
7p
7q
a
Reaction 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 ꢁC in 5e6 h.
b
Isolated yield. Data in the parentheses are with NaCN as a cyanide source.
ees 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
c
literature.24
d
ee was determined by GC on chiral GTA column.
Table 4
Catalyst loading and temperature variations in the synthesis of asymmetric cyanohydrins carbonates of benzaldehydea
O
Et
OCOO
Catalyst 1b (0.5mol%), Co-catalyst (5mol%),
+
Et
COOC
N
CH2 Cl2,25oC, N2atm.
H
R
N
C
Entry
Co-catalyst
Imidazole
N-Methylimidazole
N,N-Diisopropyl amine
Triethylamine
Pyridine
2,6-Lutidine
Al2O3
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
48
48
18
4
16
8
48
48
12
16
50
60
97
>99
92
97
84
82
95
88
30
33
55
10
45
64
35
30
32
50
Hydrotalcite
DMAP
DBU
10
a
Reaction 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.
b
c
Isolated yield.
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

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N.-ul H. Khan et al. / Tetrahedron 67 (2011) 7073e7080
Table 5
Table 7
Catalyst loading and temperature variations in the synthesis of asymmetric cyano-
Substrate scope of catalytic asymmetric cyanohydrin carbonatesa of aldehydes with
hydrins carbonatesa of benzaldehyde
1b under optimum reaction conditions
O
O
Et
OCOO
Catalyst 1b (0.5mol%), 2,6-Lutidine (5mol%),
Catalyst 1b, 2,6-Lutidine,
Et
OCOO
t
COOC
E
N
CH2 Cl2, -20oC,N2 atm.
R
H
+
R
N
C
Et
COOC
N
H
7
CH2 Cl2,N2 atm.
R
N
C
Entry
Substrate
Time (h)
Yieldb (%)
eec (%)
Entry Catalyst Co-catalyst Temp (ꢁC) Time (h) Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7i
7k
7n
7q
12
12
15
12
16
18
12
16
18
12
15
96
97
94
97
95
90
96
95
93
95
88
95
93
85
96
92
87
97
93
91
95
81d
loading
(mol %)
loading
(mol %)
1
2
3
4
5
6
7
8
2.5
1
5
5
5
5
10
5
25
25
25
25
25
8
8
8
14
6
10
12
18
97
97
97
93
98
96
96
90
64
64
67
60
58
87
95
95
0.5
0.25
0.5
0.5
0.5
0.5
9
10
11
0
5
5
ꢀ20
ꢀ40
a
a
Reaction conditions: chiral ligand 1b (0.5 mol %), benzaldehyde (1.2 mmol),
ethyl cyanoformate (1.8 mmol), 2,6-lutidine (5 mol %) at ꢀ20 ꢁC in 0.8 mL DCM.
Reaction 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.
b
b
Isolated yield.
Isolated yield.
ees were determined by HPLC on chiral OD column.
c
c
ees were determined by HPLC on chiral OD, OD-H columns.
ee was determined by chiral GC using chiral GTA column.
d
(see Experimental section). In both the cases after completion of
the catalytic reaction, the catalysts were retrieved quantitatively
and reused five times with retention of its activity and enantiose-
lectivity. 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 re-
action time in subsequent catalytic runs (Table 8). As there were no
changes in the ee of the product up to the five recycle experiments
conducted, it can be safely presumed that the catalyst structure
remained unchanged. This was further substantiated by the FTIR of
the recovered catalyst 1b, which matched well with the fresh cat-
alyst (IR spectra given in Supplementary data).
Therefore, for the rest of the catalytic experiments ꢀ20 ꢁC was
taken as optimum temperature.
To explore the effect of solvent on the activity and enantiose-
lectivity, ethyl cyanoformylation of benzaldehyde was carried out
in various solvents e.g., toluene, tolueneþisopropylalcohol,
dichloromethane (DCM), dichloromethaneþisopropylalcohol and
tetrahydrofuran using the V(V) salen complex 1b (data given in
Table 6). Out of all the solvents used, dichloromethane was found to
be the best solvent for this reaction (Table 6, entry 3).
Under the optimized reaction conditions the scope of this pro-
tocol for the ethyl cyanoformylation 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 ꢁC. Data in Table 7 shows
overall good to excellent isolated yields (90e97%) and ee (85e97%).
In the case of hexanal as representative aliphatic aldehyde, the
product ethyl cyanohydrin carbonate was obtained in 81% ee and
88% isolated yield in 15 h (entry 11).
Table 8
Reuse of catalysts 1b for O-acetylcyanationa and synthesis of asymmetric cyano-
hydrin carbonateb of benzaldehyde
Et
OCOO
Catalyst 1b (0.5mol%),
2,6-lutidine (5mol%)
N
C
o
O
2.2. Reuse of complex 1b
,
Et N
COOC
,
,
-
20
atm.
l N2
C C 2C 2
H
H
OCOC
H
3
Cyanide sources KCN and ethyl cyanoformate were used with
catalyst 1b for reuse experiments6,24 by using benzaldehyde
(3.06 mmol) as model substrate in the manner described earlier
Catalyst 1b (1mol%)
N
C
KCN,H2O,t-BuOH, Acetic anhydride,
o
,
,
N2
-
20
atm.
H
l
C C 2C 2
Table 6
Rune
1
2
3
4
5
6
Screening of solvents for the synthesis of asymmetric cyanohydrins carbonate of
Yieldc (%)
95 (99)
95 (92)
95 (99)
95 (92)
94 (98)
95 (92)
94 (97)
95 (92)
93 (97)
95 (92)
92 (96)
95 (92)
benzaldehydea with catalyst in 1b
eed (%)
Et
OCOO
a
O
Reaction conditions: chiral catalyst 1b (0.5 mol %), benzaldehyde (3.06 mmol),
2,6-lutidine (5 mol %) ethyl cyanoformate (4.59 mmol) at ꢀ20 ꢁC in DCM (0.8 mL).
Catalyst 1b (0.5mol%),
2,6-Lutidine (5mol%)
N
C
H
Et
COOC
N
b
Catalyst 1b (1 mol %), benzaldehyde (3.06 mmol), KCN (6.12 mmol), H2O
Solvent, -20 oC, N2 atm.
(2.22 mmol), t-BuOH (4.18 mmol), acetic anhydride (12.24 mmol) at ꢀ20 ꢁC in DCM
(2 mL).
c
Isolated yield.
Entry Solvent
Time (h) Yieldc (%) eed (%)
d
The ees were determined by using chiralpak HPLC OD column.
Data in parenthesis correspond to KCN as cyanide source.
e
1
2
3
4
5
Toluene
18
12
12
90
92
96
98
80
85
82
95
80
65
Tolueneþisopropyl alcoholb
Dichloromethane
Dichloromethaneþisopropyl alcoholb 10
3. Conclusions
THF
30
a
Reaction conditions: chiral ligand 1b (0.5 mol %), benzaldehyde (1.2 mmol),
This work has revealed 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 al-
dehydes. Particularly, catalyst 1b with flexible polyether linkage
2,6-lutidine (0.13 mmol), ethyl cyanoformate (1.8 mmol) at ꢀ20 ꢁC.
b
Toluene or dichloromethane 0.5 mL and isopropyl alcohol 0.3 mL.
Isolated yield.
ees were determined by HPLC on chiral OD column.
c
d

N.-ul H. Khan et al. / Tetrahedron 67 (2011) 7073e7080
7079
(a crown ether-like motif) work in cooperation to afford corre-
sponding enantio-enriched cyanohydrin derivatives (yields up to
99%) at ꢀ20 ꢁC. Synthetic procedure for the preparation of pre-
catalysts (corresponding macrocyclic ligands) once established
was very convenient and reproducible to get desired mononuclear
and dinuclear 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 cyana-
tion reaction is scalable.
hexane (5 mL), dried under reduced pressure for 1e2 h and was
used as recovered catalyst 1b for recycle experiments.
Acknowledgements
A.S. and N.H.K. are thankful to CSIR-JRF fellowship and CSIR
Network project on catalysis for financial assistance and Analytical
Division of the Institute for providing instrumentation facility.
Supplementary data
4. Experimental methods
4.1. General
Experimental procedure for the synthesis and characterization
of the chiral macrocyclic ligands, complexes and O-acetylcyano-
hydrin products, including 1H, 13C NMR, MALDI-TOF, TOF-MS data,
HPLC and GC conditions, etc. Supplementary data associated with
this article can be found, in the online version, at doi:10.1016/
j.tet.2011.07.005.
Vanadyl sulfate hydrate (Loba chemie, India), KCN (Merck), NaCN
(Merck), ethyl cyanoformate, benzaldehyde, 2-methoxy benzalde-
hyde, 3-methoxy benzaldehyde, 4-methoxy benzaldehyde,
4-chlorobenzaldehyde, 4-flurobenzaldehyde, 2-flurobenzaldehyde,
4-bromobenzaldehyde, 2-naphthaldehyde, 1-naphthaldehyde,
2-benzyloxy benzaldehyde, hydrocinnamaldehyde, hexanal and
crotonaldehyde were purchased from Aldrich Chemicals, whereas
2-methyl benzaldehyde, 3-methyl benzaldehyde and 4-methyl
benzaldehyde were purchased from Merck and were used as re-
ceived. All the solvents were dried by standard procedures, distilled
and stored under nitrogen.
References and notes
1. North, M.; Usanov, D. L.; Young, C. Chem. Rev. 2008, 108, 5146.
2. (a) Fechter, M. H.; Griengl, H. In Enzyme Catalysis in Organic Synthesis, 2nd ed;
Drauz, K., Waldmann, H., Eds.; Wiley-VCH: Weinheim, 2002; Vol. 2,
pp 974e989; (b) North, M. In Science of Synthesis; Murahashi, S.-I., Ed.; Georg
Thieme: Stuttgart, 2004; Vol. 19, pp 235e284; (c) Ramalingam, B.; Seayad, A.
M.; Chuanzhao, L.; Garland, M.; Yoshinaga, K.; Wadamoto, M.; Nagata, T.; Chai,
C. L. L. Adv. Synth. Catal. 2010, 352, 2153.
€
3. (a) Breuer, M.; Habicher, T.; Ditrich, K.; Hauer, B.; Ke
b
eler, M.; Sturmer, R.;
4.2. General procedure for 1aef catalyzed asymmetric O-
acetylcyanation of aldehyde
Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788; (b) Holt, J.; Hanefeld, U. Curr.
Org. Synth. 2009, 6, 15; (c) Oku, J.-I.; Inoue, S. J. Chem. Soc., Chem. Commun. 1981,
229; (d) Mori, A.; Ikeda, Y.; Kinoshita, K.; Inoue, S. Chem. Lett. 1989, 2119; (e)
Brunel, J. M.; Holmes, I. P. Angew. Chem., Int. Ed. 2004, 43, 2752; (f) Zuend, S. J.;
Coughlin, M. P.; Lalonde, M. P.; Jacobsen, E. N. Nature 2009, 461, 968.
4. (a) Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N. J. Org. Chem. 1993, 58, 1515;
(b) Zhou, X.-G.; Huang, J.-S.; Ko, P.-H.; Cheng, K.-K.; Che, C.-M. J. Chem. Soc.,
Dalton Trans. 1999, 3303.
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 ꢀ20 ꢁC. 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
(3ꢂ15 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/ethyl-
acetate¼95:5). The ee of O-acetylcyanohydrin was determined by
HPLC and GC analysis.
5. (a) Belokon, Y. N.; Caveda-Cepas, S.; Green, B.; Ikonnikov, N. S. V.; Khrustalev,
N. V.; Larichev, S. M.; Moskalenko, A.; North, M.; Orizu, C.; Tararov, V. I.; Tasi-
nazzo, M.; Timofeeva, G. I.; Yashkina, L. V. J. Am. Chem. Soc. 1999, 121, 3968; (b)
Belokon, Y. N.; Gutnov, A. V.; Moskalenko, M. A.; Yashkina, L. V.; Lesovoy, D. E.;
Ikonnikov, N. S.; Larichev, V. S.; North, M. Chem. Commun. 2002, 244; (c) Be-
lokon, Y. N.; Carta, P.; Gutnov, A. V.; Maleev, V.; Moskalenko, M. A.; Yashkina, L.
V.; Ikonnikov, N. S.; Voskoboev, N. V.; Khrustalev, V. N.; North, M. Helv. Chim.
Acta 2002, 85, 3301; (d) Belokon, Y. N.; Green, B.; Ikonnikov, N. S.; North, M.;
Parsons, T.; Tararov, V. I. Tetrahedron 2001, 57, 771; (e) Belokon, Y. N.; Blacker, A.
J.; Carta, P.; Clutterbuck, L. A.; North, M. Tetrahedron 2004, 60, 10433; (f) Be-
lokon, Y. N.; Blacker, A. J.; Clutterbuck, L. A.; North, M. Org. Lett. 2003, 5, 45805;
(g) Belokon, Y. N.; Green, B.; Ikonnikov, N. S.; Larichev, V. S.; Lokshin, B. V.;
Moskalenko, M. A.; North, M.; Orizu, C.; Peregudov, A. S.; Timofeeva, G. I. Eur. J.
Org. Chem. 2000, 2655.
~
6. (a) Baleizao, C.; Gigante, B.; Garcia, H.; Corma, A. Green Chem. 2002, 4, 272; (b)
~
Baleizao, C.; Gigante, B.; Garcia, H.; Corma, A. Tetrahedron Lett. 2003, 44, 6813;
~
(c) Baleizao, C.; Gigante, B.; Garcia, H.; Corma, A. J. Catal. 2003, 215, 199; (d)
~
Baleizao, C.; Gigante, B.; Garcia, H.; Corma, A. J. Catal. 2004, 221, 77; (e) Kim,
J.-H.; Kim, G.-J. Catal. Lett. 2004, 92, 123; (f) Huang, W.; Song, Y.; Bai, C.; Cao, G.;
Zheng, Z. Tetrahedron Lett. 2004, 45, 4763; (g) Huang, W.; Song, Y.; Wang, J.;
Cao, G.; Zheng, Z. Tetrahedron 2004, 60, 10469; (h) Lundgren, S.; Lutsenko, S.;
Jolnsson, C.; Moberg, C. Org. Lett. 2003, 3663.
4.3. 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.
7. (a) Watanabe, A.; Matsumoto, K.; Shimada, Y.; Katsuki, T. Tetrahedron Lett. 2004,
45, 6229; (b) Takaki, J.; Egami, H.; Matsumoto, K.; Saito, B.; Katsuki, T. Chem.
Lett. 2008, 37, 502.
8. (a) Lundgren, S.; Wingstrand, E.; Penhoat, M.; Moberg, C. J. Am. Chem. Soc. 2005,
127, 11592; (b) Homberg, A.; Lundgren, S.; Wingstrand, E.; Moberg, C.; Hault, K.
ꢁ
Chem.dEur. J. 2007, 13, 4334; (c) Casa, J.; Baeza, A.; Sansano, J. M.; Najera, C.;
ꢁ
ꢁ
Saa, J. M. Tetrahedron: Asymmetry 2003, 14, 197; (d) Baeza, A.; Najera, C.;
4.4. Reuse of catalyst 1b in asymmetric O-acetylcyanation of
benzaldehyde with KCN
ꢁ
Sansano, J. M.; Saa, J. M. Tetrahedron: Asymmetry 2005, 16, 2385.
9. Brunel, J. M.; Legrand, O.; Buono, G. Tetrahedron: Asymmetry 1999, 10, 1979.
10. Sellner, H.; Faber, C.; Rheiner, P. B.; Seebach, D. Chem. eEur. J. 2000, 6, 3692.
11. Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2002,
41, 3636.
12. (a) Shibasaki, M.; Kanai, M.; Funabashi, K. Chem. Commun. 2002, 1989; (b)
Hamashima, Y.; Sawada, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121,
2641; (c) Hamashima, Y.; Sawada, D.; Nogami, H.; Kanai, M.; Shibasaki, M.
Tetrahedron 2001, 57, 805.
For catalyst recycle experiments the general procedure for
O-acetylcyanation of benzaldehyde with KCN as described in Sec-
tion 4.1 was followed at ca. three time scale. After the reaction was
completed, the reaction mass was filtered by passing through a pad
of Celite and washed with water (3ꢂ30 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
13. Sakai, Y.; Mitote, J.; Matsumoto, K.; Katsuki, T. Chem. Commun. 2010, 5787.
ꢁ
ꢁ
14. Casas, J.; Najera, C.; Sansano, J. M.; Saa, J. M. Org. Lett. 2002, 4, 2589.
15. Qian, C.; Zhu, C.; Huang, T. J. Chem. Soc., Perkin Trans. 1 1998, 2131.
16. Holmes, I. P.; Kagan, H. B. Tetrahedron Lett. 2000, 41, 7453.
17. Ooi, T.; Miura, T.; Takaya, K.; Ichikawa, H.; Maruoka, K. Tetrahedron 2001,
57, 867.

7080
N.-ul H. Khan et al. / Tetrahedron 67 (2011) 7073e7080
18. (a) Minamikawa, H.; Hayakawa, S.; Yamada, T.; Iwasawa, N.; Narasaka, K. Bull.
Chem. Soc. Jpn. 1988, 61, 4379; (b) Narasaka, K.; Yamada, T.; Minamikawa, H.
Chem. Lett. 1987, 2073.
Agrawal, S.; Jasra, R. V. Coord. Chem. Rev. 2008, 252, 593; (e) Kureshy, R. I.; Khan,
N. H.; Abdi, S. H. R.; Patel, S. T.; Jasra, R. V. Tetrahedron Lett. 2001, 42, 2915.
25. (a) Khan, N. H.; Agrawal, S.; Kureshy, R. I.; Abdi, S. H. R.; Prathap, K. J.; Jasra, R. V.
Eur. J. Org. Chem. 2008, 4511; (b) Khan, N. H.; Agrawal, S.; Kureshy, R. I.; Abdi, S.
H. R.; Pathak, K.; Jasra, R. V. Chirality 2010, 22, 153.
26. (a) Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 2687; (b) Ready, J. M.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2002, 41, 1374; (c) Ready, J. M.; Jacobsen, E.
N. Angew. Chem. 2002, 114, 1432.
19. (a) Li, Y.; He, B.; Qin, B.; Feng, X.; Zhang, G. J. Org. Chem. 2004, 69, 7910; (b) Gou,
S.; Chen, Y.; Xiong, X.; Feng, X. J. Org. Chem. 2006, 71, 5732; (c) Wang, J.; Li, W.;
Liu, Y.; Chu, Y.; Lin, L.; Liu, X.; Feng, X. Org. Lett. 2010, 12, 1280.
ꢁ
ꢁ
20. Gama, A; Flores-Lopez, L.; Aguirre, Z. G.; Parra-Hake, M.; Somanathan, R.; Cole,
T. Tetrahedron: Asymmetry 2005, 16, 1167.
21. Zhang, Z.; Wang, Z.; Zhang, R.; Ding, K. Angew. Chem., Int. Ed. 2010, 49, 6746.
22. North, M. Angew. Chem., Int. Ed. 2010, 49, 8079.
27. (a) Haak, R. M.; Wezenberg, S. J.; Kleij, A. W. Chem. Commun. 2010, 2713; (b)
Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2011, 50, 4760.
28. Liu, H.; Shau, X.-B.; Jia, M.-X.; Jiang, X.-K.; Li, Z.-T.; Chen, G.-J. Tetrahedron 2005,
61, 8095.
29. Evans, D. A.; Truesdale, L. K. Tetrahedron Lett. 1973, 49, 4929.
30. Belokon, Y. N.; Ishibashi, E.; Nomura, H.; North, M. Chem. Commun. 2006, 1775.
31. Maity, N. C.; Abdi, S. H. R.; Kureshy, R. I.; Khan, N. H.; Suresh, E.; Dangi, G. P.;
Bajaj, H. C. J. Catal. 2010, 277, 123.
23. Qu, Y.; Jing, L.; Wu, Z.; Wu, D.; Zhou, X. Tetrahedron: Asymmetry 2010, 21, 187.
24. (a) Khan, N. H.; Agrawal, S.; Kureshy, R. I.; Abdi, S. H. R.; Mayani, V. J.; Jasra, R. V.
Tetrahedron: Asymmetry 2006, 17, 2659; (b) Khan, N. H.; Agrawal, S.; Kureshy, R.
I.; Abdi, S. H. R.; Mayani, V. J.; Jasra, R. V. J. Mol. Catal. A: Chem. 2007, 264, 140;
(c) Khan, N. H.; Agrawal, S.; Kureshy, R. I.; Abdi, S. H. R.; Mayani, V. J.; Jasra, R. V.
Eur. J. Org. Chem. 2006, 3175; (d) Khan, N. H.; Kureshy, R. I.; Abdi, S. H. R.;