A single-step, mild, neutral, catalyst-free method for cyanohydrin synthesis

Article abstract of DOI:10.1007/s00706-011-0613-4

A wide variety of carbonyl compounds can be transformed to their corresponding cyanohydrins in a single step using a dimethyl sulfoxide (DMSO)-water system in excellent yields (75-94%). The major advantages of this system are that the reaction conditions are mild and neutral; the reaction proceeds without catalyst and gives the corresponding cyanohydrins in short time (15-120 min).

Full text of DOI:10.1007/s00706-011-0613-4

Monatsh Chem (2012) 143:461–465
DOI 10.1007/s00706-011-0613-4
ORIGINAL PAPER
A single-step, mild, neutral, catalyst-free method for cyanohydrin
synthesis
Mariam S. Degani
Nutan H. Palsule Desai
•
Manoj D. Kakwani
Ranjeet Bairwa
•
•
Received: 12 July 2010 / Accepted: 5 August 2011 / Published online: 26 August 2011
Ó Springer-Verlag 2011
Abstract A wide variety of carbonyl compounds can be
transformed to their corresponding cyanohydrins in a single
step using a dimethyl sulfoxide (DMSO)–water system in
excellent yields (75–94%). The major advantages of this
system are that the reaction conditions are mild and neu-
tral; the reaction proceeds without catalyst and gives the
corresponding cyanohydrins in short time (15–120 min).
cyanide to carbonyl compound as compared with sodium
cyanide (NaCN) or potassium cyanide (KCN). However,
the initial product obtained with TMSCN is the cyanohy-
drin trimethylsilyl ether, which needs to be cleaved further
to the corresponding cyanohydrin using acid such as
hydrochloric acid, trifluoroacetic acid, etc. [5].
Catalysts such as metal ligand complexes, polymer-
supported metal catalysts, Lewis acids, ionic bases, ionic
liquids, earth metal salts, N-heterocyclic carbene, etc. in
either stoichiometric or catalytic amounts have been used
to catalyze cyanation of carbonyl compounds [6–13].
Besides, an in situ generated catalytic system consisting of
a Lewis acid and N,N-dimethylaniline N-oxide [14] has
also been used for generation of cyanohydrins using
TMSCN. Catalytic cyanosilylation of ketones with phos-
phonium salt [15] and potassium carbonate (K CO ) in
Keywords Carbonyl compounds Á Ketones Á Aldehydes Á
TMSCN Á K CO Á DMSO
2
3
Introduction
Cyanohydrins are versatile intermediates which can be
easily transformed into a wide variety of valuable com-
pounds, such as a-amino acids, a-hydroxy acids, b-amino
alcohols, vicinal diols, and a-hydroxy ketones that are
useful as pharmaceuticals, agrochemicals, and insecticides
2
3
dimethyl formamide (DMF) [16] is also reported. Most of
these procedures have drawbacks such as harsh reaction
conditions, tedious methods for work-up, and toxic or
expensive catalysts. Reaction between TMSCN and car-
bonyl compounds without catalyst has not been reported.
In continuation of our interest in process chemistry,
using various techniques including microwave-assisted
reactions and ionic liquids as solvents [17–20], we have
successfully developed a simple, catalyst-free, one-step,
environmentally benign synthetic protocol for cyanohydrin
formation from carbonyl compounds.
[
1, 2].
Cyanohydrins are usually synthesized by interaction of a
carbonyl compound with a nucleophilic cyanide source.
Several valuable cyanation reagents have been reported in
the literature [3, 4]. Amongst them, trimethylsilyl cyanide
(
TMSCN) seems to be one of the most effective and
comparatively safer sources for nucleophilic addition of
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-011-0613-4) contains supplementary
material, which is available to authorized users.
Results and discussion
RM .. BS a. i Dr we ag ani (&) Á M. D. Kakwani Á N. H. Palsule Desai Á
Department of Pharmaceutical Sciences and Technology,
Institute of Chemical Technology, Mumbai, India
e-mail: ms.degani@ictmumbai.edu.in
While synthesizing novel intermediates useful in focused
small-molecule library synthesis, we had attempted the
reaction using a reported method, i.e., K CO in DMF [16],
2
3
to catalyze addition of TMSCN to carbonyl compounds to
123

4
62
M. S. Degani et al.
O
NC OTMS
R'
NC OH
R'
This DMSO–water system was applicable to a wide
range of carbonyl compounds with excellent yields. The
reactions were monitored by thin-layer chromatography
Solvent
Catalyst
+
TMSCN
+
R
R'
R
R
a
b
(TLC) for completion, and the products were isolated and
Scheme 1
further confirmed by spectral analysis. The data illustrated
in Table 2 demonstrate that a variety of acyclic, alicyclic,
and aromatic aldehydes as well as ketones may be
employed in the DMSO–water system to obtain the cor-
responding cyanohydrin in 75–95% yields. Among all
substrates, cyclohexanone shows the maximum yield and
minimum reaction time, i.e., 95% in just 15 min. Bridged
cyclic rings such as adamantanone, camphor, etc. require
more time. In case of a,b-unsaturated carbonyl compounds,
up to 90 min reaction time was required, probably due to
the lower temperature used to achieve selectivity at the
carbonyl center. Aromatic aldehydes or ketones can also be
transformed to the corresponding cyanohydrins using the
DMSO–water system. To check the stability of the acid-
labile group in the newly developed DMSO–water system,
an N-BOC protected ketone was subjected to similar
reaction conditions. The reaction led to formation of the
corresponding cyanohydrin without cleavage of BOC,
which is acid labile. Hence it can be concluded that the
reaction can also be applicable to compounds containing
acid-labile groups.
Table 1 Effect of solvent on reaction
a
Entry
Solvent
Catalyst
Yield/%
Trimethylsilyl
ether (a)
Cyanohydrin
(b)
1
2
3
4
5
6
7
8
DMF
K
K
K
K
K
2
CO
2
CO
2
CO
2
CO
2
CO
3
3
3
3
3
90
25
25
20
–
–
DMF–water
DMSO
63
–
DMSO–water
Water
60
–
DMSO–water
Water
None
None
None
–
95
–
–
DMSO
95
–
give trimethylsilyl ether, which could be further converted
to the corresponding cyanohydrin using acid such as
hydrochloric acid, trifluoroacetic acid, etc. However the
acidic reaction conditions could not be tolerated by sub-
strates having acid-labile functional groups. Hence, to
make the reaction applicable to such compounds, a
mild, neutral, one-step synthetic methodology would be
valuable.
A plausible mechanism for synthesis of cyanohydrin
using TMSCN in the DMSO–water system is illustrated in
Scheme 2. This reaction presumably occurs via activation
of the trimethylsilyl cyanide by coordination of the DMSO
oxygen atom with the silicon atom of TMSCN, leading to
the formation of intermediate I. The observation that pH in
the DMSO–water system remains at 6–7 throughout the
reaction, while if only water is used the pH changes to 2–3
on addition of TMSCN, further indicates that hydrogen
cyanide does not form in the DMSO–water system.
The carbonyl substrate forms an intermediate II with
this activated trimethylsilyl cyanide complex. In other
reported methods [16], intermediate II breaks down to give
trimethylsilyl ether III and releases solvent, and trimethyl-
silyl ether, which are isolated. However, in our process,
unlike in the DMF–K CO system, intermediate III is
In this work, efforts have been directed to develop a
simple synthetic methodology for one-step cyanohydrin
formation in a mild and neutral reaction environment
(
Scheme 1).
Effects of different solvents on cyanohydrin formation
were studied. A set of reactions (listed in Table 1) were
attempted to optimize a suitable dipolar aprotic solvent in
conjunction with K CO , which was reported as a catalyst
2
3
earlier. It is observed that addition of water in small
quantity to the DMF–K CO system resulted in conversion
2
3
of the intermediate trimethylsilyl ether to cyanohydrins.
This was also observed in the case of the dimethyl sulf-
oxide (DMSO)–K CO system (Table 1, entry 4). Water
2
3
neither observed by TLC during the course of reaction nor
isolated. Instead, because of water, the complex II breaks
down directly to cyanohydrin and trimethylsilyl hydroxide.
In conclusion, the DMSO–water system for cyanohydrin
formation in a single step using TMSCN as cyanating agent
was developed as a novel methodology with mild and
neutral conditions and is applicable to diverse carbonyl
compounds. Further, this reaction system works at room
temperature without any catalyst or any special activation.
The reaction is also applicable to aromatic carbonyl com-
pounds and compounds having acid-labile functionalities.
The mild reaction conditions, without catalysts, good
2
3
alone as a solvent did not generate the desired product,
probably due to insolubility of substrates. To understand
the role of K CO , a reaction was attempted without it.
2
3
However, surprisingly, the DMSO–water system without
any other catalyst resulted in direct conversion of carbonyl
substrate to cyanohydrin in excellent yields.
Carbonyl compounds with diverse functional groups
were converted to their corresponding cyanohydrins using
the newly developed DMSO–water system with TMSCN,
and results are listed in Table 2.
1
23

A single-step, mild, neutral, catalyst-free method
463
Table 2 List of substrates converted to corresponding cyanohydrins
a
b
TMSCN /mmol
c
Yield /%
Entry
1
Substrates
Product
Time/min
30
m.p./°C [Lit]
1.3
85
Oil [21]
2
3
1.3
15
60
90
29 [10]
1.5
1.5
93
88
258 [22]
4
60
193 [23]
d
5
1.5
1.3
30
45
78
90
Oil [24]
Oil [25]
6
d
7
1.5
1.3
30
30
93
94
Oil [26]
Oil [27]
d
8
9
1.5
30
80
Oil [28]
123

4
64
M. S. Degani et al.
Table 2 continued
a
b
TMSCN /mmol
c
Yield /%
Entry
Substrates
Product
Time/min
40
m.p./°C [Lit]
1
0
1
1.5
75
130 [29]
1
1.5
120
75
Oil [30]
a
b
c
d
All reactions carried out using DMSO–water system (10:2) at room temperature unless otherwise specified
mmol compared with substrate (1 mmol)
Isolated yield
Reaction carried out at 0–10 °C
Scheme 2
S
O
O
O
Si
CN
R
R'
R
R'
[I]
H C
3
TMSO
R
CN
R'
S
O
H C Si CN
3
Si
O
H C
3
[
III]
R'
R
CN
S
S
S
O
O
[II]
O
H O
2
HO
CN
R'
H3C
H C Si OH
3
R
H3C
yields, and the simplicity of the procedure make this
method attractive for scale-up purpose.
recorded in DMSO-d and CDCl with a JEOL 300-MHz
6 3
high-resolution NMR spectrometer using tetramethyl-
silane (TMS) as internal standard. Multiplicities are
abbreviated as follows: singlet (s), doublet (d), triplet
(t), multiplet (m), and broad (br). Melting points were
determined on Veego VMP-DS melting point apparatus.
Analytical TLC was performed on precoated plastic
sheets of silica gel G/UV-254 of 0.2 mm thickness
(Merck).
Experimental
Infrared (IR) measurements were done as KBr pellets for
1
solids using a PerkinElmer Spectrum RXI FT-IR. The H
1
and C nuclear magnetic resonance (NMR) spectra were
3
1
23

A single-step, mild, neutral, catalyst-free method
Representative general procedure
465
7. Cordoba R, Csaky AG, Plumet J (2004) Arkivoc (iv):94
8
9
. Lundgren S, Ihre H, Moberg C (2008) Arkivoc (vi):73
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9:38
3
To a solution of carbonyl compound (0.5 mmol) in 5 cm
3
DMSO–water (5:1 v/v) trimethylsilyl cyanide (0.7 mmol)
was added slowly. The reaction mixture was stirred at room
temperature. The reaction was monitored by TLC for
consumption of starting material. The reaction mixture was
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1
1
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3
extracted with ethyl acetate (2 9 25 cm ), and the com-
3
bined layer was washed with water (2 9 10 cm ) and
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1
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concentrated in vacuo to obtain a crude mixture. The
products were purified from the crude mixture by flash
chromatography using silica gel G as stationary phase and
petroleum ether:ethylacetate (8:2) as mobile phase.
1
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Acknowledgments The authors N.H.P.D. and R.B. thank UGC, and
M.D.K. thanks DBT, New Delhi for their financial support. Authors
are grateful to Centaur Pharmaceuticals Pvt. Ltd. for recording NMR
spectra.
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