A facile direct conversion of aldehydes to esters and amides using acetone cyanohydrin

Article abstract of DOI:10.1016/j.tetlet.2005.09.173

Aromatic aldehydes with electron-withdrawing groups undergo rapid reactions with a variety of alcohols and secondary amines to afford the corresponding esters and amides, respectively, in high yields, when treated with NaCN or acetone cyanohydrin and base under ambient reaction conditions. In case of α,β-unsaturated aldehydes, simultaneous reduction of the CC bond along with esterification occurred to produce the saturated esters in high yields.

Full text of DOI:10.1016/j.tetlet.2005.09.173

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8303–8306
A facile direct conversion of aldehydes to esters and amides
using acetone cyanohydrin
I. Victor Paul Raj and A. Sudalai*
Chemical Engineering and Process Development Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Received 15 August 2005; revised 22 September 2005; accepted 28September 2005
Available online 14 October 2005
Abstract—Aromatic aldehydes with electron-withdrawing groups undergo rapid reactions with a variety of alcohols and secondary
amines to afford the corresponding esters and amides, respectively, in high yields, when treated with NaCN or acetone cyanohydrin
and base under ambient reaction conditions. In case of a,b-unsaturated aldehydes, simultaneous reduction of the C@C bond along
with esterification occurred to produce the saturated esters in high yields.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
electron deficient aldehydes to esters and amides medi-
ated by acetone cyanohydrin in the presence of base.
The direct transformation of aldehydes into the corre-
sponding esters1 and amides2 under mild conditions is
often required in organic synthesis especially in the syn-
thesis of natural products.3 Although such functional
group transformation of aldehydes into esters in the
presence of alcohols has been reported,4 these methods
usually require harsh conditions and are effective for a
limited range of substrates (electron-rich aldehydes5
and primary alcohols). Recently, several new procedures
During our investigation of the hydrocyanation of 4-
nitrobenzaldehyde with acetone cyanohydrin in the
presence of Et3N in methanol as solvent, we found
surprisingly that the corresponding methyl ester 2 was
obtained in 92% yield instead of the expected cyano-
hydrin 1 (Scheme 1). Control experiments indicated that
no reaction took place in the absence of either the ace-
tone cyanohydrin or Et3N. Both KOH and Et3N could
be used as the base for this transformation although
t-BuOK and DABCO were found to be less effective.
The results in Table 1 show that a variety of solvents
could be employed successfully for the reaction of
4-nitrobenzaldehyde with methanol. Although most of
the polar solvents displayed comparable activity, meth-
anol was found to give the best yield. However, when
involving oxone,6 SnO2/SBA-1-H2O2 and pyridinium
7
hydrobromide perbromide8 have been employed for
the direct oxidative conversion of aldehydes to esters.
This transformation generally involves an oxidative
pathway and requires more than stoichiometric amount
of oxidants and long reaction times. Also these reagents
are unsatisfactory for aldehydes containing electron-
withdrawing groups. Moreover, formation of minor
amounts of acids often complicates the oxidative pro-
cess. Direct transformation of aldehydes into amides
is also an important method in organic synthesis and
usually requires transition metal catalysts such as
palladium,9 ruthenium10 and rhodium.11 However, these
systems suffer from use of stoichiometric amount of oxi-
dants coupled with low yields of the products. We wish
to report a facile method for the direct conversion of
OH
CN
O2N
1
CHO
O
i
OMe
O2N
O2N
2
Scheme 1. Reaction conditions: (i) 4-nitrobenzaldehyde (5 mmol),
acetone cyanohydrin (5 mmol), Et3N (7.5 mmol), MeOH (5 mL),
25 °C, 2 h.
Keywords: Esterification; Amidation; Reduction; Sodium cyanide.
*
Corresponding author. Tel.: +91 020 25893300; fax: +91 020
25893359; e-mail: a.sudalai@ncl.res.in
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.173

8304
I. V. P. Raj, A. Sudalai / Tetrahedron Letters 46 (2005) 8303–8306
Table 1. Esterification of 4-nitrobenzaldehyde with methanol using
Table 3. Cyanide mediated esterification and reduction of a,b-unsatu-
acetone cyanohydrin: effect of solvents
rated aldehydes with alcohols
Entry
Solvent
Yielda (%)
OH
CHO
CO2R'
1
2
3
4
5
6
7
8
CH3OH
CH3CN
THF
Benzene
CH2Cl2
DMF
92
70
54
20
23
57
83
NaCN or
CN
Et3N, R'OH
R
R
4
Entry Aldehyde
Alcohol
CH3OH
Yield of 4a (%)
Acetone
H2O
CHO
CHO
1
1
93
b
8
a Isolated yield after column chromatographic purification.
b 4-Nitrobenzoic acid was obtained.
OH
2
86
CHO
CHO
3
4
69
88
OH
water was employed as solvent, the only product
obtained was the corresponding carboxylic acid. In
order to understand the scope and generality of the
reaction, a wide range of aldehydes was subjected to
the reaction with a variety of alcohols under these reac-
tion conditions. As can be seen, the method worked
exceedingly well in the case of aromatic aldehydes with
electron-withdrawing groups such as halo, nitro, CF3,
cyano, etc. (Table 2). Unfortunately, the reaction failed
for electron-rich benzaldehydes as well as aliphatic
aldehydes perhaps because the nucleophilic addition of
cyanide ion onto electron-rich aromatic substrates is
more difficult.
OH
CHO
OH
5
76
MeO2C
CHO
OH
OH
OH
6
66
61
64
CF3
CHO
7
MeO
Alcohols such as ethanol, allyl alcohol, propargyl alco-
hol and 2-propanol, etc., when subjected to the reaction,
afforded esters in excellent yields. When 4-nitrobenzal-
dehyde was treated with ethane-1,2-diol the correspond-
ing diester was obtained in 35% yield.
CHO
CHO
8
MeO
OH
9
57
MeO
A noteworthy feature of this protocol is that a,b-unsat-
urated aldehydes when subjected to these reaction con-
ditions gave the corresponding saturated esters (Table
OMe
a Isolated yield after column chromatographic purification.
Table 2. Acetone cyanohydrin-mediated esterification of activated
aromatic aldehydes with alcohols
3). de Vries et al.12 and Kawabata and Hayashi et al.13
have reported similar observations using RuCl3ÆH2O/
PCy3 and a Lewis base, respectively. However, these
reactions suffer from disadvantages such as high temper-
atures, low yields, expensive ligands etc. The present
method is superior to the ruthenium-catalyzed method
from the viewpoint of the high yield of the product,
the use of inexpensive reagents and the mildness of the
reaction conditions. Thus both ester formation and
reduction of the C@C bond were achieved in a single
step for a,b-unsaturated aldehydes when treated with
NaCN or acetone cyanohydrin in the presence of an
alcohol. A wide range of substituted cinnamaldehydes
can be converted into saturated esters when subjected
to these conditions.
O
OH
CHO
OR'
CN
base,
R'OH
R
R
3
Entry
R
Base
Yield of 3a (%)
R0 = methyl
Allylb
Propargylb
c
a
b
c
d
e
f
g
h
3-NO2
4-NO2
4-Cl
Et3N
Et3N
KOH
KOH
Et3N
KOH
KOH
Et3N
78(49)
64
70
78
62
75
63
75
85
92 (75)c
82
4-Br
73
4-CN
3-CF3
4-F
8
0
76
8
3
70
60
61
62
62
67
85
65
58
We have applied the ester formation–reduction strategy
to the synthesis of nabumetone 8, a non-steroidal anti-
inflammatory drug14 (Scheme 2). Thus, alcohol 515 on
reaction with Vilsmeyer–Haack reaction, gave the
unsaturated aldehyde 6, which was subjected to the
cyanide-mediated ester formation–reduction to afford
2-CN
a Isolated yield after column chromatographic purification.
b Acetonitrile was used as solvent.
c The number in the parentheses refers to yields when 2-propanol was
used as the alcohol component.

I. V. P. Raj, A. Sudalai / Tetrahedron Letters 46 (2005) 8303–8306
8305
OH
O
OH
CN
CHO
O
CHO
CN
X
a
b
H
base
MeO
MeO
MeO
O2N
O2N
O2N
O2N
O
6
5
O
O
O
c
OMe
ROH
CN
MeO
or R2NH
8
7
A
X = OR or NR2
Scheme 2. Reagents and conditions: (a) POCl3, DMF, 100 °C, 47%;
(b) acetone cyanohydrin or NaCN, Et3N, CH2Cl2, 25 °C, 2 h, 61%;
(c) MeMgI, THF, ꢀ55 °C, 51%.
Figure 1. Proposed mechanism for the conversion of aldehydes into
esters and amides.
the saturated ester 7 in 61% yield. Treatment of ester 7
with a Grignard reagent gave nabumetone in 51%
yield.
OH
CN
OH
CHO
or
double bond migration
Ar
CN
Ar
NaCN
H
The methodology also worked very well for the direct
conversion of aldehydes into amides. When 4-nitrobenz-
aldehyde was treated with cyclic secondary amine such
as morpholine, pyrrolidine, piperidine, etc., under the
same reaction conditions, the corresponding carboxylic
amides were obtained in good yields (54–63%) (Scheme
3).
O
H
OH
ROH
tautomerization
CN
Ar
CN
OR
Ar
C
B
O
Ar
Figure 2. Proposed mechanism for the conversion of enals into
Mechanistically, we believe that the transformation of
the aldehydes into esters or amides proceeds through
an acyl cyanide intermediate A, as confirmed by its iso-
lation and characterization. The first step may involve
the formation of cyanohydrins. Subsequently, the cya-
nohydrins are converted to the acyl cyanides A by the
way of hydride transfer to acetone (Fig. 1). In the case
of a,b-unsaturated aldehydes, the formation of enol B
by double bond migration of cyanohydrin followed by
tautomerization, provides the corresponding saturated
acyl cyanide C (Fig. 2). The intermediates A and C
may then be converted to esters or amides by reaction
with alcohols and amines, respectively.
saturated esters.
2. Experimental
2.1. General procedure for the esterification and
amidation reactions
A mixture of the aldehyde (5.0 mmol), Et3N or KOH
(7.5 mmol), alcohol or secondary amine (7.5 mmol)
and acetone cyanohydrin (5.0 mmol) in 5 mL of solvent
was stirred for 3 h under an argon atmosphere at 25 °C.
The progress of the reaction was monitored by TLC.
After completion, the solvent was removed under
reduced pressure. The crude product so obtained was
further purified by column chromatography (silica gel)
using a mixture of petroleum ether and ethyl acetate
(9:1) as eluent.
In conclusion, this methodology provides a simple pro-
cedure for the single-step conversion of electron-defi-
cient aldehydes into the corresponding esters and
amides on reaction with either an alcohol or a secondary
amine in excellent yields mediated by acetone cyanohy-
drin or NaCN and base. This protocol is complementary
to existing methods of ester formation, which fail in the
case of electron-deficient aldehydes.
2.2. Selected spectral data
2.2.1. Propargyl 4-bromobenzoate. Yield: 85%; gum.
IR (Neat, cmꢀ1): 1216, 1531, 1608, 1733, 3021, 3306;
1H NMR (200 MHz, CDCl3):
d
2.53–2.50 (t,
O
O
OH
CN
J = 4.0 Hz, 1H), 4.91–4.89 (d, J = 4.0 Hz, 2H), 7.60–
7.56 (d, J = 8.0 Hz, 2H), 7.94–7.90 (d, J = 8.0 Hz, 2H);
13C NMR (75 MHz, CDCl3): d 52.57, 75.33, 128.33,
129.62, 130.87, 131.74, 135.14, 139.29, 164.69; MS
(m/z, % relative intensity): 238(M +, 2) 183 (54), 155
(25), 115 (34), 104 (27), 75 (64), 50 (100). Analysis
C10H7BrO2 requires C, 50.24; H, 2.95; Br, 33.42. Found
C, 50.20; H, 2.91; Br, 33.40.
CHO
Et3N, R2NH
NR2
OH
+
O2N
O2N
O2N
9
10
Yield of 10 (%)
Yield of 9 (%)
R2N =
O
N
31
33
34
63
57
54
N
2.2.2. 4-Nitrobenzoyl nitrile. Yield: 32%; colourless
solid; mp: 115 °C (lit.16 116 °C). IR (CHCl3, cmꢀ1) 1102,
1526, 1606, 1731, 2245, 2450, 2924, 3453; 1H NMR
(200 MHz, CDCl3): d 8.33–8.16 (m, 4H); 13C NMR
(75 MHz CDCl3): d 72.75, 121.31, 126.52, 133.80,
N
Scheme 3. Direct amidation of aldehydes.

8306
I. V. P. Raj, A. Sudalai / Tetrahedron Letters 46 (2005) 8303–8306
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Acknowledgements
V.P.R.I. thanks CSIR, New Delhi, for the award of
research fellowships. Financial Grants from DST, New
Delhi (Sanction No SR/S1/OC-22/2002) is gratefully
acknowledged. The authors thank Dr. B. D. Kulkarni,
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