DMAP-catalyzed cyanation of aldehydes and ketones with ethyl cyanoformate

Article abstract of DOI:10.1016/j.tetlet.2010.04.123

The cyanation of carbonyl compounds with ethyl cyanoformate is catalyzed by 4-dimethylaminopyridine (DMAP) to afford the corresponding cyanohydrin carbonates in excellent yields. The system provides a convenient method for cyanation of carbonyl compounds

Full text of DOI:10.1016/j.tetlet.2010.04.123

Tetrahedron Letters 51 (2010) 3547–3549
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Tetrahedron Letters
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DMAP-catalyzed cyanation of aldehydes and ketones with ethyl cyanoformate
a
a
Shohei Aoki a, Shunsuke Kotani b, , Masaharu Sugiura , Makoto Nakajima
*
a Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
b Priority Organization for Innovation and Excellence, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The cyanation of carbonyl compounds with ethyl cyanoformate is catalyzed by 4-dimethylaminopyridine
(DMAP) to afford the corresponding cyanohydrin carbonates in excellent yields. The system provides a
convenient method for cyanation of carbonyl compounds without using metal catalysts or solvents.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 26 March 2010
Revised 24 April 2010
Accepted 28 April 2010
Available online 8 May 2010
The nucleophilic addition of cyanide to carbonyl compounds is a
powerful method for the construction of carbon–carbon bonds and
represents an invaluable tool in organic synthesis.1,2 Although
hydrogen cyanide (HCN) is the simplest cyanide source for cyana-
tion of carbonyl compounds, it is strongly toxic and difficult to
handle. Several alternative cyanating reagents have been devel-
oped. Trimethylsilyl cyanide3 has most commonly been used as a
cyanide ion source because it is safer and easier to handle than
hydrogen cyanide. Acyl cyanides4 and alkyl cyanoformates5 have
been used as alternative cyanating reagents to afford the O-car-
bonylated cyanohydrins (Fig. 1). With these reagents, several
methods using tertiary amines,5 tributyltin cyanide,6 or dimethyl
sulfoxide4b,7 as an activator have recently been reported. Here,
we report a metal-free cyanation of aldehydes and ketones with
ethyl cyanoformate in the presence of a catalytic amount of 4-
dimethylaminopyridine (DMAP).
were less reactive than aliphatic aldehydes (entries 5–10). There-
fore, the use of 5 mol % catalyst was required for completion of
the reaction. The cyanation of p-anisaldehyde (4e) bearing an elec-
tron-donating substituent was quite slow, but provided a good
yield after 24 h (entry 5). Introduction of an electron-withdrawing
group at the para-position increased the reactivity (entry 6). Prod-
ucts were obtained in excellent yields for the reaction of sterically
hindered aromatic aldehydes, such as 1- or 2-naphthaldehyde (4h
O
O
TMS CN
EtO
CN
Ph
CN
3
1
2
Figure 1. Cyanide sources.
We initially examined the cyanation of 3-phenylpropanal (4a)
with several cyanating reagents (1–3) in the presence of 1 mol %
of DMAP in acetonitrile (Table 1).8 Although the product yields
were low for trimethylsilyl cyanide (1) and benzoyl cyanide (2)
(entries 1 and 2), ethyl cyanoformate (3) gave the corresponding
cyanohydrin carbonate (7a) in an excellent yield (97%) (entry 3).9
No product was obtained in the absence of DMAP (entry 4), imply-
ing that DMAP was essential for cyanation with cyanoformate 3.
The concentration greatly influenced the rate of the cyanation.
The reaction in 0.5 M acetonitrile completed within 0.5 h to afford
the corresponding product (entry 5).
Table 1
Cyanation of 3-phenylpropanal (4a) with cyanide sources (1–3)a
R
O
O
DMAP (1 mol %)
+
RCN
Ph
H
CH3CN, rt
Ph
CN
4a
1-3
5-7a
Entry
RCN
CH3CN (mL)
Time (h)
Yieldb (%)
With the optimal conditions in hand, we explored the scope of
aldehydes for the cyanation (Table 2).10 Aliphatic aldehydes under-
went cyanation in good to high yields in the presence of 1 mol %
DMAP (entries 1–3), although the sterically congested aldehyde
4c resulted in a moderate yield. In contrast, aromatic aldehydes
1
2
1
2
3
3
3
5
5
5
5
1
2
2
2
2
<10
Trace
97
0
96
3
4c
5
0.5
a
Unless otherwise noted, reactions were carried out by addition of a cyanide
source (0.55 mmol) to a solution of 3-phenylpropanal (4a) (0.5 mmol) and DMAP
(1 mol %) in CH3CN at room temperature.
b
Isolated yield.
The reaction was conducted without catalyst.
* Corresponding author. Tel./fax: +81 96 371 4878.
E-mail address: skotani@gpo.kumamoto-u.ac.jp (S. Kotani).
c
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.123

3548
S. Aoki et al. / Tetrahedron Letters 51 (2010) 3547–3549
O
O
O
N
Table 2
Cyanation of various aldehydes (4) with ethyl cyanoformate (3) catalyzed by DMAPa
EtO
CN
O
OEt
Me2N
O
I
R1 R2
NC
O
O
DMAP
O
OEt
CN
7a-j
+
EtO
CN
R
H
CH3CN, rt
R
O
O
Aldehyde
4a-j
3
N
OEt
N
OEt
Entry
Aldehyde
DMAP mol%
Time (h)
Yieldb (%)
Me2N
CN
Me2N
1
2
3
4
5
6
7
8
PhCH2CH2CHO 4a
iPrCHO 4b
tBuCHO 4c
1
1
1
5
5
5
5
5
5
5
0.5
1
2
8
24
2
8
6
8
24
96
83
55
99
81
98
97
97
99
78
II
R1 R2
NC
III
O
PhCHO 4d
R1 R2
4-MeOC6H4CHO 4e
4-BrC6H4CHO 4f
2-Furfural 4g
1-Naphthaldehyde 4h
2-Naphthaldehyde 4i
4-HO2CC6H4CHO 4j
Figure 2. Proposed reaction mechanism for cyanation catalyzed by DMAP.
9
10c,d
acetophenone (8c), an aromatic ketone, gave the cyanohydrin
derivative in a low yield (entry 4). Acyclic ketones (8d and 8e) gave
the cyanohydrins in 87% and 73% yields, respectively (entries 5 and
6), although the cyanation of a sterically hindered ketone, pinaco-
lone (8f), was slow (entry 7).
A proposed mechanism for the cyanation catalyzed by DMAP is
shown in Figure 2. First, the nitrogen atom of the pyridine ring of
DMAP (I) attacks the carbonyl carbon of ethyl cyanoformate to
form the cationic carbamate intermediate (II).12 Next, the released
cyanide anion reacts with aldehydes or ketones, and the alkoxide
anion of the cyanohydrin (III) is generated. Finally, the alkoxide
is carboxylated to afford the corresponding cyanohydrin carbonate,
and DMAP is regenerated to participate in a subsequent catalytic
cycle (I).
In conclusion, we successfully demonstrated the effective and
convenient cyanation of various aldehydes and ketones using
DMAP as a nucleophilic catalyst. The system provides an effective
method for cyanation of carbonyl compounds without metal cata-
lysts or solvents. Investigations to clarify the detailed reaction
mechanism and to develop asymmetric version are currently
underway.
a
Unless otherwise noted, reactions were carried out by addition of ethyl cya-
noformate (0.55 mmol) to a solution of aldehydes (0.5 mmol) and DMAP in CH3CN
(1 mL) at room temperature.
b
Isolated yield.
c
The reaction was conducted using 2.5 equivalents of ethyl cyanoformate (3).
EtOH (3 mL) was used instead of acetonitrile.
d
and 4i). The reaction of aldehyde 4j, which contains a carboxyl
group, yielded the desired product in 78% yield using 2.5 equiv of
cyanide source 3 (entry 10). It should be noted that the current
method tolerates carboxyl groups. Furthermore, the current meth-
od is effective and convenient for the synthesis of cyanohydrin
derivatives because simple extraction or chromatography affords
the corresponding products.
Next, we investigated application of the DMAP-catalyzed cyana-
tion to ketones (Table 3).11 The reaction of cyclopentanone (8a)
proceeded quite slowly to give the corresponding cyanohydrin in
a low yield (entry 1). The reactivities of ketones were much lower
than those of aldehydes. As shown in Table 1, concentration was
important for this cyanation. The reaction of 8a was performed
using 10 mol % DMAP without solvent (entry 2). The reaction did
proceed to afford the corresponding cyanohydrin carbonate in a
good yield (85%). The reaction of cyclohexanone (8b) gave a quan-
titative yield for the same reaction time (entry 3). The reaction of
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture, Sports, Sci-
ence and Technology of Japan.
Table 3
Cyanation of various ketones (8) with ethyl cyanoformate (3) catalyzed by DMAPa
Supplementary data
O
O
O
DMAP (10 mol %)
CN
neat, rt
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.123.
O
OEt
CN
+
R1 R2
EtO
R1
R2
9a-f
Ketone
8a-f
3
References and notes
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1c
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Acetophenone 8c
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44
a
Unless otherwise noted, reactions were carried out by addition of ethyl cya-
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without solvent at room temperature.
b
Isolated yield.
The reaction was conducted in acetonitrile (1 mL).
c

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and DMAP (0.61 mg, 0.005 mmol, 1 mol %) in acetonitrile (1 mL) was added
ethyl cyanoformate (3) (0.055 mL, 0.55 mol, 1.1 equiv) at room temperature
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3): To a stirred mixture of ketone 8b (0.45 mmol, 1.0 equiv.) and DMAP
(5.5 mg, 0.045 mmol, 10 mol %) was added ethyl cyanoformate (3) (0.049 mL,
0.5 mol, 1.1 equiv) at room temperature under argon atmosphere. The mixture
was stirred at the same temperature for 24 h. The mixture was purified by
column chromatography (silica gel: 6 g, hexane–EtOAc: 4/1) to give the
product 9b (88.0 mg, 99% yield) as a colorless oil.
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observed in DMAP-promoted acylation of alcohols.