Cyanobenzoylation and hydrocyanation of aldehydes with benzoyl cyanide using no catalyst

Article abstract of DOI:10.1021/ol0348295

(Matrix presented) In the presence of MS 4A in DMSO, cyanobenzoylation of various aldehydes with benzoyl cyanide proceeded very smoothly to give the corresponding cyanohydrin benzoates in high to excellent yields without an acid or a base. On the other hand, reaction of aldehydes with BzCN in DMSO-H₂O also occurred readily to afford the corresponding free cyanohydrins exclusively.

Full text of DOI:10.1021/ol0348295

ORGANIC
LETTERS
2003
Vol. 5, No. 15
2679-2681
Cyanobenzoylation and Hydrocyanation
of Aldehydes with Benzoyl Cyanide
Using No Catalyst
Tsutomu Watahiki, Sayoko Ohba, and Takeshi Oriyama*
Department of EnVironmental Sciences, Faculty of Science, Ibaraki UniVersity,
2-1-1 Bunkyo, Mito 310-8512, Japan
tor@mx.ibaraki.ac.jp
Received May 14, 2003
ABSTRACT
In the presence of MS 4Å in DMSO, cyanobenzoylation of various aldehydes with benzoyl cyanide proceeded very smoothly to give the
corresponding cyanohydrin benzoates in high to excellent yields without an acid or a base. On the other hand, reaction of aldehydes with
BzCN in DMSO−H O also occurred readily to afford the corresponding free cyanohydrins exclusively.
2
Hydrocyanation and cyanosilylation of aldehydes are im-
portant carbon-carbon bond-forming reactions, because they
give versatile intermediates such as cyanohydrins and cy-
anohydrin silyl ethers.1 Among various cyanide ion sources,
trimethylsilyl cyanide is a safer and easily handled reagent
compared to hydrogen cyanide, and various cyanosilylations
of aldehydes catalyzed by Lewis acids have been already
developed.2 Recently, the direct preparation of cyanohydrin
esters by the reaction of aldehydes with acyl cyanides has
been also reported.3 Acyl cyanides are also safer and
commercially available reagents.4 Although these reactions
are very efficient methods to give cyanohydrin derivatives,
base catalysts such as potassium carbonate,5 1,4-diazabicyclo
[2.2.2]octane (DABCO)6 are required to promote the cy-
anobenzoylation.
In contrast, very recently, we have shown that the silylation
of alcohols with trialkylsilyl chloride in DMSO-hexane
proceeds very smoothly at room temperature without a
catalyst.7 This reaction presumably occurs via an activation
of the trialkylsilyl chloride by coordination of the DMSO
oxygen atom to the silicon atom. Therefore, we envisioned
that if an acyl cyanide was activated by DMSO in a similar
way, cyanobenzoylation of aldehyde with acyl cyanide would
take place efficiently to afford the corresponding cyanohydrin
ester without a base catalyst. From the viewpoint of green
chemistry, a noncatalytic process is very significant and
attractive for synthetic organic chemistry. However, efficient
cyanobenzoylation or hydrocyanation without a catalyst has
not been reported so far. Herein, we wish to report efficient
and convenient methods to produce cyanohydrin benzoate
(2) or cyanohydrin (3) selectively from various aldehydes
(1) with benzoyl cyanide under catalyst-free conditions
(Scheme 1).
(1) (a) Cox, R. F. B.; Stormont, R. T. Organic Syntheses; Wiley: New
York, 1943; Collect. Vol. II, p 7. (b) Wagner, E. C.; Baiser, M. Organic
Syntheses; Wiley: New York, 1955; Collect. Vol. III, p 324. (c) Effenberger,
F. Angew. Chem., Int. Ed. Engl. 1994, 33, 1555. (d) Gregory, R. J. H. Chem.
ReV. 1999, 99, 3649.
(2) (a) Evans, D. A.; Truesdale, L. K.; Carroll, G. L. J. Chem. Soc.,
Chem. Commun. 1973, 55. (b) Vougioukas, A. E.; Kagan, H. B. Tetrahedron
Lett. 1987, 28, 5513. (c) Kobayashi, S.; Tsuchiya, Y.; Mukaiyama, T. Chem.
Lett. 1991, 537. (d) Scholl, M.; Fu, G. C. J. Org. Chem. 1994, 59, 7178.
(e) Yang, Y.; Wang, D. Synlett 1997, 1379.
(3) (a) Marvel, C. S.; Brace, N. O.; Miller, F. A.; Johnson, A. R. J. Am.
Chem. Soc. 1949, 71, 34. (b) Photis, J. M. J. Org. Chem. 1981, 46, 182. (c)
Scholl, M.; Lim, C.-K.; Fu, G. C. J. Org. Chem. 1995, 60, 6229. (d)
Okimoto, M.; Itoh, T.; Chiba, T. J. Org. Chem. 1996, 61, 4835. (e)
Kawasaki, Y.; Fujii, A.; Nakano, Y.; Sakaguchi, S.; Ishii, Y. J. Org. Chem.
1999, 64, 4214. (f) 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.
(4) Hu¨nig, S.; Schaller, R. Angew. Chem., Int. Ed. Engl. 1982, 21, 36.
(5) Okimoto, M.; Chiba, T. Synthesis 1996, 1188.
(6) Hoffmann, H. M. R.; Ismail, Z. M.; Hollweg, R.; Zein, A. R. Bull.
Chem. Soc. Jpn. 1990, 63, 1807.
(7) Watahiki, T.; Matsuzaki, M.; Oriyama, T. Green Chem. 2003, 5, 82.
10.1021/ol0348295 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/03/2003

Scheme 1. Cyanobenzoylation or Hydrocyanation of
Table 2. Effect of Additive for Cyanobenzoylation of
3-Phenylpropanal (1a)a
Aldehyde with Benzoyl Cyanide
run
additive
yieldb of 2a [%]
yieldb of 3a [%]
1
2
3
4
5
6
MS 4Å (40 mg)
MS 3Å (40 mg)
MS 5Å (40 mg)
MgSO4 (40 mg)
MS 4Å (100 mg)
MS 4Å (150 mg)
92
90
72
91
90
92
7
8
20
7
tr
0
Initially, we undertook to examine the solvent effect for
the cyanobenzoylation of 3-phenylpropanal (Table 1). The
a All reactions were carried out in DMSO using aldehyde 1a (0.3 mmol)
and BzCN (0.36 mmol) at rt for 6 h. b Yields of isolated products.
Table 1. Effect of Solvent for Cyanobenzoylation of
3-Phenylpropanal (1a)a
run
solvent
yieldb of 2a [%]
yieldb of 3a [%]
Table 3. Synthesis of Various Cyanohydrin Benzoates (2a-h)
from Various Aldehydes (1a-h)a
1
2
3
4
5
CH2Cl2
MeCN
THF
DMF
DMSO
3
38
15
64
53
4
27
55
26
39
run
RCHO (1)
time [h]
yieldb [%]
1
2
3
4
Ph(CH2)2CHO (1a )
CH3(CH2)5CHO (1b)
c-C6H11CHO (1c)
PhCH(CH3)CHO (1d )
t-BuCHO (1e)
PhCHO (1f)
p-BrC6H4CHO (1g)
2-NaphCHO (1h )
6
6
6
1
24
3
92
81
90
80
97
89
89
84
a All reactions were carried out using aldehyde 1a (0.3 mmol) and BzCN
(0.36 mmol) at rt for 6 h. b Yields of isolated products.
5
6c
7c
8c
3
3
reaction of 3-phenylpropanal (1a) with 1.2 equiv of benzoyl
cyanide in CH2Cl2 at room temperature for 6 h scarcely
afforded the corresponding cyanohydrin products (2a and
3a, run 1). On the other hand, when MeCN or THF was
used as a solvent, combined yields of cyanohydrin benzoates
(2a) and free cyanohydrins (3a) were moderate (runs 2 and
3). In the cases of using DMF or DMSO, the reactions were
carried out smoothly (runs 4 and 5). As expected, DMSO
turned out to be the most effective solvent and to activate
benzoyl cyanide efficiently.
Under the above conditions, the aldehyde was transformed
into the cyanohydrin benzoate as well as the free cyanohydrin
simultaneously because benzoyl cyanide is hydrolyzed by a
trace amount of water in the reaction mixture and hydrogen
cyanide is generated. Therefore, to prevent the hydrolysis
of the benzoyl cyanide, the reaction was carried out in the
presence of various dehydrating agents.
When cyanobenzoylation of aldehyde was performed with
40 mg of molecular sieves (MS) 4Å, the yield of desired 2a
could be greatly improved and the formation of 3a was
suppressed (Table 2, run 1). MS 3Å and MgSO4 were also
effective as dehydrating agents (runs 2 and 4). Additionally,
by increasing the loading of MS 4Å, 2a could be synthesized
exclusively in excellent yield (92%) and no 3a was obtained
(run 6).
a All reactions were carried out in DMSO using aldehyde 1 (0.3 mmol)
and BzCN (0.36 mmol) in the presence of MS 4Å (150 mg) at rt, unless
otherside stated. b Yields of isolated products. c Reactions were carried out
at 60 °C.
hand, cyanobenzoylation of aromatic aldehydes needed a
slightly higher reaction temperature (60 °C) (runs 6-8).
Next, to compare the reactivity of reagents, we attempted
the preparation of cyanohydrin derivatives from 3-phenyl-
propanal with various acyl cyanides and trimethylsilyl
cyanide (Table 4). By using p-toluoyl cyanide,8 the corre-
sponding cyanohydrin p-methylbenzoate (2i) was similarly
formed in 91% yield (run 2). In contrast, the reaction of
aldehyde with acetyl cyanide gave the corresponding cy-
anohydrin acetate (2j) in only 16% yield (run 3). This result
can be considered to be caused by easy hydrolysis or lower
reactivity of the acetyl cyanide compared to that of the
benzoyl cyanide. Additionally, in the case of trimethylsilyl
cyanide, the cyanohydrin (3a) could be isolated in 75% yield
by treatment of 1 N HCl solution for desilylation after
cyanosilylation (run 4). From these control experiments, it
is clear that benzoyl cyanide is the most promising cyanation
agent under these reaction conditions.
Finally, we investigated hydrocyanation of aldehydes by
adding water instead of MS 4Å (Table 5). We presumed that
if water is added intentionally in a reaction mixture, benzoyl
cyanide would be hydrolyzed and hydrocyanation would
occur by hydrogen cyanide. The reaction of 3-phenylpropanal
Representative and successful examples for the synthesis
of various cyanohydrin benzoates from aliphatic and aromatic
aldehydes are collected in Table 3. Open-chain and cyclic
aliphatic aldehydes were cyanobenzoylated in high to excel-
lent yields under the optimal reaction conditions (runs 1-5).
Especially, it should be noted that the sterically hindered
trimethylacetaldehyde (1e), which branched at the R-position
to the carbonyl group, was transformed into the correspond-
ing cyanohydrin benzoate in 97% yield (run 5). On the other
(8) For some reports of synthesis of the substituted acyl cyanides, see:
(a) Olah, G. A.; Arvanaghi, M.; Prakash, G. K. S. Synthesis 1983, 636. (b)
Murahashi, S.; Naota, T.; Nakajima, N. Tetrahedron Lett. 1985, 26, 925.
(c) Murahashi, S.; Naota, T. Synthesis 1993, 433.
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Org. Lett., Vol. 5, No. 15, 2003

Table 4. Synthesis of Various Cyanohydrin Derivatives from 3-Phenylpropanal (1a) Using Various Cyanating Reagentsa
a All reactions were carried out in DMSO using aldehyde 1a (0.3 mmol) and RCN (0.36 mmol) in the presence of MS 4Å (150 mg) at rt for 6 h. b Yields
of isolated products. c The corresponding cyanohydrin (3a) was obained in 53% yield. d After reaction, 1 N HCl/rt/0.5 h.
In summary, we have presented highly efficient and con-
Table 5. Synthesis of Various Cyanohydrins (3a-f) from
Various Aldehydes (1a-f)a
venient methods for the cyanobenzoylation or hydrocyanation
of various aldehydes with benzoyl cyanide in DMSO. These
reactions proceeded smoothly under mild reaction condi-
tions, and various cyanohydrin benzoates or cyanohydrins
were obtained in high to excellent yields. It is possible to
obtain cyanohydrin benzoate or free cyanohydrin by adding
MS 4A or water, respectively. This is the first example for
the synthesis of cyanohidrin derivatives using no catalyst.
Accordingly, these reactions are very attractive from the
standpoints of green chemistry, because the atom economy
is extremely high to consume almost all of the reagent in
the case of cyanobenzoylation. Further research addressing
the scope and elucidation of the reaction mechanism is under
way in our laboratory.
run
RCHO (1)
time [h]
yieldb [%]
1
2
3
4
5
6
Ph(CH2)2CHO (1a )
CH3(CH2)5CHO (1b)
c-C6H11CHO (1c)
PhCH(CH3)CHO (1d )
t-BuCHO (1e)
6
6
24
6
3
6
91
82
100
93
74
60
PhCHO (1f)
a All reactions were carried out in DMSO-hexane (5:1) using aldehyde
1 (0.3 mmol), BzCN (0.36 mmol) at rt. b Yields of isolated products.
with benzoyl cyanide in DMSO-H2O (5:1) was performed
smoothly to afford the corresponding free cyanohydrin
exclusively in high yield (run 1). Furthermore, this method
could be applied to selective syntheses of various cyanohy-
drins. Hydrocyanation proceeded efficiently both with steri-
cally hindered aldehydes as well as with open-chain ones in
high to excellent yields (runs 2-5). However, hydrocyanation
of an aromatic aldehyde occurred more slowly than those
of aliphatic aldehydes, and the corresponding cyanohydrin
was obtained in moderate yield (run 6).
Acknowledgment. T.W. thanks the Sasakawa Scientific
Research Grant from The Japan Science Society for generous
financial support.
Supporting Information Available: Experimental pro-
cedures and 1H NMR, 13C NMR, and IR spectra for
compounds 2a-j and 3a-f. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0348295
Org. Lett., Vol. 5, No. 15, 2003
2681