Indium-mediated coupling of bromoacetonitriles with aromatic acyl cyanides: convenient synthesis of aromatic α-cyano ketones

Article abstract of DOI:10.1016/S0040-4039(02)00925-5

Indium-mediated coupling of bromoacetonitrile and 2-bromopropionitrile with a variety of aromatic acyl cyanides afforded the corresponding aromatic α-cyano ketones in moderate to good yields under mild and neutral conditions.

Full text of DOI:10.1016/S0040-4039(02)00925-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4813–4815
Indium-mediated coupling of bromoacetonitriles with aromatic
acyl cyanides: convenient synthesis of aromatic a-cyano ketones
Byung Woo Yoo,a,* Sun Kyun Hwang,a Dong Yoon Kim,a Jin Woo Choi,a Jae Jung Ko,a
Kyung Il Choib and Joong Hyup Kimb
aDepartment of Chemistry, Korea University, Jochiwon, Chungnam 339-700, South Korea
bBiochemicals Research Center, Korea Institute of Science and Technology, Cheongryang, Seoul 130-650, South Korea
Received 10 April 2002; accepted 10 May 2002
Abstract—Indium-mediated coupling of bromoacetonitrile and 2-bromopropionitrile with a variety of aromatic acyl cyanides
afforded the corresponding aromatic a-cyano ketones in moderate to good yields under mild and neutral conditions. © 2002
Elsevier Science Ltd. All rights reserved.
Indium-mediated reaction is one of the attractive syn-
thetic methods for a carbon–carbon bond formation1
and has gained much attention over the last decade in
a variety of reactions such as Reformatsky reactions,2
allylation3 and propargylation4 reactions of carbonyl
compounds, or aldimines,5 coupling of carbonyl deriva-
tives.6 Recently, the a-halo-organoindium reagents
formed from indium metal and Br2CR2 (R=CN,
CO2Et) have been successfully employed in the cyclo-
propanation of alkenes, and in the epoxidation of
carbonyl compounds.7 It was also reported that the
indium(I) halide-mediated coupling reactions of dibro-
moacetonitrile and trichloroacetonitrile with carbonyl
compounds provide b-hydroxy nitriles.8 Relative to
cyanomethylation of aldehydes and ketones, little atten-
tion has been paid to the coupling of carboxylic acid
derivatives with bromoacetonitriles. To the best of our
knowledge, the indium-mediated cyanomethylation has
never been applied to carboxylic acid derivatives. We
have found that the indium-mediated reaction of acyl
cyanides 1 with bromoacetonitriles 2 provides various
a-cyano ketones 3 (Scheme 1). The versatile synthetic
utility of a-cyano ketones has been described in a
number of publications devoted to their preparation
and utilization.9 A general method for a-cyano ketones
is a Claisen-type condensation with an ester of nitrile
(or an ester) containing an a-hydrogen. However, the
majority of these procedures seemed somewhat cumber-
some and the nature of the deprotonating agent may
have a crucial influence on the selectivity and the yield
of the reaction. For synthetic applications, the present
procedure should prove to be more practical than exist-
ing methodologies, provided that the synthesis can be
efficiently achieved under simple and mild conditions.
We wish to report herein our study on the reaction of
organoindium reagents derived from bromoacetonitrile
with aromatic acyl cyanides to afford the corresponding
a-cyano ketones. Generally, the reactions were clean
and proceed efficiently in moderate to good yields at
room temperature under sonication. The indium-medi-
ated reactions of bromoacetonitrile and 2-bromopropio-
nitrile with a series of aromatic acyl cyanides are sum-
marized in Table 1. Acyl cyanides were prepared by the
literature procedure.10 Unfortunately, when the sub-
strate is benzoyl chloride or benzoyl anhydride, the
reaction results in a complex mixture under the same
conditions. Although the mechanism of the reaction is
still not clarified, it is assumed that the reaction of
bromoacetonitrile with indium powder smoothly pro-
ceeds to form organoindium reagent, (NCCHR)3In2Br3,
which reacts with carbonyl compounds to give the
corresponding a-cyano ketones. It was known that
(NCCHR)3In2Br3 did not react with benzaldehyde in
O
O
R
CN
In/sonication
THF
+
Ar
Ar
CN
Br
CN
R
2
1
3
R = H, CH3,
Scheme 1.
Keywords: acyl cyanide; coupling; indium and compounds; cyano
ketone.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00925-5

4814
B. W. Yoo et al. / Tetrahedron Letters 43 (2002) 4813–4815
Table 1. Synthesis of aromatic a-cyano ketones mediated by indium
trile reacts faster and produces better yields than
bromoacetonitrile. All products obtained showed
NMR, IR and mass spectral data compatible with the
structure.
the absence of additive such as chlorotrimethylsilane
and the desired hydroxy nitrile product was not
obtained at all.11 However, in our study when acyl
cyanide was chosen as a substrate, the reaction pro-
ceeded successfully without additives. It is noteworthy
that practically no reaction occurred in the absence of
sonication. The reaction was carried out in several
solvents but failed in DMF, CH3CN, THF/H2O, DMF/
H2O and water. THF has been found to be the most
suitable solvent for the reaction.12 In the course of the
process, substituents such as methoxy, chloro, and
bromo groups on aromatic rings (entries 3–6) are not
affected under the reaction condition. In order to assess
the generality of the process, the reaction was studied
with a variety of acyl cyanides. As shown in Table 1,
the furfuroyl cyanide reacted with bromoacetonitrile to
give the expected a-cyano ketone (entry 10), but the
application of this method to aliphatic acyl cyanide
proved unsuccessful and only recovered starting mate-
rial was isolated (entries 11 and 12). 2-Bromopropioni-
In conclusion, a mild and neutral preparation method
for aromatic a-cyano ketones was achieved by the
indium-mediated coupling of bromoacetonitrile and 2-
bromopropionitrile with various aromatic acyl
cyanides. We believe that this procedure will present a
better and more practical alternative to the existing
methodologies.
Acknowledgements
This work was financially supported by Korea Institute
of Science and Technology (2E16800) and partially by
Korea University.

B. W. Yoo et al. / Tetrahedron Letters 43 (2002) 4813–4815
4815
References
Venkateswara Rao, G. Tetrahedron Lett. 1993, 34, 1647;
(c) Baek, H.; Lee, S.; Yoo, B.; Ko, J.; Kim, S.; Kim, J.
Tetrahedron Lett. 2000, 41, 8097.
1. For reviews, see: (a) Cintas, P. Synlett 1995, 1087; (b) Li,
C. J.; Chan, T. H. Tetrahedron 1999, 55, 11149.
7. Araki, S.; Butsugan, Y. J. Chem. Soc., Chem. Commun.
2. (a) Araki, S.; Ito, H.; Butsugan, Y. Synth. Commun.
1988, 18, 453; (b) Johar, P.; Araki, S.; Butsugan, Y. J.
Chem. Soc., Perkin Trans. 1 1992, 711; (c) Araki, S.;
Katsumura, N.; Kawasaki, K.; Butsugan, Y. J. Chem.
Soc., Perkin. Trans. 1 1991, 499; (d) Banik, B.; Ghatak,
A.; Becker, F. J. Chem. Soc., Perkin. Trans. 1 2000, 2179.
3. (a) Araki, S.; Ito, H.; Butsugan, Y. J. Org. Chem. 1988,
53, 1831; (b) Isaac, M.; Chan, T.-H. Tetrahedron Lett.
1995, 36, 8957; (c) Loh, T.-P.; Li, X.-R. Tetrahedron Lett.
1997, 38, 869; (d) Loh, T.-P.; Zhou, J.-R.; Li, X.-R.
Tetrahedron Lett. 1999, 40, 9333; (e) Paquette, L.; Roth-
harr, R. R. J. Org. Chem. 1999, 64, 217; (f) Chappell, M.;
Halcomb, R. L. Org. Lett. 2000, 2, 2003.
4. (a) Yi, X. H.; Meng, Y.; Li, C. J. J. Chem. Soc., Chem.
Commun. 1998, 449; (b) Isaac, M. B.; Chan, T. H. J.
Chem. Soc., Chem. Commun. 1995, 1003; (c) Kirihara,
M.; Takuwa, T.; Takizawa, S.; Momose, T.; Nemeto, H.
Tetrahedron 2000, 56, 8275; (d) Cho, Y. S.; Lee, J. E.;
Pae, A. N.; Choi, K. I.; Koh, H. Y. Tetrahedron Lett.
1999, 40, 1725; (e) Alcaide, B.; Almendros, P.; Arag-
oncillo, C. Org. Lett. 2000, 2, 1411; (f) Yoo, B.; Lee, S.;
Choi, K.; Keum, S.; Ko, J.; Choi, K.; Kim, J. Tetra-
hedron Lett. 2001, 42, 7287.
1989, 1286.
8. (a) Nobrega, J. A.; Goncalves, S. M. C.; Peppe, C.
Tetrahedron Lett. 2001, 42, 4745; (b) Nobrega, J. A.;
Goncalves, S. M. C.; Peppe, C. Tetrahedron Lett. 2000,
41, 5779.
9. (a) Marshall, J. A.; Peterson, J. C.; Lebioda, L. J. Am.
Chem. Soc. 1984, 106, 6006; (b) Mehmandoust, M; Buis-
son, D.; Azerad, R. Tetrahedron Lett. 1995, 36, 6461; (c)
Itoh, T.; Fukuda, T.; Fujisawa, T. Bull. Chem. Soc. Jpn.
1989, 62, 3851; (d) Itoh, T.; Takagi, Y.; Fujisawa, T.
Tetrahedron Lett. 1989, 30, 3811; (e) Rachid, B.; Jacques,
G.; Monique, H.; Michel, T. J. Chem. Soc., Chem. Com-
mun. 1992, 50; (f) Kahne, D.; Collum, D. B. Tetrahedron
Lett. 1981, 22, 5011 and references cited therein.
10. Karl, E.; William, P. Tetrahedron Lett. 1974, 26, 2275.
11. Araki, S.; Yamada, M.; Butsugan, Y. Bull. Chem. Soc.
Jpn. 1994, 67, 1126.
12. Representative experimental procedure: Indium (517 mg,
4.5 mmol) was added to a stirred solution of bromoace-
tonitrile (720 mg, 6.0 mmol) in THF (10 mL) and the
resulting mixture was stirred at room temperature for 1 h.
To this solution was added dropwise a solution of ben-
zoyl cyanide (393 mg, 3.0 mmol) in THF (1 mL) at room
temperature. Stirring was continued for 6 h under sonica-
tion and the progress of the reaction was monitored by
TLC. The reaction mixture was filtered through celite and
extracted with ether. The combined organic layer was
washed with brine and dried over anhydrous Na2SO4.
The solvent was removed and the residue was purified by
column chromatography on silica gel (hexane:ethyl ace-
tate=3:1) to afford benzoyl acetonitrile (283 mg, 65%).
5. (a) Beuchet, P.; Le Marrec, N.; Mosset, P. Tetrahedron
Lett. 1992, 33, 5959; (b) Kobayashi, S.; Busujima, T.;
Nagayama, S. Chem. Commun. 1998, 19; (c) Basile, T.;
Bocoum, A.; Savoia, D.; Umani-Ronchi, A. J. Org.
Chem. 1994, 59, 7766; (d) Loh, T.-P.; Sook-Chiang, D.;
Xu, K.-C.; Sim, K.-Y. Tetrahedron Lett. 1997, 38, 865.
6. (a) Lim, H.; Keum, G.; Kang, S.; Chung, B.; Kim, Y.
Tetrahedron Lett. 1996, 37, 5341; (b) Kalyanam, N.;