High pressure mediated three component Strecker synthesis of α-aminonitriles from ketones, aromatic amines and trimethylsilyl cyanide

Article abstract of DOI:10.1016/S0040-4039(02)02270-0

High pressure (600 MPa) reaction conditions, in the absence of a catalyst, have proved to be a powerful way to stimulate the three component Strecker reaction synthesis of α-aminonitriles in high yields. Examples of two types of double Strecker reactions were also described.

Full text of DOI:10.1016/S0040-4039(02)02270-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9167–9169
High pressure mediated three component Strecker synthesis of
a-aminonitriles from ketones, aromatic amines and
trimethylsilyl cyanide†
Kiyoshi Matsumoto,a,* Jong Chul Kim,a Naoto Hayashia and Ge´rard Jennerb,*
aGraduate School of Human and Environmental Studies, Kyoto University, Kyoto 606-8501, Japan
bLaboratoire de Pie´zochimie Organique (UMR 7509), Faculte´ de Chimie, Universite´ Louis Pasteur, 67008 Strasbourg, France
Received 28 August 2002; revised 2 October 2002; accepted 4 October 2002
Abstract—High pressure (600 MPa) reaction conditions, in the absence of a catalyst, have proved to be a powerful way to
stimulate the three component Strecker reaction synthesis of a-aminonitriles in high yields. Examples of two types of double
Strecker reactions were also described. © 2002 Elsevier Science Ltd. All rights reserved.
Among the organic syntheses, multicomponent reac-
tions as a special case of a domino process are fascinat-
ing, environmentally friendly, and recently have been
extensively investigated in connection with combinato-
rial chemistry since the desired product can be obtained
in a one-pot process from simple building blocks.1
However, such reactions under high pressure have
hardly been investigated.2 a-Aminonitriles are very
important intermediates, particularly in the preparation
of a-amino acids and other biologically useful
molecules.3 Thus, an asymmetric version of this reac-
tion has been also extensively as well as intensively
studied.4 The preferred synthetic route remains well
established Strecker reaction associating an aldehyde,
an amine and a cyanide source.5 However, all these
methods have focused on reactions involving aldehydes
as the carbonyl compound and amines as aliphatic
amines. The Strecker synthesis applied to ketones and
aromatic amines remains a difficult reaction, except
when NH4Cl is used.6 Only simple cyclic ketones are
reactive yielding a-aminonitriles under catalytic condi-
tions.7 It appears, therefore, that the high pressure
promoted one-pot Strecker reaction of a ketone, an
aromatic amine and TMSCN (trimethylsilyl cyanide) is
an interesting challenge.
In a first step, we examined the Strecker reaction with
aniline and various ketones at a fairly high pressure
(600 MPa) in the absence of a catalyst. The preliminary
results are summarized in Table 1 (Scheme 1).8 For
example, at 600 MPa, acetone underwent reaction with
aniline 2 and TMSCN (entry 2) to give 4a in quantita-
tive yield, although the same reaction at atmospheric
pressure took place only in low yield (entry 1). Specifi-
cally, acetophenone 1d with 2 did not afford the corre-
sponding product 4d at 0.1 MPa (entry 5),9 whereas at
Scheme 1.
Keywords: Strecker reaction; high pressure; a-aminonitriles; trimethylsilyl cyanide.
* Corresponding authors. Fax: +81-75-753-2969; e-mail: kiyoshi.matsumoto@ma1.seikyou.ne.jp
† This paper is dedicated to Professor T. Mukaiyama on the occasion of his 75th birthday.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02270-0

9168
K. Matsumoto et al. / Tetrahedron Letters 43 (2002) 9167–9169
Table 1. Pressure promoted Strecker synthesis with ketones, aniline and TMSCN in toluene for 24 h
Entry
R1
R2
Pressure (MPa)
Temp (°C)
Product
Yielda (%)
1
2
3
4
5
6
7
8
Me
Me
Me
Et
Me
Me
Me
Me
Me
Ph
Me
Me
Et
Et
Ph
Ph
4-MePh
1%-Naphthyl
2%-Naphthyl
Ph
-(CH2)6-
-(CH2)12
0.1
600
600
600
0.1
600
600
600
600
600
600
600
30
30
30
30
30
30
30
30
30
30
30
30
4a
4a
4b
4c
4d
4d
4e
4f
4g
–
22
99
98
95
0
88
82
68
9
96
10
11
12
Trace
97
4h
4i
-
94b
a Isolated yield based on ketones.
b For 48 h.
for an efficient reaction. Among the solvents examined
thus far, acetonitrile gave the best result. However, in
the cases of single Strecker reactions (Scheme 1), a
comparable yield of product was obtained in acetoni-
trile. It is speculated that the solubility of 5 at 600 MPa
might be responsible for the solvent effect, the exact
reason is not clear at present and will be a subject of
future communications.
600 MPa, an 88% yield of the anticipated product 4d
was obtained (entry 6). The reactions under high pres-
sure were dependent on the substituent of ketone.
When the chain length of ketones increased, the yield
was slightly reduced (entries 2, 3, 4, 11 and 12) pre-
sumably because of steric hindrance. When an aromatic
substituent replaced an aliphatic substituent (entries 2,
6), the yield was slightly reduced, probably due to the
same reason as well as the stabilization of the acyl
carbon through delocalization by the phenyl group.
Acetonaphthones also gave good yields (entries 8, 9).
On comparison of 1%- and 2%-acetonaphthone, the low
yield of 4f, in comparison with that of 4g, is likely to be
due to the peri-hydrogen effect of the 1%-isomer (steric
hindrance). Only diphenylketone could not be reacted
owing probably to the prohibitive bulk of the two
phenyl groups (entry 10).
Conversely, 1,4-diaminobenzene 7 smoothly underwent
another type of double Strecker reaction to give 8 in
77% of an isolated yield (Scheme 3).
In this study we have successfully extended Strecker
reaction to give high yields of aminonitriles by using
high pressure reaction conditions.10,11
Acknowledgements
The present high pressure strategy is also amenable to
the double Strecker reaction. For example, 1,4-diacetyl-
benzene 5 with 2 molar amounts of aniline and
TMSCN gave the corresponding product 6 (Scheme 2,
Table 2). In this event, the choice of solvent was crucial
We thank the Ministry of Education, Science, Sports,
and Culture, Japan for support. The authors are also
grateful to the Ministry of Education, Science, Sports,
and Culture, Japan for purchasing the high-field NMR
instruments (JEOL JNM-A500 and JNM-EX270) by
the special fund to K.M. as a representative in 1992.
Thanks are also extended to The Kyoto University
Foundation for Cooperative Work for G. Jenner to
stay in Japan in 2001. J. C. Kim thanks the Korea
Science and Engineering Foundation for support dur-
ing his participation in this project. Finally, the authors
express their thanks to Dr. Robert A. Bulman
(National Radiological Protection Board, Chilton, Did-
cot, Oxfordshire OX11 0RQ, UK) for checking the
English in this paper.
Scheme 2.
Table 2. The effect of solvent on double Strecker reaction
Entry
Pressure (MPa)
Temp (°C)
Time (h)
Solv.
Yield (%)
1
2
3
4
5
0.1
600
600
600
600
rt
72
24
48
24
24
CH3CN
Toluene
Toluene
CH2Cl2
CH3CN
5
0
0
48
93
30
30
30
30

K. Matsumoto et al. / Tetrahedron Letters 43 (2002) 9167–9169
9169
5. (a) Strecker, S. Liebigs Ann. Chem. 1870, 155, 177; (b)
Shafran, Y. M.; Bakulev, V. A.; Mokrushin, V. S. Russ.
Chem. Rev. 1989, 148.
6. Org. Synth. I, 21, 355; III, 66, 88, 225; IV, 274; V, 437.
7. Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.;
Rossi, M. Synlett 1999, 315.
8. Typical procedure for the synthesis of 4: A mixture of
ketone (3.0 mmol), aniline (3.0 mmol) and TMSCN (3.6
mmol) is diluted with toluene in a 4 ml Teflon capsule
which is stored at 30°C for 24–48 h under high pressure.
The mixture was cooled at 0°C and filtered. The solid was
washed repeatedly with cyclohexane, and dried in vac-
uum. In the cases where the precipitates did not appear
on cooling, the mixture was concentrated under reduced
pressure, and the residue was chromatographed on silica
gel.
9. In connection with this, no reaction of acetophenone with
TMSCN without catalyst either at 0.1 and 300 MPa has
been reported: Jenner, G. Tetrahedron Lett. 1999, 40, 491;
see also, Choi, M. C.; Chen, S. S.; Matsumoto, K.
Tetrahedron Lett. 1997, 38, 6669.
10. High pressure apparatuses are now only moderately
expensive, and can be employed, usefully and without
much extra effort, in a much wider context than that
originally envisaged. For examples of the reviews from
our laboratories for organic reactions under high pres-
sure: Jenner, G. Tetrahedron 2002, 58, 5185; Jenner, G.
Tetrahedron 1997, 58, 5185; Matsumoto, K.; Acheson, R.
M., Eds. Organic Reactions at High Pressures; New
York: John Wiley & Sons, 1991; Ciobanu, M.: Mat-
sumoto, K. Liebigs Ann./Recueil 1997, 623; Matsumoto,
K.; Kaneko, M.; Katsura, H.; Hayashi, N.; Uchida, T.;
Acheson, R. M. Heterocycles 1998, 47, 1135.
Scheme 3.
References
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