Catalytic acylcyanation of imines with acetylcyanide

Article abstract of DOI:10.1055/s-2006-951543

Aldimines react with acetyl cyanide in the presence of a catalytic amount of a thiourea catalyst to give the corresponding N-acetylated amino nitriles in high yields. The scope of the reaction is broad and both aromatic as well as aliphatic aldimines can

Full text of DOI:10.1055/s-2006-951543

LETTER
3275
Catalytic Acylcyanation of Imines with Acetylcyanide
O
rganocatalyt
u
A
cylcyana
b
tionof Imin
h
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Fax +49(208)3062999; E-mail: list@mpi-muelheim.mpg.de
Received 15 August 2006
Initial experiments focused on the examination of differ-
ent catalysts for this transformation (Table 1).6 While the
highly acidic TFA (trifluoroacetic acid) did not give any
conversion in dichloromethane (entry 1), moderately
acidic phenylphosphinic acid 3a gave good conversion
(entry 2). In the context of these studies we then found that
the reaction cannot only be catalyzed by stronger, specific
acid catalysts but also by hydrogen-bonding-type, general
acid catalysts.7
Abstract: Aldimines react with acetyl cyanide in the presence of a
catalytic amount of a thiourea catalyst to give the corresponding N-
acetylated amino nitriles in high yields. The scope of the reaction is
broad and both aromatic as well as aliphatic aldimines can readily
be used.
Key words: acylcyanation, a-amino nitrile, Brønsted acid cataly-
sis, organocatalysis, acetyl cyanide
The Strecker reaction of imines with HCN provides one of
the most efficient methods for the preparation of a-amino
nitriles, which are useful intermediates in the synthesis of
a-amino acids.1 However, the Strecker reaction has limi-
tations in particular due to the volatile and highly toxic na-
ture of HCN. In this regard, trimethylsilyl cyanide
(TMSCN) offers certain advantages. However, due to its
high toxicity and price, access to alternative cyanation re-
agents is desirable. For example, acyl cyanides are not
only less toxic and readily available but also have already
been used in the acylcyanation of carbonyl compounds.2
Surprisingly however, while the reaction of acetyl cyanide
and analogous a-oxonitriles with aldehydes and ketones
has been studied extensively in recent years, its reaction
with imines has been significantly less investigated. Thus
in 1958, Dornow et al. first reported the reaction of acyl
cyanides with imines and later described a triethylamine-
catalyzed version.3 Survey of the literature reveals that
there are no other catalytic versions of this atom-econom-
ic yet rarely used approach to a-amino nitriles.4
Table 1 Catalytic Acylcyanation of Imine 1a
O
MeCOCN (2)
N
Ph
Me
N
Ph
catalyst 3
CH2Cl2, 0 °C
Ph
H
Ph
CN
1a
4a
H
H
F3C
N
N
CF3
H
P
O
S
OH
CF3
CF3
3a
3b
Entrya
Catalyst
TFA
3a
mol%
20
20
10
2
Time (h)
Conv. (%)b
1
2
3
4
5
72
24
24
24
24
0
90
99
98
93
3b
Recently, Brønsted acid and hydrogen-bonding catalysis
have emerged as powerful strategies for organocatalysis.5
Inspired by these studies and realizing the potential of the
acylcyanation of imines for the synthesis of a-amino ac-
ids, we were encouraged to investigate the catalytic addi-
tion of acyl cyanides to imines (Scheme 1).
3b
3b
1
a All reactions were performed using 0.1 mmol of imine 1a and 0.15
mmol of acetyl cyanide (2).
b Determined by GC.
O
We identified Schreiner’s thiourea catalyst 3b, in particu-
lar, to be highly efficient in promoting the reaction (entry
3).8 In each instance, the reaction was carried out with 1.5
equivalents of acetyl cyanide. Decreasing the catalyst
loading from 10 mol% to 2 mol% essentially preserved
the conversion (entry 4). Reducing the catalyst loading to
only 1 mol% reduced the yield somewhat (entry 5).9 Con-
sequently, either 2 mol% or 5 mol% of catalyst 3b was
used in subsequent experiments.
R2
H
R2
R3
N
N
R3COCN
R1
R1
CN
catalyst
1
4
Scheme 1 Catalytic acylcyanation of imines
Using dichloromethane as the solvent and thiourea 3b as
the catalyst (2–5 mol%), we decided to explore the scope
of this reaction (Table 2). It turned out that the selected re-
SYNLETT 2006, No. 19, pp 3275–3276
Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-951543; Art ID: G27406ST
© Georg Thieme Verlag Stuttgart · New York
0
1
.1
2
.2
0
0
6

3276
S. C. Pan et al.
LETTER
mixture. The flask was cooled to 0 °C and stirred for 10 min. Acetyl
cyanide (0.2 mL, 1.5 equiv) was added, and the mixture was stirred
for 24 h at 0 °C. The mixture was directly subjected to silica gel col-
umn chromatography to give 464 mg (1.76 mmol, 88% yield) of the
pure product 4a as a colorless liquid.
action conditions are broadly useful for a variety of differ-
ent substrates. Both aromatic aldimines (entries 1–4) with
electron-donating or -withdrawing substituents, as well as
heteroaromatic aldimines (entries 5 and 6), can be used
with similar efficiencies. Furthermore, aliphatic
branched, unbranched, and unsaturated aldimines can
also be employed to give moderate to good yields (entries
7–10).
Acknowledgment
We thank Degussa, Merck, Saltigo, and Wacker for the donation of
chemicals and support of our work and Novartis for a Young Inve-
stigator award to B.L. Our work was supported by the Max-Planck-
Gesellschaft, the Deutsche Forschungsgemeinschaft (Priority Pro-
gram 1179 Organocatalysis), and the Fonds der Chemischen Indu-
strie.
Table 2 Catalytic Acylcyanation of Various Imines
O
3b (2–5 mol%)
MeCOCN (2)
N
Ph
Me
N
Ph
R
H
CH2Cl2, 0 °C
R
CN
1
4
References and Notes
Entrya
R
Time (h)
24
Yield (%)b
(1) For reviews, see: (a) Gröger, H. Chem. Rev. 2003, 103,
2795. (b) Yet, L. Angew. Chem. Int. Ed. 2001, 40, 875.
(c) Spino, C. Angew. Chem. Int. Ed. 2004, 43, 1764.
(2) (a) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M.
Angew. Chem. Int. Ed. 2002, 41, 3636. (b) Tian, J.;
Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Org. Lett.
2003, 5, 3021. (c) Yamagiwa, N.; Tian, J.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 3413. (d) Tian,
S.-K.; Deng, L. J. Am. Chem. Soc. 2001, 123, 6295.
(e) Casas, J.; Baeza, A.; Sansano, J. M.; Nájera, C.; Saá, J.
M. Tetrahedron: Asymmetry 2003, 14, 197. (f) Belokon, Y.
N.; Blacker, A. J.; Clutterbuck, L. A.; North, M. Org. Lett.
2003, 5, 4505. (g) Lundgren, S.; Wingstrand, E.; Penhoat,
M.; Moberg, C. J. Am. Chem. Soc. 2005, 127, 11592.
(h) Belokon, Y. N.; Ishibashi, E.; Nombra, H.; North, M.
Chem. Commun. 2006, 16, 1775.
(3) (a) Dornow, A.; Lüpfert, S. Chem. Ber. 1956, 89, 2718.
(b) Dornow, A.; Lüpfert, S. Chem. Ber. 1957, 90, 1780.
(c) Dornow, A.; Lüpfert, S. US Patent 2849477, 1958.
(4) (a) Gardent, M. J.; Delépine, M. M. C. R. Acad. Sci. 1958,
247, 2153. (b) Rai, M.; Krishan, K.; Singh, A. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1978, 16, 834.
(c) Sakamoto, M.; Akiyama, Y.; Furumi, N.; Ishii, K.;
Tomimatsu, Y.; Date, T. Chem. Pharm. Bull. 1983, 31, 2623.
(5) For reviews, see: (a) Schreiner, P. R. Chem. Soc. Rev. 2003,
32, 289. (b) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth.
Catal. 2006, 348, 999. (c) Taylor, M. S.; Jacobsen, E. N.
Angew. Chem. Int. Ed. 2006, 45, 1520. (d) Connon, S. J.
Chem. Eur. J. 2006, 12, 5418. (e) Pihko, P. M. Angew.
Chem. Int. Ed. 2004, 43, 2062. (f) Connon, S. J. Angew.
Chem. Int. Ed. 2006, 45, 3909.
(6) Under our reaction conditions using triethylamine as the
catalyst only 4% conversion of imine 1a to product 4a was
achieved.
(7) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719.
(8) (a) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217.
(b) Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9,
407.
(9) Even in the absence of catalyst, significant conversion
(>30%) to the product was observed.
(10) Using the chiral phosphoric acid catalyst 3,3¢-bis[(2,4,6-
tris(isopropyl)phenyl]-5,5¢,6,6¢,7,7¢,8,8¢-octahydro-1,1-
binaphthyl hydrogen phosphate (10 mol%) at –40 °C,
product 4a was obtained in 92% yield and 69:31 er.
1
2
Ph
88
84
79
83
67
96
76
64
82
81
4-MeOC6H4
4-ClC6H4
2-ClC6H4
2-Furyl
24
3
24
4
24
5
24
6
3-Pyridyl
i-Pr
24
7c
8c
9c
10c
48
t-Bu
48
1-Cyclohexenyl
t-BuCH2
48
48
a All reactions were performed using 2 mol% of the catalyst unless
otherwise stated.
b Yields of pure product after silica gel column chromatography.
c 5 mol% of the catalyst.
Mechanistically, the reaction may proceed via an initial
reaction of the imine with acetyl cyanide to form an acyl
iminium–cyanide ion pair. Its recombination to product 4
may be urea-catalyzed.
In summary, we have developed a new efficient and po-
tentially useful variant of the Strecker reaction, the gener-
al Brønsted acid catalyzed acylcyanation of imines with
acetyl cyanide as a new cyanide source. The operational
simplicity, practicability, and mild reaction conditions
render it an attractive approach for the generation of dif-
ferent N-acyl a-amino nitriles. Further studies in our lab-
oratory aim at expanding the scope of the reaction to
include ketimines and at developing an asymmetric cata-
lytic version.10
Preparative Experiment for the Acylcyanation of Imines
The imine 1a (2.0 mmol) and catalyst 3b (2 mol%) were placed in
a dry Schlenk flask. Then, dry CH2Cl2 (4 mL) was added to the
Synlett 2006, No. 19, 3275–3276 © Thieme Stuttgart · New York