(Bromodimethyl)sulfonium bromide catalyzed one-pot synthesis of α-aminonitriles

Article abstract of DOI:10.1055/s-2006-926421

A novel, simple and efficient one-pot synthesis of α-aminonitriles has been achieved by a three-component condensation of carbonyl compounds, amines and trimethylsilyl cyanide in the presence of (bromodimethyl)sulfonium bromide as a catalyst at room temperature. The products were obtained in high yields and in short reaction times. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926421

PAPER
1419
(
Bromodimethyl)sulfonium Bromide Catalyzed One-Pot Synthesis of
1
a-Aminonitriles
(
B
Bromodimethyl)
i
sulfoni
s
um Brom
w
ide-Catalyzed
O
ne
a
-Pot Synthe
n
sis of
a
-A
m
a
inonitriles th Das,* R. Ramu, B. Ravikanth, K. Ravinder Reddy
Organic Chemistry Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)7160512; E-mail: biswanathdas@yahoo.com
Received 7 September 2005; revised 2 December 2005
TMSCN
CN
Abstract: A novel, simple and efficient one-pot synthesis of a-ami-
nonitriles has been achieved by a three-component condensation of
carbonyl compounds, amines and trimethylsilyl cyanide in the pres-
ence of (bromodimethyl)sulfonium bromide as a catalyst at room
temperature. The products were obtained in high yields and in short
reaction times.
catalyst (10 mol%)
MeCN, r.t.
R-CHO
+
R'NH2
R
NHR'
1
2
1
–2 h
77–92%
3
For R, R' see Table 1
Scheme 1 Catalyst: (bromodimethyl)sulfonium bromide
Keywords: a-aminonitriles, carbonyl compounds, amines, trimeth-
ylsilyl cyanide, (bromodimethyl)sulfonium bromide
_
+
Me2S Br Br
R
O
+
:NH2R'
NR' + HBr + Me2SO
TMSCN
a-Aminonitriles are important intermediates for the syn-
2
R
H
2
H
thesis of a-amino acids and different nitrogen-containing
1
3
heterocycles such as imidazoles and thiadiazoles. These
compounds are usually prepared by nucleophilic addition
of a cyanide anion to imines. The classical Strecker reac-
tion for the synthesis of a-aminonitriles involves the treat-
ment of carbonyl compounds with alkaline cyanides and
CN
R
NHR'
3
Scheme 2
4
salts of amines in aqueous medium. The experimental
procedure is tedious and, thus, several modified methods
have been reported using a variety of cyanide reagents
A series of a-aminonitriles has been prepared following
the above methods using various aldehydes and amines
(
such as diethyl phosphorocyanidate, a-trimethylsilyloxy
5
(
Table 1). Aromatic, aliphatic and heterocyclic aldehydes
nitrile and tri-n-butyltin cyanide) as well as catalysts
such as Sc(OTf) , Pr(OTf) , clay, RuCl , VO(OTf) ,
worked well. Conjugated aldehydes also afforded the de-
sired products in high yields. Previously, some methods
(
3
3
3
2
6
InCl , etc.) under various reaction conditions. However,
3
6a
failed to produce a-aminonitriles from these aldehydes.
many of these methods require expensive reagents such as
6
e,f
Aliphatic, aromatic and cyclic amines produced satisfac-
tory results. Both primary and secondary aliphatic amines
reacted. Trimethylsilyl cyanide has been used as a safer
and more effective cyanide anion source compared to var-
ious other cyanide reagents (such as diethyl phosphorocy-
anidate, a-trimethylsilyloxy nitrile and tri-n-butyltin
metal triflates, longer reaction times, harsh reaction
conditions and give unsatisfactory yields. Moreover, we
have observed that boron halides used for the preparation
of a-aminonitriles are deactivated or decomposed by
amines and water produced during imine formation. Thus,
there is a need to develop a facile one-pot synthesis of a-
aminonitriles using an inexpensive reagent.
5
cyanide) used in the Strecker process. a-Aminonitriles
were prepared here in short reaction times and in high
yields. The coupling reaction took place at room temper-
ature under mild reaction conditions. Acid-sensitive alde-
hydes such as furfuraldehyde and cinnamaldehyde
afforded the corresponding a-aminonitriles without form-
ing polymerized or decomposed products. No additive
was required. The reaction also produced no undesired
side product (such as cyanohydrin trimethylsilyl ether, an
adduct between the aldehyde and trimethylsilyl cyanide)
because of rapid formation of the imine intermediate. The
structures of all the products were assigned from their
We recently observed that (bromodimethyl)sulfonium
7
bromide is an efficient catalyst for the synthesis of a-ami-
nonitriles by a three-component condensation of carbonyl
compounds, amines and trimethylsilyl cyanide
(
Scheme 1).
The mechanism of the reaction possibly involves the ini-
tial formation of an imine by reaction between an alde-
hyde and an amine in the presence of the catalyst. The
imine is subsequently attacked by TMSCN to form a-ami-
nonitrile and this step may be catalyzed by in situ gener-
7
f
1
ated HBr (Scheme 2).
spectroscopic ( H NMR and MS) data.
SYNTHESIS 2006, No. 9, pp 1419–1422
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x
.
x
x
.2
0
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Advanced online publication: 04.04.2006
DOI: 10.1055/s-2006-926421; Art ID: P13605SS
Georg Thieme Verlag Stuttgart · New York
©

1
420
B. Das et al.
PAPER
Table 1 (Bromodimethyl)sulfonium Bromide-Catalyzed Synthesis of a-Aminonitrilesa
Entry
a
Aldehyde (1)
Amine (2)
Product (3)
Time (h)
1.5
Yield (%)b
80
Ref.
6a
CN
CHO
NH2
N
H
b
1
89
6a
CN
CN
CN
CHO
NH2
N
H
c
d
e
1.5
2
85
86
87
6b
6a
–
CHO
CHO
CHO
NH2m
N
H
O
NH
N
O
Cl
1
CN
Cl
NH2
N
H
f
1
1
1
1
88
92
86
89
6b
–
CN
MeO
CHO
NH2
NH2
N
H
MeO
g
h
i
CN
F
CHO
N
H
F
OMe
–
CN
CHO
MeO
NH2
N
H
6a
NH2
CHO
O
H
N
O
CN
CN
j
Me
1
2
81
83
–
CHO
Me
NH2
N
H
k
6b
CHO
NC
NH2
N
H
l
CHO
2
1
77
82
–
CN
NH2
NH2
N
H
m
Me
6b
CN
CHO
N
H
Me
Synthesis 2006, No. 9, 1419–1422 © Thieme Stuttgart · New York

PAPER
(Bromodimethyl)sulfonium Bromide Catalyzed One-Pot Synthesis of a-Aminonitriles
1421
a
Table 1 (Bromodimethyl)sulfonium Bromide-Catalyzed Synthesis of a-Aminonitriles (continued)
Entry
n
Aldehyde (1)
Amine (2)
Product (3)
Time (h)
2
Yield (%)b
89
Ref.
CN
6a
CHO
N
H
N
o
p
CN
CN
1
83
79
6b
6a
NH2
NH2
CHO
CHO
O
N
H
O
1.5
N
H
a
1
The structures of all the products were settled from their spectral ( H NMR and MS) data.
Yields refer to those of pure isolated products fully characterized by spectral data.
b
7
1
The catalyst (bromodimethyl)sulfonium bromide is an
inexpensive reagent. It worked efficiently in the present
conversion to produce a-aminonitriles at room tempera-
ture. No product was formed in absence of this catalyst.
H NMR: d = 7.60–7.48 (m, 2 H), 7.47–7.34 (m, 3 H), 7.15 (d,
J = 8.0 Hz, 2 H), 6.61 (d, J = 8.0 Hz, 2 H), 5.29 (d, J = 8.0 Hz, 1 H)
.07 (d, J = 8.0 Hz, 1 H).
4
+
MS (EI, 70 eV): m/z = 244, 242 (M ), 215, 178, 126.
The same catalyst was employed earlier to carry out some Anal. Calcd for C H N Cl: C, 69.42; H, 4.54; N, 11.57. Found: C,
1
4
11
2
synthetic transformations but its utilities were not proper- 69.58; H, 4.37; N, 11.43.
7
6a
ly explored. Compared to other catalysts [such as InCl ,
3
6
b
6c
6d
6e
Compound 3g
KSF clay, BiCl , RuCl and Pr(OTf) ] used earlier
3
3
3
Mp 91–93 °C.
for the preparation of a-aminonitriles, (bromodimeth-
yl)sulfonium bromide was superior in terms of conver-
sion, reaction rate and required amount of the catalyst.
1
H NMR: d = 7.65–7.52 (m, 2 H), 7.31–7.08 (m, 4 H), 6.89 (t,
J = 8.0 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 2 H), 5.39 (s, 1 H).
+
MS (EI, 70 eV): m/z = 226 (M ), 199, 134.
In conclusion, we have developed a convenient and effi-
cient one-pot synthesis of a-aminonitriles by a three-com-
ponent condensation of carbonyl compounds, amines and
trimethylsilyl cyanide in the presence of (bromodimeth-
yl)sulfonium bromide as a catalyst. The simple experi-
mental procedure, mild reaction conditions, inexpensive
catalyst, short reaction times and high yields are the ad-
vantages of the present procedure.
Anal. Calcd for C H N F: C, 74.33; H, 4.86; N, 12.38. Found: C,
14 11
2
7
4.45; H, 4.92; N, 12.24.
Compound 3h
Mp 94–96 °C.
1
H NMR: d = 7.62–7.51 (m, 2 H), 7.47–7.36 (m, 3 H), 6.78 (d,
J = 8.0 Hz, 2 H), 6.67 (d, J = 8.0 Hz, 2 H), 5.29 (d, J = 8.0 Hz, 1
H), 3.84 (d, J = 8.0 Hz, 1 H), 3.72 (s, 3 H).
+
MS (70 eV): m/z = 238 (M ), 211, 210, 146.
Melting points were measured on a Büchi 510 instrument and are
Anal. Calcd for C H N O: C, 75.63; H, 5.88; N, 11.76. Found: C,
75.72; H, 5.92; N, 11.54.
1
5
14
2
1
uncorrected. H NMR spectra were recorded in CDCl on a Varian
3
Gemini 200 MHz spectrometer using TMS as an internal standard.
EI-MS were measured on a VG Micromass 7070H (70eV) instru-
ment. Column Chromatography was carried out with silica gel 100–
Compound 3j
Mp 75–77 °C.
2
00 mesh and TLC with Silica gel GF254.
1
H NMR: d = 7.62–7.53 (m, 2 H), 7.49–7.36 (m, 3 H), 7.02 (d,
J = 8.0 Hz, 2 H), 6.63 (d, J = 8.0 Hz, 2 H), 5.32 (d, J = 8.0 Hz, 1
H), 3.82 (d, J = 8.0 Hz, 1 H), 2.26 (s, 3 H).
Preparation of a-Aminonitriles; General Procedure
To a mixture of an aldehyde (1 mmol), an amine (1 mmol) and tri-
methylsilyl cyanide (1.2 mmol) in MeCN (10 mL) (bromodimeth-
yl)sulfonium bromide (10 mol%) (prepared by the reported
+
MS (EI, 70 eV): m/z = 222 (M ), 195, 180.
Anal. Calcd for C H N : C, 81.08; H, 6.30; N, 12.61. Found: C,
7b
15 14
2
method ) was added and the mixture was stirred at r.t. The reaction
was monitored by TLC. After completion the solvent was removed
8
1.22; H, 6.23; N, 12.54.
in vacuo. The reaction was quenched with H O (10 mL) and extract-
ed with EtOAc (3 × 10 mL). The extract was concentrated and sub-
jected to column chromatography over silica gel (EtOAc–hexane,
2
Compound 3l
Light-yellow oil.
1
H NMR: d = 7.22 (t, J = 8.0 Hz, 2 H), 6.82 (t, J = 8.0 Hz, 1 H),
1
:9) as eluent to afford pure a-aminonitrile.
6
.63 (d, J = 8.0 Hz, 2 H), 4.06–4.15 (m, 2 H), 1.82–1.91(m, 2 H),
1
.20–1.55 (m, 6 H), 0.91 (t, J = 7.0 Hz, 3 H).
Compound 3e
Mp 108–110 °C.
+
MS (EI, 70 eV): m/z = 202 (M ), 187, 175, 145.
Synthesis 2006, No. 9, 1419–1422 © Thieme Stuttgart · New York

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B. Das et al.
PAPER
Anal. Calcd for C H N : C, 77.18; H, 9.97; N, 13.85. Found: C,
(5) (a) Harusawa, S.; Hamada, Y.; Shioiri, T. Tetrahedron Lett.
1979, 20, 4663. (b) Mai, K.; Patil, G. Tetrahedron Lett.
13
18
2
7
7.23; H, 9.92; N, 13.91.
1
1
984, 25, 4583. (c) Kobayashi, S.; Ishitani, H. Chem. Rev.
999, 99, 1069.
Acknowledgment
(
6) (a) Ranu, B. C.; Dey, S. S.; Hajra, A. Tetrahedron 2002, 58,
2529. (b) Yadav, J. S.; Reddy, B. V. S.; Easwaraiah, B.;
The authors thank UGC and CSIR New Delhi for financial assi-
stance.
Srinivas, M. Tetrahedron 2004, 60, 1767. (c) De, S. K.;
Gibbs, R. A. Tetrahedron Lett. 2004, 45, 7407. (d) De, S.
K. Synth. Commun. 2005, 35, 653. (e) De, S. K.; Gibbs, R.
A. Synth. Commun. 2005, 35, 961. (f) Royer, L.; De, S. K.;
Gibbs, R. A. Tetrahedron Lett. 2005, 46, 4595.
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Synthesis 2006, No. 9, 1419–1422 © Thieme Stuttgart · New York