Bromodimethylsulfonium bromide mediated Michael addition of amines to electron deficient alkenes

Article abstract of DOI:10.1016/j.tetlet.2007.03.163

Bromodimethylsulfonium bromide has been found to be an efficient catalyst for the Michael addition of a wide variety of amines to electron deficient alkenes at room temperature. The protocol is very simple and chemoselective. Aliphatic and benzylic amines undergo conjugate addition within a very short period under solvent-free conditions and provide excellent yields of products.

Full text of DOI:10.1016/j.tetlet.2007.03.163

Tetrahedron Letters 48 (2007) 3805–3808
Bromodimethylsulfonium bromide mediated Michael addition
of amines to electron deficient alkenes
a,
a
a
b
*
Abu T. Khan, Tasneem Parvin, Sarifuddin Gazi and Lokman H. Choudhury
a
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
Department of Basic Sciences and Social Sciences, North-Eastern Hill University, Shillong 793 022, India
b
Received 25 February 2007; revised 17 March 2007; accepted 29 March 2007
Available online 5 April 2007
Abstract—Bromodimethylsulfonium bromide has been found to be an efficient catalyst for the Michael addition of a wide variety of
amines to electron deficient alkenes at room temperature. The protocol is very simple and chemoselective. Aliphatic and benzylic
amines undergo conjugate addition within a very short period under solvent-free conditions and provide excellent yields of products.
ꢀ
2007 Published by Elsevier Ltd.
The conjugate addition of amines to electron deficient
alkenes is an important and widely used transformation
in organic synthesis owing to the importance of the
resultant b-amino ketones, esters, nitriles or amides. It
provides an easy route to b-amino acid derivatives as
well as for the synthesis of heterocycles containing a
mation. Over the years, numerous methods have been
developed using a variety of reagents such as SnCl /
4
4
5
6
7
FeCl3,
InCl3,
CeCl Æ7H O–NaI,
Yb(OTf)3,
3
2
8
9
10
11
12
Cu(OTf)2, CAN, Bi(NO ) , Bi(OTf)3, LiClO4,
3 3
KF/alumina, SmI2,14 etc. Recently, additional meth-
13
ods have been reported, among them Cu(acac) /ionic
2
1
15
b-amino carbonyl unit. These b-amino carbonyl com-
liquid, ionic liquid/quaternary ammonium salt in
1
6
17
18
pounds are versatile synthetic intermediates for the
synthesis of a variety of biologically important natural
products, antibiotics and are useful in fine chemicals
water, boric acid in water, b-cyclodextrin, ZrO-
1
9
20
Cl Æ8H O, borax, etc., are notable. Although these
2
2
methods are quite useful, many suffer from limitations
such as the requirement for a large excess of reagents,
long reaction times, harsh reaction conditions and also
involvement of toxic solvents such as acetonitrile or
1,2-dichloroethane. Hence, there is a need to develop a
convenient, environmentally friendly method for conju-
gate addition of amines to electron deficient alkenes.
2
and pharmaceuticals. The conventional method for
the preparation of these compounds is via the Mannich
3
reaction; however, it has several shortcomings includ-
ing long reaction times, low yields and harsh reaction
conditions.
An alternative method for preparing these compounds is
via Michael addition. Both from an atom economic
point of view as well as simplicity of the procedure,
the Michael addition is the preferred method for the
preparation of b-amino carbonyl compounds. Either
acid or base can be used as a promoter for this transfor-
Bromodimethylsulfonium bromide (BDMS) is a readily
2
1
accessible, cheap and highly effective reagent as well as
2
2
a catalyst for various organic transformations. In
continuation of our work on the development of new
synthetic methodologies, we have observed that
R
N
R3
R
R3
+
-
NH + R2
Me2S Br Br
R1
EWG
R1
EWG
rt
R2
1
2
3
R= H/ alkyl; R = alkyl/benzyl; R = H; R = H/Me; EWG = CN, COMe, COEt, CONH
2
Scheme 1.
*
0
Corresponding author. Tel.: +91 361 2582305; fax: +91 361 2690762; e-mail: atk@iitg.ernet.in
040-4039/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.03.163

3806
A. T. Khan et al. / Tetrahedron Letters 48 (2007) 3805–3808
bromodimethylsulfonium bromide efficiently catalyzes
the conjugate addition of various amines to electron
deficient alkenes at room temperature (Scheme 1).
In a preliminary experiment pyrolidine (5 mmol) was
treated with acrylonitrile (5 mmol) in the presence of
bromodimethylsulfonium bromide (0.25 mmol) under
Table 1. Bromodimethylsulfonium bromide mediated Michael addition of amines to conjugated alkenes under solvent-free conditions
a
b
Entry
Amine a
Unsaturated alkene b
Time (min)
Product c
Yield (%)
CN
CN
1
NH
CN
5
N
98
2
3
NH
5
5
99
93
CN
CN
N
CN
O
NH
O
N
CN
4
NH2
10
N
H
92
CN
CN
O
NH2
N
H
5
6
15
15
91
85
CN
OMe
NH2
N
H
OMe
O
O
OMe
7
NH
5
97
N
OMe
O
OMe
O
8
9
NH
NH
5
5
N
OMe
96
97
84
O
O
OMe
O
N
OMe
O
O
O
OMe
O
NH2
1
1
0
1
15
N
H
OMe
O
OEt
O
NH2
10
85
N
OEt
H
O
OEt
NH2
1
1
1
2
3
4
20
5
89
94
88
N
H
OEt
O
O
OEt
NH
N
OEt
O
O
OMe
O
O
NH
20
O
N
OMe
Ph
O
O
Ph
OMe
1
1
1
1
5
6
7
8
NH
15
5
83
91
89
0
N
N
OMe
O
NH2
NH
NH2
O
O
O
NH2
O
NH
15
O
N
NH2
CN
NH2
CN
120
NH
a
1
13
All the products were fully characterized by recording IR, H, C NMR and elemental analyses.
Isolated yields.
b

A. T. Khan et al. / Tetrahedron Letters 48 (2007) 3805–3808
3807
NH2
O
+
-
Me S Br Br
OMe
2
O
OMe
+
+
+
N
NH
rt
O
N
OMe
H
5
mmol
5 mmol
5 mmol
95%
0%
Scheme 2. Chemoselective conjugate addition of aliphatic amines in the presence of aromatic amines.
Table 2. Comparison of the present protocol with reported methods
a
b
Product
Catalyst (mol %)
Reaction conditions/solvent
Time min/[h]
Yield (%)
1
2
LiClO
ZrClO
CAN (10)
4
(100)
rt/solvent-free
rt/solvent-free
Ultrasonication/THF
[1]
15
20
[1.5]
[2]
[6]
5
80
94
96
95
90
84
99
1
9
4
Æ8H O/montmorillonite (0.075 g/mmol)
2
9
CN
17
N
H
3
BO
3
(10)
rt/H
rt/H
rt/H
2
2
2
O
O
O
20
Borax (10)
18
b-Cyclodextrin (100)
BDMS (5)
rt/solvent-free
1
9
O
ZrClO
BO
Borax (10)
BDMS (5)
4
Æ8H
2
O/montmorillonite (0.075 g/mmol)
rt/solvent-free
35
[3]
[3]
5
76
85
92
97
17
N
OMe
H
3
3
(10)
rt/H
rt/H
2
O
O
2
0
2
O
Solvent-free
a
Corresponding reference.
Isolated yield.
b
solvent-free conditions at room temperature, providing
the corresponding Michael adduct, exclusively, within
Next, to exemplify the chemoselectivity of this present
protocol a competitive study was carried out using a
mixture of 5 mmol of pyrrolidine, 5 mmol of aniline
and 5 mmol of methyl acrylate as shown in Scheme 2.
The Michael adduct of pyrrolidine was obtained exclu-
sively and clearly reflects the chemoselectivity of ali-
phatic amines versus aromatic amines.
5
min in 98% yield (Table 1, entry 1). Product 1c
1
13
was characterized by H and C NMR spectroscopy
2
3
as well as by comparison with authentic data. Interest-
ingly, the crude product obtained after aqueous
work-up was found to be pure as there was no detect-
able amount of impurities or starting material in
1
the H NMR of the crude product. Encouraged by
The catalytic activity of bromodimethylsulfonium bro-
mide was ascertained by the fact that in the absence of
the catalyst, the reaction of pyrrolidine with acrylonitrile
afforded only a 20% yield of adduct even after 6 h of stir-
ring at room temperature. The efficacy and generality of
the present protocol can be realized by comparing some
of the results presented here with recently reported
methods as shown in Table 2, which compares reaction
time, % yields and reaction conditions.
this, other secondary amines such as piperidine and
morpholine (entries 2 and 3) were treated with the
same Michael acceptor under the same experimental
2
4
conditions and the corresponding Michael adducts
were isolated in excellent yields within a short time.
Similarly, the primary amines n-butylamine and benzyl-
amine (entries 4 and 5) underwent Michael addition
smoothly providing good yields of the desired adducts.
The present protocol represents an improvement over
some of the recently reported methods in terms of
reaction time as well as % yields obtained. Similarly,
the a,b-unsaturated esters methyl acrylate and ethyl
acrylate reacted with a wide variety of amines under
the same conditions to afford very good yields of the
corresponding Michael adducts (entries 6–13). Methyl
methacrylate and methyl trans-cinnamate also under-
went Michael addition with morpholine and pyrrol-
idine, respectively, without any difficulty (entries 14
and 15).
In summary we have developed a simple and efficient
2
4
methodology for the conjugate addition of amines to
electron deficient alkenes using bromodimethylsulfo-
nium bromide as an inexpensive and efficient catalyst.
This method demonstrates the potential of BDMS as
an efficient promoter.
Acknowledgements
T.P. is thankful to IITG for a research fellowship. The
authors are also grateful to the Director, IIT Guwahati,
for providing the general research facility to carry out
this work. We are grateful to the referee for his valuable
comments and suggestions. This work is dedicated to
my former teacher Late Professor D. K. Majumder,
Department of Chemistry, Kalyani University, 741
235, India for his constant encouragement and moral
support.
Likewise acrylamide underwent Michael addition with
pyrrolidine and morpholine (entries 16 and 17) in very
good yields. However, in an attempt to react an aro-
matic amine, the same protocol was unsuccessful and
yielded only the starting material even after 2 h of stir-
ring (entry 18). Interestingly, the present protocol could
be used on a 100 mmol scale using only 2 mol % of
catalyst.

3808
A. T. Khan et al. / Tetrahedron Letters 48 (2007) 3805–3808
16. Xu, L.-W.; Li, J.-W.; Zhou, S.-L.; Xia, C.-G. New J.
References and notes
Chem. 2004, 28, 183–184.
1
1
1
2
2
7. Chaudhuri, M. K.; Hussain, S.; Kantam, M. L.; Neelima,
B. Tetrahedron Lett. 2005, 46, 8329–8331.
8. Surendra, K.; Krishnaveni, N. S.; Sridhar, R.; Rao, K. R.
Tetrahedron Lett. 2006, 47, 2125–2127.
9. Hashemi, M. M.; Eftekhari-Sis, B.; Abdollahifar, Amir;
Khalili, B. Tetrahedron 2006, 62, 672–677.
0. Hussain, S.; Bharadwaj, S. K.; Chaudhuri, M. K.; Kalita,
H. Eur. J. Org. Chem. 2007, 374–378.
1. (a) Choudhury, L. H. Synlett 2006, 1619–1620; (b)
Khan, A. T.; Ali, A.; Goswami, P.; Choudhury, L. H.
J. Org. Chem. 2006, 71, 8961–8963; (c) Das, B.; Krish-
naiah, M.; Katta, V. Tetrahedron Lett. 2006, 47, 4457–
1
2
. (a) Jung, M. E. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 4, pp 30–41; (b) Cardillo, G.; Tomasini, C. Chem.
Soc. Rev. 1996, 117–128; (c) Liu, M.; Sibi, M. P.
Tetrahedron 2002, 58, 7791–8035.
. (a) Corey, E. J.; Reichard, G. A. Tetrahedron Lett. 1989,
30, 5207–5210; (b) Graul, A.; Castaner, J. Drugs Future
1997, 22, 956–968.
3
. Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc.
000, 122, 8180–8186.
. Wen, L.; Li, L.; Xia, C.-G. Helv. Chim. Acta 2004, 87,
522–1526.
2
4
1
4
460.
5
6
. Loh, T. P.; Wei, L. L. Synlett 1998, 975–976.
. (a) Bartoli, G.; Bartolacci, M.; Giuliani, A.; Marcantoni,
E.; Massimo, M.; Torregiani, E. J. Org. Chem. 2005, 70,
2
2. (a) Khan, A. T.; Mondal, E.; Borah, B. M.; Ghosh, S.
Eur. J. Org. Chem. 2003, 4113–4117; (b) Khan, A. T.;
Islam, S.; Majee, A.; Chattopadhyay, T.; Ghosh, S.
J. Mol. Catal. A: Chem. 2005, 239, 158–165; (c) Khan,
A. T.; Sahu, P. R.; Majee, A. J. Mol. Catal. A: Chem.
1
69–175; (b) Bartoli, G.; Bosco, M.; Marcantoni, E.;
Pertrini, M.; Sambri, L.; Torregiani, E. J. Org. Chem.
001, 66, 9052–9055.
2
2
005, 226, 207–212; (d) Khan, A. T.; Mondal, E.; Ghosh,
7
8
9
. (a) Jenner, G. Tetrahedron Lett. 1995, 36, 233–236; (b)
Matsubara, S.; Yoshiyoka, M.; Utimoto, K. Chem. Lett.
994, 827–830.
. (a) Wabnitz, T. C.; Spencer, J. B. Tetrahedron Lett. 2002,
3, 3891–3894; (b) Xu, L.-W.; Li, J.-W.; Xia, C.-G.; Zhou,
S.-L.; Hu, X.-X. Synlett 2003, 2425–2427.
. Duan, Z.; Xuan, X.; Li, T.; Yang, C.; Wu, Y. Tetrahedron
Lett. 2006, 47, 5433–5436.
S.; Islam, S. Eur. J. Org. Chem. 2004, 2002–2009; (e) Das,
B.; Holla, H.; Srinivas, Y. Tetrahedron Lett. 2007, 48, 61–
6
1
4.
3. Ranu, B. C.; Dey, S. S.; Hajra, A. ARKIVOC 2002, vii,
6–81.
4. Representative experimental procedure for the Michael
reaction (1c): To a mixture of acrylonitrile (265 mg,
2
2
4
7
5
mmol) and pyrrolidine (355 mg, 5 mmol), bromo-
1
1
0. Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109–
114.
1. Varala, R.; Alam, M. M.; Adapa, S. R. Synlett 2003, 720–
22.
2. Azizi, N.; Saidi, M. R. Tetrahedron 2004, 60, 383–387.
3. Yang, L.; Xu, L.-W.; Xia, C.-G. Tetrahedron Lett. 2005,
6, 3279–3282.
4. Reboule, I.; Gil, R.; Collin, J. Tetrahedron Lett. 2005, 46,
761–7764.
dimethylsulfonium bromide (56 mg, 0.5 mmol) was added
and the reaction mixture stirred at room temperature.
The reaction was complete within 5 min as indicated by
TLC. The reaction mixture was extracted with ethyl
acetate (2 · 20 mL) and the combined extract was
2
7
1
1
dried over Na SO and evaporated to leave a crude
2 4
4
1
product, which was sufficiently pure as ascertained by H
NMR of the crude product. The Michael adduct (Table 1,
entry 1) was characterized by recording IR, H and
1
1
7
1
13
C
5. Kantam, M. L.; Neeraja, V.; Kavita, B.; Neelima, B.;
NMR spectra as well as by comparison with reported
Chaudhuri, M. K.; Hussain, S. Adv. Synth. Catal. 2005,
2
3
data.
347, 763–766.