Silica gel accelerated aza-Michael addition of amines to α,β-unsaturated amides

Article abstract of DOI:10.1016/j.tetlet.2008.06.099

A novel method to synthesize β-amino amide has been developed via conjugated addition of amine to bulky α,β-unsaturated amides promoted by silica gel. The silica gel worked efficiently to accelerate the reaction and afforded the related adduct in good to excellent yield.

Full text of DOI:10.1016/j.tetlet.2008.06.099

Tetrahedron Letters 49 (2008) 5147–5149
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Silica gel accelerated aza-Michael addition of amines to a,b-unsaturated amides
b
a
a
b
Lisha You a, , Song Feng , Rui An , Xinhong Wang , Donglu Bai
*
a School of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cai Lun Road, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China
b Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel method to synthesize b-amino amide has been developed via conjugated addition of amine to
Received 9 April 2008
Revised 18 June 2008
Accepted 20 June 2008
Available online 25 June 2008
bulky
reaction and afforded the related adduct in good to excellent yield.
Ó 2008 Elsevier Ltd. All rights reserved.
a,b-unsaturated amides promoted by silica gel. The silica gel worked efficiently to accelerate the
Keywords:
Aza-Michael addition
Amines
a
,b-Unsaturated amides
Silica gel
b-Amino amides and derivatives play an important role on nat-
ten caused severe environmental problems. Over last few years,
several groups have reported sub-stoichiometric use of some Lewis
acids such as Yb(OTf)3, Bi(OTf)3, Bi(NO3)3, hydrated CeCl3–NaI
supported on silica gel or clay.7 Despite their remarkable success,
however, the literature reveals that these catalysts are very
substrate-selective. In addition, use of these heavy metal salts
coupled with solvents are not desirable for a ‘green’ reaction.
Herein, we developed an efficient and practical procedure for the
ural and synthetic products with a wide range of biological activi-
ties1 and pharmacological properties.2 The synthesis of b-amino
amides has gained considerable attention due to their biologically
important application.3 Among the reported synthetic methodolo-
gies to b-amino amides, the simplest and most widely used meth-
od is the conjugate addition of amines to
a,b-unsaturated amides
and derivatives.4
Michael reactions promoted by Lewis acids or base catalyst is
one of the most important carbon–nitrogen bond-forming reac-
tions in organic synthesis.5 In particular, they are atom-efficient
procedures and thus are inherently ‘green’ transformations. Sev-
eral Lewis acids, such as AlCl3, TiCl4, or SnCl4 have been employed
to this addition.6 However, their use in stoichiometric amount of-
conjugate addition of amines to a,b-unsaturated amides and
derivatives promoted on a surface of silica gel.
Compared with other methodologies, easy recycling of the
catalyst and scaling up of the reactions are important attributes
of silica gel. Meanwhile, the reaction was relatively more facile
than other catalysis system. Potassium fluoride supported on
H
N
H
N
O
O
R1
R2
Slica gel
70°, CH3CN
+
N
HN
CCH2CH2N
R3
R4
N
CCH CH2
O
O
2
2
1
R1=R3= alkyl, R2=alkyl amine , R4= alkyl
Scheme 1. The synthesis of bis-huperzine B via Michael addition promoted by silica gel.
* Corresponding author. Tel.: +86 21 5132 2183.
E-mail addresses: youlisha@shutcm.com, youlisha@126.com (L. You).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.099

5148
L. You et al. / Tetrahedron Letters 49 (2008) 5147–5149
Table 1
Michael addition of amines to
a, b-unsaturated amides
Entry
1
Amines
Amides
Producta
Yieldb (%) (time, h)
92(3)11
O
O
n-BuNH2
n-Bu
N
NH2
NH2
H
O
O
O
2
3
PhCH2NH2
NH
93(5)11
89(5)11
Ph
N
NH2
NH2
NH2
H
O
O
N
N
NH2
O
O
O
4
5
6
7
8
95(5)11
93(5)11
92(5)11
90(8)
NH
NH2
NH2
NH2
O
NH
N
NH2
O
O
NH
O
N
NH2
NH
2
O
O
O
NH2
NH2
N
NH2
N
H
O
n-Bu
Ph
n-BuNH2
94(5)
N
H
N
O
O
O
9
PhCH2NH2
90(5)
N
N
N
N
H
O
10
88(10)
NH
N
N
O
O
O
O
11
12
13
87(10)
72(10)
84(10)
NH
NH
N
N
N
N
N
O
N
N
O
O
NH
N
N
O
O
O
O
O
14
15
65(16)
62(24)
55(24)
NH2
N
N
N
N
H
N
O
O
PhNH2
N
H
N
N
16
PhNHMe
N
a
All products were characterized by IR, 1H NMR, and 13C NMR spectra data.12
Isolated yield.
b

L. You et al. / Tetrahedron Letters 49 (2008) 5147–5149
5149
alumina was reported to exhibit similar effects.8 So far only few
papers have reported the interesting function of silica gel in Mi-
chael addition and its application (see Scheme 1).
In our previous reports on the preparation of dual acetylcholin-
esterase (AChE) inhibitors,9 several methods which have been em-
ployed to build the carbon–nitrogen bond and link the two
Huperzine B molecules failed to furnish the target compound bis-
huperzine B. It was the strong steric hindrance at the huperzine
B molecule which made it very difficult to link the two parts of tar-
get compounds by usual methods. The problem was solved occa-
sionally by using silica gel to accelerate the conjugated addition
gel was tested for a particular reaction, the loss of obvious activity
was not observed.
In conclusion, we have developed a mild and efficient method
for the synthesis of b-amino amides and derivatives via conjugated
addition of amines to a,b-unsaturated amides promoted on a sur-
face of silica gel. The best results are realized by using the silica gel
usually used for flash chromatography. The applicability of this
‘green’ methodology to a variety of amines including aromatic
and hindered amines is an attractive feature, which can be benefi-
cial for synthetic and industrial chemists.
of amines to
a,b-unsaturated amides and derivatives of huperzine
References and notes
B(1). The method was utilized repeatedly to afford many other
highly potent and selective AChE dual inhibitors (2).5 The success-
ful applications on this case encouraged us to further explore the
silica gel’s effects on conjugated addition of amine to a,b-unsatu-
rated amides. Therefore, we report the method using silica gel as
1. (a) Chen, I. L.; Chang, K. M.; Miaw, C. L., et al. Bioorg. Med. Chem. 2007, 15, 6527;
(b) Czajgucki, Z.; Andruszkiewicz, R.; Kamysz, W. J. Pept. Sci. 2006, 12, 653; (c)
Banoglu, E.; Akoglu, C.; Unlu, S.; Ergun, C.; Kupeli, E.; Yesilada, E.; Sahin, M. F.
Arzneimittel-Fors. 2005, 55, 520.
2. (a) Adessi, C.; Frossard, M. J.; Boissard, C.; Fraga, S.; Bieler, S.; Ruckle, T.; Vilbois,
F.; Robinson, S. M.; Mutter, M.; Banks, W. A.; Soto, C. J. Biol. Chem. 2003, 278,
13911; (b) Kitagawa, K.; Mizobuchi, N.; Hama, T.; Hibi, T.; Konishi, R.; Futaki, S.
Chem. Phar. Bull. 1997, 45, 1782; (c) Preiml, M.; Hillmayer, K.; Klempier, N.
Tetrahedron Lett. 2003, 44, 5057.
3. (a) Guzow, K.; Ganzynkowicz, R.; Rzeska, A.; Mrozek, J.; Szabelski, M.;
Karolczak, J.; Liwo, A.; Wiczk, W. J. Phys. Chem. B 2004, 108, 3879; (b) Rijkers,
D. T. S.; Hoppener, J. W. M.; Posthuma, G.; Lips, C. J. M.; Liskamp, R. M. J. Chem.
Eur. J. 2002, 8, 4285; (c) Toth, G.; Keresztes, A.; Tomboly, C.; Peter, A.; Fulop, F.;
Tourwe, D.; Navratilova, E.; Varga, E.; Roeske, W. R.; Yamamura, H. I.; Szucs, M.;
Borsodi, A. Pure Appl. Chem. 2004, 76, 951.
4. (a) Ishihara, T.; Mantani, T.; Konno, T.; Yamanaka, H. Tetrahedron 2006, 62,
3783; (b) Nelson, S. G.; Spencer, K. L.; Cheung, W. S.; Mamie, S. J. Tetrahedron
2002, 58, 7081.
promoter to accelerate this kind of aza-Michael addition.
In order to make our method be successful, the type of silica
gel used is critical, herein, 200–300 mesh of GF254 silica gel
(Qingdao, China) normally used for flash chromatography was
employed in corresponding experiments. In a typical experiment,
a mixture of amine and a,b-unsaturated amide in a ratio of 1.1:1.0
was mixed with silica gel (0.1–1 g, GF254, 200–300 mesh). To the
mixture was added acetonitrile, and the resulting mixture was
heated at reflux for 3–24 h. The mixture was concentrated under
reduced pressure to afford a solid residue. The desired product
was then isolated by flash column chromatography over silica
gel.10
5. (a) BenAyed, T.; Amiri, H.; ElGaied, M. M.; Villieras, J. Tetrahedron 1995, 51,
9633; (b) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1992.
6. (a) Bull, S. D.; Davies, S. G.; Delgado-Ballester, S.; Fenton, G.; Kelly, P. M.; Smith,
A. D. Synlett 2000, 1257; (b) Davies, S. G.; McCarthy, T. D. Synlett 1995, 700.
7. (a) Varala, R.; Alam, M. M.; Adapa, S. R. Synlett 2003, 720. and references cited
therein.; (b) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109; (c) Bartoli,
G.; Bosco, M.; Marcantoni, E.; Petrini, M.; Sambri, L.; Torregiani, E. J. Org. Chem.
2001, 66, 9052 and references cited therein; (d) Shaikh, N. S.; Deshpande, V. H.;
Bedekar, A. V. Tetrahedron 2001, 57, 9045.
8. Khan, A. T.; Ghosh, S.; Choudhury, L. H. Eur. J. Org. Chem. 2006, 2226.
9. (a) Feng, S.; Wang, Z. F.; He, X. C.; Zheng, S. X.; Xia, Y.; Jiang, H. L.; Tang, X. C.;
Bai, D. L. J. Med. Chem. 2005, 48, 655; (b) Feng, S.; Xia, Y.; Han, D.; Zheng, C.; He,
X. C.; Tang, X. C.; Bai, D. L. Bioorg. Med. Chem. Lett. 2005, 15, 523; (c) He, X. C.;
Feng, S.; Wang, Z. F.; Shi, Y. F.; Zheng, S. X.; Xia, Y.; Jiang, H. L.; Tang, X. C.; Bai,
D. L. Bioorg. Med. Chem. 2007, 15, 1394.
Our investigations showed that aromatic and aliphatic amines
reacted smoothly with a,b-unsaturated amides in the presence of
silica gel. The corresponding Michael addition adducts were ob-
tained in high to excellent yields. To obtain the optimized reaction
condition, different types of solvents were examined. Acetonitrile
was found to be the favorite solvent for this reaction. A series of ali-
phatic and aromatic amines were employed as substrates to per-
form conjugate addition with
a,b-unsaturated amides promoted
by silica gel, and the results was summarized in Table 1.
Several aliphatic primary amines (entries 1, 2 and 7–9) under-
went nucleophilic addition to a,b-unsaturated amides in the pres-
10. General procedure for Michael additions: Representative one is as follows. To a
solution of the amine (2 mmol) in acetonitrile (10 mL) was added
a,b-
ence of silica gel to yield the desired adducts in excellent yields.
Aliphatic secondary amines, for example, piperidine (entries 3–6)
on treatment with acrylamide on silica gel afforded the target ad-
duct in good yield. Encouraged by these good results, we turned
our attention to aromatic amines, which were proved inefficient
according to many reports. To our satisfaction, the aromatic
amines under similar conditions also gave corresponding adducts
in reasonable yields (entries 15 and 16). The slight difference in
Michael addition yields in the presence of silica gel between ali-
unsaturated amide (2 mmol), followed by silica gel (GF254, 200–300 mesh,
1 g). The resulting mixture was heated at reflux for 4 h. After cooled to rt, the
mixture was concentrated under reduced pressure. The solid residue was
washed with EtOAc/methanol (5:1) for three times, the combined organic
phase was concentrated and the crude was purified by chromatography eluting
with various ratios of EOAc to petroleum to afford the product. These
compounds are identified by IR, 1H NMR, and 13C NMR spectra data.
11. (a) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991; (b) Azizi, N.; Saidi, M. R.
Tetrahedron 2004, 60, 383.
12. Selected NMR (300 M, CDCl3) spectral data for the products:
Entry 8: 1H NMR: d = 0.96 (t, 3H, J = 7.1 Hz), 1.22 (t, 6H, J = 6.8 Hz), 1.33–1.41
(m, 4H), 2.30 (t, 2H, J = 7.6 Hz), 2.55 (t, 2H, J = 7.1 Hz), 2.83 (t, 2H, J = 7.8 Hz),
3.24 (q, 4H, J = 6.8 Hz). 13C NMR: d = 12.0, 13.2, 20.1, 32.5, 33.1, 41.0, 48.9, 49.5,
170.5. Entry 10: 1H NMR: d = 0.96 (t, 3H, J = 7.1 Hz), 1.22 (t, 6H, J = 6.8 Hz),
2.30–2.52 (m, 6H), 2.64 (t, 2H, J = 7.8 Hz), 3.24 (q, 4H, J = 6.8 Hz), 13C NMR:
d = 12.8, 13.2, 31.5, 41.0, 48.9, 49.5, 171.7. Entry 12: 1H NMR: d = 1.24 (t, 6H,
J = 6.8 Hz), 1.4–1.5 (m, 6H), 2.21–2.40 (m, 6H), 2.64 (t, 2H, J = 7.8 Hz), 3.28 (q,
4H, J = 6.8 Hz). 13C NMR: d = 12.9, 25.1, 31.5, 41.6, 51.7 171.5. Entry 15: 1H
NMR: d = 1.21 (t, 6H, J=6.8 Hz), 2.40 (t, 2H, J = 7.0 Hz), 2.64 (t, 2H, J = 7.8 Hz),
3.34 (t, 2H, J = 7.0 Hz), 6.7–7.1 (m, 5H), 13C NMR: d = 12.9, 33.2, 38.7, 41.3, 51.7,
113.0, 117.1, 130.4, 147.6, 171.5.
phatic and aromatic amine with
a,b-unsaturated amides might
be caused by the electron-donating effects. It has also been ob-
served that the reaction is greatly influenced by the steric hinder-
ance of the conjugated amides; that is, N-substituted acrylamide
reacts slower than the nonsubstituted acrylamide on the N-posi-
tion (Table 1, entries 1, 8, 3 and10). The recovered silica gel was
washed with methanol and dried under vacuum (0.5 mmHg) at
120–130 °C, then employed for further reaction. The recycled silica