A Convenient and Effective Method for Synthesizing β-Amino-α ,β-Unsaturated Esters and Ketones

Article abstract of DOI:10.1081/SCC-120028364

A convenient and effective method for the preparation of β-amino-α, β-unsaturated esters and ketones has been developed through silica gel-catalyzed and solvent-free reactions of β-dicarbonylic compounds with ammonia and primary amines.

Full text of DOI:10.1081/SCC-120028364

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A Convenient and Effective Method for Synthesizing
β‐Amino‐α,β‐Unsaturated Esters and Ketones
Yuanhe Gao a , Qihan Zhang a & Jiaxi Xu a
a Key Laboratory of Bioorganic Chemistry and Molecular Engineering, Ministry of
Education, Department of Chemical Biology, College of Chemistry and Molecular
Engineering, Peking University, Beijing, 100871, China
Published online: 20 Aug 2006.
To cite this article: Yuanhe Gao , Qihan Zhang & Jiaxi Xu (2004): A Convenient and Effective Method for Synthesizing
β‐Amino‐α,β‐Unsaturated Esters and Ketones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:5, 909-916
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 5, pp. 909–916, 2004
A Convenient and Effective Method for
Synthesizing b-Amino-a,b-Unsaturated
Esters and Ketones
*
Yuanhe Gao, Qihan Zhang, and Jiaxi Xu
Key Laboratory of Bioorganic Chemistry and Molecular Engineering,
Ministry of Education, Department of Chemical Biology, College of
Chemistry and Molecular Engineering, Peking University, Beijing, China
ABSTRACT
A convenient and effective method for the preparation of b-amino-
a,b-unsaturated esters and ketones has been developed through silica
gel-catalyzed and solvent-free reactions of b-dicarbonylic compounds
with ammonia and primary amines.
Key Words: Amination; b-Diketone; b-Keto ester; b-Amino-
a,b-unsaturated ketone; b-amino-a,b-unsaturated ester; Silica gel.
*
Correspondence: Jiaxi Xu, Key Laboratory of Bioorganic Chemistry and Molecular
Engineering, Ministry of Education, Department of Chemical Biology, College of
Chemistry and Molecular Engineering, Peking University, Beijing 100871, China;
Fax: þ86-10-62751708; E-mail: jxxu@chem.pku.edu.cn.
909
DOI: 10.1081/SCC-120028364
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Gao, Zhang, and Xu
INTRODUCTION
b-Amino-a,b-unsaturated esters and ketones are useful synthetic
intermediates,[1] particularly in the construction of heterocyclic compounds
such as dihydropyridines,[2–5] pyridines,[6,7] pyrimidines,[8] indoles,[9] and
isothiazoles.[10] Recently b-amino-a,b-unsaturated acids have also been
widely used in synthesis of b-amino acids and peptidyl mimetics.[11–13]
Several methods for the preparation of b-amino-a,b-unsaturated esters
and ketones have been developed. The generally employed method for their
preparation entails the reaction between b-dicarbonylic compounds and
amines in benzene with azeotropic removal of water.[14,15] However, there
are problems associated with the use of low boiling amines as starting
materials.[16] It is necessary either to pass a rapid stream of gaseous amine
through the refluxing diketone solution,[17] or to operate a reaction in an
autoclave at 130–1508C.[18,19] Moreover, the first procedure requires a large
excess of amine. For the latter methods, the reaction cannot be easily moni-
tored, the yields are not quantitative, and polymerization occurs.[16] Some
successful modifications have been reported, such as the use of ammonium or
alkylammonium acetate,[20] Lewis acids such as boron trifluoride etherate,[17]
alumina (neutral) or montmorillonite K-10 as solid catalysts in benzene[21,22]
or as solid supports.[23,24] Other methods such as addition of an amine to a b-
halovinyl ketone[25] or ester,[26] hydrogenation (Raney-Ni) of isoxazoles,[27]
palladium catalyzed amination of electron-deficient olefins,[28] palladium
induced dehydrogenation of a b-amino ketone,[29] are also described in the
literature. Herein we describe an effective and convenient method for prepa-
ration of b-amino-a,b-unsaturated esters and ketones in very high yield
through silica gel-catalyzed and solvent-free reactions of b-dicarbonylic
compounds with ammonia and primary amines.
RESULTS AND DISCUSSION
As part of our program directed towards the synthesis of pharmaceutically
active dihydropyridine derivatives, we had to synthesize b-amino-a,b-
unsaturated esters and ketones as starting materials. Reviewing literature
examples, a convenient and solvent-free method for the preparation using
montmorillonite K-10 as solid support has been reported.[23,24] In this method
amines can be applied in aqueous solution and the use of solvents for removal
of water is avoided. Due to the unavailability of montmorillonite K-10 in our
hands we rationalized that silica gel having weak acidity would be suitable
replacement as solid support for the reaction. Firstly, we found that an almost
quantitative yield was obtained in reactions of acetoacetone and ethyl

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Synthesizing b-Amino-a,b-Unsaturated Esters and Ketones
911
Scheme 1. Synthesis of b-amino-a,b-unsaturated ketones and esters.
acetoacetate with ammonia by using silica gel. After extensive optimization
we found that the same results were obtained by using a catalytic amount of
silica gel as catalyst. In this work we describe a convenient and effective
method for the preparation of a series of b-amino-a,b-unsaturated esters and
ketones in very high yields through silica gel-catalyzed and solvent-free
reactions of ammonia, primary amines and b-keto esters including a b-keto
lactone, acetoacetone (Sch. 1). The results are summarized in the Table 1.
Anilines worked very well, but required relative long reaction time.
In this method, amines can be used either as such or in aqueous solution.
In case of liquid products, after filtration and evaporation, almost pure com-
pounds (.98% purities) were obtained in nearly quantitative yield. Pure
products can be obtained by chromatographic separation on silica gel for low
yielding products. Solid products were obtained through extraction by wash-
ing with dichloromethane and crystallization or flash column chromatography
on silica gel. As can be seen for products 3e, 3j, 3o and 3t, the reaction also
leads to good yields for amines with a bulky group (MeCHPh). The
advantages of the procedure reported here are: (i) high yields; (ii) high purity
of the desired products; and (iii) easy workup.
All known products were characterized and their spectroscopic data are in
agreement with those reported in the literature.[24,30–38]
CONCLUSION
In summary, a convenient, effective and environment-friendly method
for preparation of b-amino-a,b-unsaturated esters and ketones has been
developed through silica gel-catalyzed and solvent-free reactions of
b-dicarbonylic compounds with ammonia and primary amines.
EXPERIMENTAL
Melting points were measured on a Yanaco MP-500 melting point
apparatus and are uncorrected. IR spectra were recorded on a Bruker Vector

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Gao, Zhang, and Xu
Table 1. Synthesis of b-amino-a,b-unsaturated ketones and esters.
Reaction Yield
(%)
Product
R1
Me
R2
R3
Me
R4
time
Mp (8C)
3a
H
H
24 hr
99
30–32
(33–35)[24]
31–33
3b
Me
H
Me
Me
3 hr
99
(37–39)[24]
Oil (Oil)[24]
48–49
(49–50)[24]
71–72.5
3c
3d
Me
Me
H
H
Me
Me
Bn
Ph
30 min
35 hr
92
95
3e
Me
H
Me
PhCHCH3
2 hr
99
(70–71)[30]
Oil (Oil)[24]
Oil (Oil)[24]
Oil (Oil)[24]
Oil (Oil)[24]
Oil (Oil)[31]
36–37
3f
Me
Me
Me
Me
Me
H
H
H
H
H
OEt
OEt
OEt
OEt
OEt
H
Me
4 hr
8 hr
99
99
99
86
99
99
3g
3h
3i
Bn
Ph
30 min
24 hr
2 hr
3j
3k
PhCHCH3
H
22(CH2)322 OEt
22(CH2)322 OEt
22(CH2)322 OEt
10 min
(55–57)[32]
44–45
3l
Me
Bn
10 min
10 min
99
99
(45–46)[33]
62–63
3m
(26–27)[34]
Oil (Oil)[35]
Oil (Oil)[36]
74–76
3n
3o
3p
3q
22(CH2)322 OEt
22(CH2)322 OEt
Ph
PhCHCH3
24 hr
30 min
5 hr
99
99
99
99
Me
Me
22(CH2)2O22 H
22(CH2)2O22 Me
4 hr
107–108
(96–98)[37]
119–120
3r
3s
3t
Me
Me
Me
22(CH2)2O22 Bn
2 hr
48 hr
3.5 hr
99
78
99
(100.9–101.4)[38]
94–95
22(CH2)2O22 Ph
(74.7–77.4)[38]
67–68
22(CH2)2O22 PhCHCH3
(78–79)[38]
1
22 FT-IR spectrophotometer. H and 13C NMR spectra were recorded on a
Varian Mercury 300 (300 MHz) spectrometer in CDCl3 solution with TMS as
an internal standard and chemical shifts are reported in ppm. Mass spectra
were obtained on a VG-ZAB-HS spectrometer. CH analyses were performed
on an Elementar Vario EL analyzer.

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913
Synthesis of b-Amino-a,b-Unsaturated Esters and Ketones;
General Procedure
Amine 2 (12 mmol, pure amine, or ammonia or amine in an aqueous
solution) was added dropwise to the suspension of silica gel (100 mg, 10 mg
for diketone, Qingdao Ocean Chemical Industrial Co.) in the dicarbonylic
compound 1 (10 mmol) and the resulting mixture was stirred at room
temperature for 10 min–24 hr (monitored by TLC). For liquid products, crude
products were obtained after removal of silica gel by filtration. Pure liquid
products were obtained by purification on a silica gel column. For solid
products, crude products were obtained after extraction with dichloromethane
and removal of solvent. The purification was performed by column
chromatography on silica gel using hexane/acetone as eluent.
2-(1-Aminoethylidene)butyrolactone (3p)
Colorless crystal. Mp 74–768C. IR (KBr): 1685 (C55O), 3324 and 3423 (NH)
cm21. 1H NMR (300 MHz, CDCl3): d ¼ 1.93 (s, 3H, CH3), 2.82 (t, J ¼ 7.6 Hz,
2H, CH2), 4.29 (t, J ¼ 7.6 Hz, 2H, CH2). 13C NMR (75.5 MHz, CDCl3):
d ¼ 20.41, 25.76, 65.10, 87.02, 154.45, 172.93. MS (EI): m/z ¼ 127 (Mþ, 83),
98 (Mþ-HCO, 20), 83 (Mþ-CO2, 11), 69 (Mþ-CO2CH2, 100). Calcd for C6H9NO2
(127.14) C: 56.68; H: 7.13; N: 11.02. Found: C: 56.51; H: 7.33; N: 11.12.
ACKNOWLEDGMENTS
The project was supported by NSFC (No. 20272002), the Excellent
Young Teachers Program and the Scientific Research Foundation for the
Returned Oversea Chinese Scholars of Ministry of Education of China, and
Peking University (President grant).
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Received in the USA October 3, 2003

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