Uncatalyzed, anti-Michael addition of amines to β-nitroacrylates: practical, eco-friendly synthesis of β-nitro-α-amino esters

Article abstract of DOI:10.1016/j.tetlet.2008.04.076

A variety of primary and secondary amines give the conjugate reaction with β-nitroacrylates, via an anti-Michael addition, without any catalyst and/or solvent, allowing good yields of β-nitro-α-amino esters.

Full text of DOI:10.1016/j.tetlet.2008.04.076

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3865–3867
Uncatalyzed, anti-Michael addition of amines to b-nitroacrylates:
practical, eco-friendly synthesis of b-nitro-a-amino esters
*
*
´
´
Roberto Ballini , Noelia Araujo Bazan, Giovanna Bosica, Alessandro Palmieri
`
Green Chemistry Group, Dipartimento di Scienze Chimiche dell’Universita di Camerino, Via S. Agostino 1, 62032 Camerino, Italy
Received 9 January 2008; revised 8 April 2008; accepted 11 April 2008
Available online 15 April 2008
Abstract
A variety of primary and secondary amines give the conjugate reaction with b-nitroacrylates, via an anti-Michael addition, without
any catalyst and/or solvent, allowing good yields of b-nitro-a-amino esters.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Solvent free; Anti-Michael addition; Uncatalyzed reaction; Amines; b-Nitro-a-amino esters
b-Nitro amino esters are an important class of building
blocks for the synthesis of a variety of important targets
such as (i) a,b-dehydro-a-amino acids,1 which are common
components of naturally occurring peptides 2 and (ii) b-
nitro-a-amino acids that have been studied as enzyme
inhibitor3 and as precursors in the synthesis of a variety
of a-amino acids and diamino acids.4,5 In addition, the
nitro group, which is often entitled a ‘chemical chameleon’,
can be easily transformed into other useful functional
groups including amines, aldehydes, or acid moieties via
nucleophilic addition reaction, reduction reaction, Meyer
reaction, and other conversions,6 thus giving the opportu-
nity for further elaborations into a variety of other chemi-
cal structures.
Inspite of the great importance of the b-nitro amino
esters, only few methods have been reported for their syn-
thesis. In fact, they can be obtained starting from nitroalk-
anes by their nucleophilic reaction with bromoglycine
derivative,1 or with imines.7 In addition, athree-com-
ponent synthesis of b-nitro-a-amino acids, starting from
nitroalkanes, amines and glyoxalate, was reported,8 but
the limited number of substrates reported and the modest
yields obtained seem to indicate that the procedure is not
of general application.
The aza-Michael reaction is widely recognized as one of
the most important C–N bond-forming reactions in
organic synthesis.9 The most common procedures require
basic or acidic activators;10 however, to avoid the side reac-
tions that are normally encountered in the presence of
strong acid or base, a number of alternative methods have
been developed and, in this context, various Lewis-acid-
induced reactions and microwave-accelerated reactions
have been reported.11 However, many of these procedures
involve the use of expensive catalysts, stoichiometric
amounts of the reagents, poor regioselectivity, and
extended reaction times.
b-Nitroacrylates are an emerging class of electron-poor
alkenes, having two electron-withdrawing groups in a-
and b-positions,12 employed as versatile electrophilic
acceptors13 under different catalytic systems.
During our studies on the conjugate additions of
nucleophiles to b-nitroacrylates,12b,13g we found that the
reaction of 1 equiv of amines 1 with 1 equiv of b-nitroacryl-
ates 2, performed at room temperature and under solvent-
free and catalyst-free conditions, allows good yields of
b-nitro-a-amino esters 3, via an anti-Michael fashion14,15
(see Scheme 1).
*
Corresponding authors. Tel.: +39 0737 402270; fax: +39 0737 402297
(R.B.); tel.: +39 0737 402341; fax: +39 0737 402297 (A.P.).
E-mail addresses: roberto.ballini@unicam.it (R. Ballini), alessandro.
palmieri@unicam.it (A. Palmieri).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.076

3866
R. Ballini et al. / Tetrahedron Letters 49 (2008) 3865–3867
In conclusion, the method shows the following advanta-
NO2
O2N
R2
H
N
1
ges from the economical and ecological points of view: very
mild conditions, short reaction times, good yields, atom
economy (100%), minimal production of waste, limited
energy consumption, and environmentally benign.
COOEt
R2
+
R1
R
COOEt
N
R1
3a-k
2
R
Scheme 1.
Acknowledgments
Table 1
The prepared b-nitro-a-amino esters
The authors thank the University of Camerino and
MUR-Italy (PRIN 2006, project: Sintesi Organiche Ecos-
ostenibili Mediate da Nuovi Sistemi Catalitici) for financial
support.
Entry Amine 1
R2
Et
Et
Yielda (%) Time drb
of 3
(h)
1
2
PhNH2
3a (92)
2
1:1
Supplementary data
NH
3b (88)
3c (90)
1.5
1.5
75:25
O
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.04.076.
3
Et
1:1:1:1
Ph
NH2
4
5
6
7
8
p-MeOC6H4NH2 n-Pr
p-MeOC6H4NH2 n-Bu
3d (88)
3e (95)
3f (91)
3g (89)
3h (92)
2.5
2
1.5
1.5
1.5
1:1
1:1
1:1
1:1
1:1
References and notes
BnNH2
n-Bu
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¨
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9
Ph
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b-nitroacrylates in order to verify the synthetic potentiality
of our method. A variety of both primary and secondary
amines and b-nitroacrylates produce very good yields
(78–95%) of the anti-Michael adducts 3 (Table 1), under
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uents R2 bonded to C-3 of b-nitroacrylate, which respect
to the volume of ethyl group present in compound 3b.
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matic or aliphatic nature of the amines as well as from their
cyclic or acyclic structures. Because the preparation of 3
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of the reaction (checked by TLC) the crude mixture was
directly charged on a chromatographic column to give
the pure adducts, avoiding any tedious and dangerous
workup. Thus, this anti-aza-Michael reaction constitutes
a general, practical manner to obtain an important class
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convenient reaction conditions. In fact, the latter com-
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R. Ballini et al. / Tetrahedron Letters 49 (2008) 3865–3867
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condition: see Ref. 5.
15. General procedure: Amine 1 (2 mmol) was added to b-nitroacrylate 2
(2 mmol), then the mixture was stirred at room temperature for the
appropriate time (see Table 1), after this the crude product was
directly charged on the head of the flash chromatography column and
eluted by a mixture of hexane and ethyl acetate.