Tetrahedron Letters
Solvent-free Brønsted acid-catalyzed Michael addition
of nitrogen- and carbon-containing nucleophiles by ultrasound
activation
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Xiu-Jiang Du, Zhi-Peng Wang, Yan-Ling Hou, Cheng Zhang, Zheng-Ming Li, Wei-Guang Zhao
State Key Laboratory of Elemento-Organic Chemistry, National Pesticide Engineering Research Center (Tianjin), Nankai University, Tianjin 300071, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method has been developed for the Michael addition of nitrogen- and carbon-containing nucleo-
philes to cyclic enones. Using this conjugate addition reaction, a variety of different nucleophiles can
react with a range of cyclic enones in the presence of p-toluenesulfonic acid under solvent-free ultra-
sound irradiation conditions affording the corresponding C–N or C–C adducts in good to excellent yields.
Comparatively, performing the reaction under ultrasound irradiation gives higher yields, is more efficient
and environmentally benign than performing it at high pressure.
Received 13 October 2013
Revised 5 December 2013
Accepted 17 December 2013
Available online 30 December 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Michael addition
Cyclic enones
Ultrasound
Solvent-free
p-Toluenesulfonic acid
Introduction
to those that could be achieved using the high pressure method.10
In this Letter, we wish to report the development of an efficient
The conjugate addition of nitrogen- and carbon-containing
nucleophiles to ,b-unsaturated carbonyl compounds (i.e., Michael
solvent-free ultrasound method for the functionalization of enones
via a reaction with a variety of different Michael donors.
a
reaction) is a powerful tool in organic synthesis for the construc-
tion of CÀN and CÀC bonds. Reactions of this type have been suc-
cessfully applied to the preparation of pharmacologically
important b-substituted carbonyl compounds.1,2 In many cases,
these reactions can be catalyzed or promoted under strongly basic
conditions, Brønsted acid or Lewis acid catalysis. The application of
these catalysts to these reactions may be less effective, however,
when weakly nucleophilic systems such as amides or nitrogen-
containing heterocycles are used as the nucleophiles.3,4 During
the course of the last decade, tremendous progress has been made
toward the development of green versions of this important trans-
formation using high reaction temperatures,5 high pressures,6 and
UVA irradiation.7 Although the use of a high pressure reaction rep-
resents an efficient green method, it can be difficult in practice to
achieve sufficiently high compaction pressures. High-powered
ultrasound (US) can be used to generate cavitations capable of
inducing temperatures of several thousand degrees and pressures
in excess of 1000 atm inside bubbles.8,9 Our previous studies have
shown that the use of an ultrasound method for sterically con-
gested Passerini reactions generated results that were far superior
Results and discussion
The Michael addition between cyclohex-2-enone (1a) and benz-
amide (2a) was selected as a model reaction for the optimization of
the reaction conditions. This reaction was initially investigated
using a conventional procedure from the literature,11 where a mix-
ture of cyclohexenone 1a (1.2 equiv) and benzamide (2a) in aceto-
nitrile was heated for 24 h in the presence of p-TsOH (10 mol %).
Unfortunately, this procedure only provided a trace amount of
the desired product (Table 1, entry 1). When the reaction was
performed under a pressure of 0.6 GPa over a reaction time of
10 h, the yield increased to 75% (Table 1, entry 3). To determine
the effects of ultrasound irradiation on this reaction, a series of
experiments were carried out using a sonic horn as an ultrasound
source, with the other conditions same as those already described
in the literature.12 The reaction mixture was irradiated in acetoni-
trile at 20 kHz/675 W (pulse-on time, 1.2 s; pulse-off time, 1.5 s)
for 2 h. Pleasingly, the use of ultrasound effectively enhanced the
rate of the reaction. Although the yield for the reaction remained
unchanged under the high pressure and ultrasound irradiation
conditions, the reaction time was reduced significantly from 10
to 2 h. Solvent-free reactions have proven to be efficient and
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0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.