Solvent and catalyst free azo-Michael addition under high-speed vibration milling

Article abstract of DOI:10.1007/s11426-012-4605-y

Under the high-speed vibration milling conditions, the solvent and catalyst-free azo-Michael addition of chalcone derivatives and amines was found to proceed efficiently in excellent yields at ambient temperature in short reaction time. In most cases, con

Full text of DOI:10.1007/s11426-012-4605-y

SCIENCE CHINA
Chemistry
July 2012 Vol.55 No.7: 1252–1256
doi: 10.1007/s11426-012-4605-y
• ARTICLES •
Solvent and catalyst free azo-Michael addition under high-speed
vibration milling
LI YuJin*, CAO YongWen, XU FengShuang, FANG WenMing, YU WuBin,
JIA JianHong & GAO JianRong
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology; Zhejiang University of Technology,
Hangzhou 310032, China
Received October 3, 2011; accepted January 17, 2012; published online May 17, 2012
Under the high-speed vibration milling conditions, the solvent and catalyst-free azo-Michael addition of chalcone derivatives
and amines was found to proceed efficiently in excellent yields at ambient temperature in short reaction time. In most cases,
conventional side reactions were avoided and thus quantitative yields were achieved. The influences of the vibration frequency
and reaction time on the azo-Michael addition were investigated.
azo-Michael addition, solvent and catalyst-free, HSVM, chalcone
were inspired to perform Michael reaction [17, 18]. Michael
1 Introduction
reaction is one of the most efficient methods for car-
bon-carbon bond formation and has wide synthetic applica-
tions [19–22]. Generally, Michael additions are conducted
in a suitable solvent in the presence of a strong base, such as
NaOH, KOH, Ba(OH)2, and NaOEt [23–25]. However,
these drastic conditions often cause side reactions, such as
bis-addition, auto-condensation, rearrangement and retro
Michael additions, leading to low yields and difficulty in
purification of the target product, and thus making it un-
suitable for the synthesis of desired compounds [26, 27].
To avoid the aforementioned problems, solvent-free con-
ditions are undoubtedly an important method to be consid-
ered [28]. From these points of view, our group has applied
the HSVM technique to synthesize β-enamino ketones (es-
ters) [29]. Herein, we report our study on the azo-Michael
addition of chalcones with aliphatic amine or aromatic
amines in the absence of a catalyst. In our present protocol,
the azo-Michael addition reactions were found to proceed
efficiently under solvent and catalyst-free conditions in
very short reaction time under the HSVM conditions
(Scheme 1).
Environmental concerns about the solvent-based chemistry
have stimulated renewed interest in the study of chemical
reactions under solvent-free conditions [1–5]. Mechano-
chemistry is seldom attempted in organic synthesis. Even if
attempted, mechanical processing of organic reactants is
sometimes followed by additional treatment (usually heat-
ing) [6, 7], or occasionally it is carried out in the presence of
a solvent [8]. During the past two decades, solvent-free or-
ganic synthesis has received considerable attention owing to
growing worldwide concerns over chemical wastes and fu-
ture resources. Recently the technique of ‘high-speed vibra-
tion milling’ (abbreviated as HSVM) has been successfully
utilized in organic reactions [9–11]. Beginning with re-
search largely from Wang’s group in China, there have been
many reports on fullerene and non-fullerene mechano-
chemical reactions under HSVM conditions [12–16]. In the
course of their study on mechanical organic synthesis，they
*Corresponding author (email: lyjzjut@zjut.edu.cn)
© Science China Press and Springer-Verlag Berlin Heidelberg 2012
chem.scichina.com www.springerlink.com

Li YJ, et al. Sci China Chem July (2012) Vol.55 No.7
1253
3-(Benzylamino)-1-(4-methoxyphenyl)-3-(4-nitrophenyl)
propan-1-one (3h)
2 Experimental
1H NMR (500 MHz, CDCl3)  8.36–6.88 (m, 13H, ArH),
4.45 (dd, J = 8.5, 4.4 Hz, 1H), 3.86 (s, 3H), 3.62 (d, J = 1.5
Hz, 2H), 3.32 (d, J = 8.4 Hz, 1H), 3.27 (d, J = 4.5 Hz, 1H).
The reagents were obtained from commercial sources. The
1H NMR spectra were recorded at 500 MHz in CDCl3 with
a Bruker AM 500 spectrometer. The HSVM was achieved
with Retsch MM301 (Retsch GmbH, Haan, Germany).
3-(Benzylamino)-1-(4-methoxyphenyl)-3-phenylpropan-1-
one (3i)
General procedure for the synthesis of compound 3
1H NMR (500 MHz, CDCl3)  7.92–6.86 (m, 14H, ArH),
4.33 (dd, J = 8.8, 4.1 Hz, 1H), 3.85 (s, 3H), 3.61 (m, 2H),
3.30 (d, J = 8.8 Hz, 1H), 3.26 (d, J = 4.1 Hz, 1H).
A mixture of compound 1 (1 mmol) and amine 2 (1 mmol)
was vigorously shaken by HSVM for a designated time. The
obtained product 3 was purified by column chromatography
on silica gel with petroleum ether–EtOAc (3:1) as an eluent.
3-(p-Toluidino)-1,3-diphenylpropan-1-one (3j)
1H NMR (500 MHz, CDCl3)  7.92–6.45 (m, 14H, ArH),
4.97 (dd, J = 7.6, 5.3 Hz, 1H), 4.43(s, 1H), 3.45 (dd, J =
28.2, 6.5 Hz, 2H), 2.17 (s, 3H).
3-(Benzylamino)-1,3-diphenylpropan-1-one (3a)
1H NMR (500 MHz, CDCl3)  7.90 (d, J = 7.0 Hz, 2H),
7.54 (t, J = 7.5 Hz, 1H), 7.53–7.20 (m, 12H, ArH), 4.34 (dd,
J = 9.0, 4.5 Hz, 1H), 3.65 (d, J =13.0 Hz, 1H), 3.58 (d, J =
13.0 Hz, 1H), 3.40–3.28 (m, 2H), 1.77 (bs, NH).
3-(p-Toluidino)-3-(3-nitrophenyl)-1-ph5enylpropan-1-one
(3k)
1H NMR (500 MHz, CDCl3)  8.32–6.46 (m, 13H, ArH),
5.08 (t, J = 6.2 Hz, 1H), 4.54(s, 1H), 3.51 (d, J = 6.3 Hz,
2H), 2.18 (s, 3H).
3-(Benzylamino)-3-(3-bromophenyl)-1-phenylpropan-1-one
(3b)
1H NMR (500 MHz, CDCl3)  8.01–7.18 (m, 14H, ArH),
4.31 (dd, J = 8.5, 4.5 Hz, 1H), 3.66–3.57 (m, 2H), 3.36–3.25
(m, 2H), 1.91(bs, NH).
3-(4-Methoxyphenylamino)-1,3-diphenylpropan-1-one (3l)
1H NMR (500 MHz, CDCl3)  7.91–6.53 (m, 14H, ArH),
4.92 (dd, J = 7.7, 5.1 Hz, 1H), 4.29 (s, 1H), 3.68 (s, 3H),
3.46 (d, J = 5.1 Hz, 1H), 3.42 (d, J = 7.8 Hz, 1H).
3-(Benzylamino)-3(3-nitrophenyl)-1-phenylpropan-1-one
(3c)
1H NMR (500 MHz, CDCl3)  8.36–7.20 (m, 14H, ArH),
4.47 (dd, J = 8.5, 4.0 Hz, 1H), 3.67–3.58 (m, 2H), 3.39–3.31
(m, 2H), 1.77(bs, NH).
3-(3-Chlorophenylamino)-1,3-diphenylpropan-1-one (3m)
1H NMR (500 MHz, CDCl3)  8.30–6.41 (m, 14H, ArH),
5.08 (t, J = 6.0 Hz, 1H), 4.81 (s, 1H), 3.52 (d, J = 6.2 Hz,
2H).
3-(Benzylamino)-1-phenyl-3-(4-(trifluoromethyl)-phenyl)-
propan-1-one (3d)
1H NMR (500 MHz, CDCl3)  7.97–7.21 (m, 14H, ArH),
4.42 (dd, J = 8.5, 4.0 Hz, 1H), 3.67–3.58 (m, 2H), 3.42–3.30
(m, 2H).
1-Phenyl-3-(piperidin-1-yl)-3-(4-(trifluoromethyl)-phenyl)-
propan-1-one (3n)
1H NMR (500 MHz, CDCl3)  7.91–7.39 (m, 9H, ArH),
4.29 (dd, J = 7.7, 5.8 Hz, 1H), 3.61 (dd, J = 16.7, 5.7 Hz,
1H), 3.41 (dd, J = 16.7, 7.9 Hz, 1H), 2.84–2.27 (m, 4H),
1.52 (m, 4H), 1.36 (dd, J = 11.5, 5.7 Hz, 2H).
3-(Benzylamino)-3-(4-bromophenyl)-1-(4-methoxyphenyl)-
propan-1-one (3e)
1H NMR (500 MHz, CDCl3)  7.91–7.23 (m, 13H, ArH),
4.40 (dd, J = 8.5, 4.0 Hz, 1H), 3.85 (s, 3H), 3.64–3.57 (m,
2H), 3.30–3.24 (m, 2H).
3-(3-Bromophenyl)-1-phenyl-3-(piperidin-1-yl)propan-1-
one (3o)
1H NMR (500 MHz, CDCl3)  7.95–7.13 (m, 9H, ArH),
4.30–4.05 (m, 1H), 3.58 (dd, J = 16.6, 6.1 Hz, 1H), 3.35 (dd,
J = 16.5, 7.5 Hz, 1H), 2.36 (m, 4H), 1.57–1.46 (m, 4H),
1.40–1.28 (m, 2H).
3-(Benzylamino)-1-(4-methoxyphenyl)-3-(4-(trifluoromethyl)-
phenyl)propan-1-one (3f)
1H NMR (500 MHz, CDCl3)  7.90–6.87 (m, 13H, ArH),
4.29 (dd, J = 8.7, 4.1 Hz, 1H), 3.86 (s, 3H), 3.66–3.57 (m,
2H), 3.31–3.19(m, 2H).
1-(4-Methoxyphenyl)-3-phenyl-3-(piperidin-1-yl)propan-1-
one (3p)
3-(Benzylamino)-1,3-bis(4-methoxyphenyl)propan-1-one
1H NMR (500 MHz, CDCl3)  7.92–6.90 (m, 9H, ArH),
4.20 (dd, J = 7.5, 6.1 Hz, 1H), 3.87 (s, 3H), 3.53 (dd, J =
16.1, 6.0 Hz, 1H), 3.35 (dd, J = 16.2, 7.5 Hz, 1H), 2.48–
2.28 (m, 4H), 1.51 (m, 4H), 1.40–1.26 (m, 2H).
(3g)
1H NMR (500 MHz, CDCl3)  7.90–6.87 (m, 13H, ArH),
4.27 (dd, J = 8.6, 4.2 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.60
(m, 2H), 3.28 (d, J = 8.6 Hz, 1H), 3.24 (d, J = 4.2 Hz, 1H).

1254
Li YJ, et al. Sci China Chem July (2012) Vol.55 No.7
3-(3-Nitrophenyl)-1-phenyl-3-(piperidin-1-yl)propan-1-one
(3q)
1H NMR (500 MHz, CDCl3)  8.18–7.42 (m, 9H, ArH),
4.36 (dd, J = 8.1, 5.5 Hz, 1H), 3.64 (dd, J = 16.8, 5.5 Hz,
1H), 3.44 (dd, J = 16.8, 8.1 Hz, 1H), 2.39 (m, 4H),
1.58–1.47 (m, 4H), 1.37 (dd, J = 11.5, 5.8 Hz, 2H).
As shown in Table 1, higher vibration frequency of the
vibration mill accelerated the reaction process significantly.
It is easy to understand that the faster milling vibration
gives the higher energy, and therefore the local pressure is
applied to the reaction system. Furthermore, it was found
that the decrease of the reaction time resulted in lower
yields. The result indicated that the azo-Michael addition
was obtained in good yield in the absence of any catalyst
under HSVM conditions.
1-(4-Methoxyphenyl)-3-(piperidin-1-yl)-3-(4-(trifluoromethyl)-
phenyl)propan-1-one (3r)
From the above results, the reaction conditions of the vi-
bration frequency (30 Hz), reaction time (25 min) and raw
material mole ratio (1:1) were selected for investigating the
addition reaction of different amines 2 and chalcone or sub-
stitutional chalcone 1 (Scheme 2).
1H NMR (500 MHz, CDCl3)  7.92–6.89 (m, 8H, ArH),
4.18 (dd, J = 7.3, 6.1 Hz, 1H), 3.87 (s, 3H), 3.51 (dd, J =
16.4, 5.9 Hz, 1H), 3.29 (dd, J = 16.4, 7.5 Hz, 1H), 2.40 (d,
J = 5.1 Hz, 2H), 2.33 (d, J = 4.9 Hz, 2H), 1.58–1.46 (m, 4H),
1.40–1.29 (m, 2H).
3 Results and discussion
The azo-Michael reaction of chalcone and benzylamine was
first examined and found to proceed efficiently in excellent
yield under HSVM under solvent and catalyst-free condi-
tions. All solvent-free reactions were performed using a
high-speed vibration mill consisting of a capsule and a
milling ball made of stainless steel [30]. The capsule con-
taining the milling ball was fixed on a vibration arm of a
homebuilt mill, and was vibrated vigorously at a maximum
rate of 1800 rpm. The solvent-free mechanochemical reac-
tion of chalcone 1 with benzylamine 2 under the HSVM
conditions afforded essentially pure product 3 after washing
the reaction mixture with water in most cases.
To explore this reaction system, we have carried out this
azo-Michael reaction at different vibration frequency and
reaction time. It was found that the vibration frequency of
the applied vibration mill had a significant effect on this
reaction (Table 1).
Scheme 2
This protocol does not require use of any base as cata-
lysts and any organic solvent during the reaction process
and HSVM alone is enough to promote the reaction effi-
ciently. The yield of the azo-Michael addition is summa-
rized in Table 2.
As shown in Table 2, the azo-Michael addition reactions
generally gave products 3 in remarkably high yields. The
electron-withdrawing and electron-donating of chalcone 1
could participate in the reaction of benzyl amine and chal-
cone. This protocol can be extended to the azo-Michael ad-
dition of other amines such as secondary amine piperidine
to chalcones with good yield in almost all cases. It is easy to
understand that the lower reactivity of phenylamine gave
the lower yield of this azo-Michael addition (entry 11, 12,
13). Compared with existing methods, the main advantages
of the present procedure are milder conditions, higher yield,
shorter reaction time and occurrence of no side reactions.
For example, compound 3a was previously prepared in 64%
yield which was catalyzed by natural phosphate in MeOH at
room temperature for 24 h [31], whereas under our solvent-
free HSVM conditions, it was obtained in 98.1% yield at
room temperature for 25 min. The reasons for the efficiency
of the current solvent-free procedure may be an enhanced
second-order reaction rate resulting from ultimately high
concentrations of reactants with no use of a solvent. Fur-
thermore, in the HSVM technique, the high mechanical en-
ergy caused by local high pressure, friction, shear strain, etc.
can significantly reinforce the reaction [13].
Scheme 1
Table 1 Michael addition of benzylamine to chalcone 1 at different vi-
bration frequency and reaction time under HSVM conditions
Entry
Vibration frequency (Hz)
Time (min)
Yield (%)a)
1
2
3
4
5
6
7
10
20
30
30
30
30
30
25
25
25
10
15
20
25
66
90
99
78
82
96
99
4 Conclusion
In summary, a powerful method was described for azo-
Michael addition of chalcones with amines in quantitative
a) The yield of 1H NMR.

Li YJ, et al. Sci China Chem July (2012) Vol.55 No.7
1255
Table 2 azo-Michael addition of different amines to chalcone under HSVM conditions
Entry
1
R1
H
R2
H
2
Product 3
3a [31]
3b
Yield (%)a)
98
benzyl amine
benzyl amine
benzyl amine
benzyl amine
benzyl amine
benzyl amine
benzyl amine
benzyl amine
benzyl amine
p-Me-aniline
p-Me-aniline
p-MeO-aniline
m-Cl-aniline
piperidine
2
m-Br
m-NO2
p-CF3
p-Br
p-CF3
p-OCH3
p-NO2
H
H
99
3
H
3c
98
4
H
3d
99
5
–OCH3
–OCH3
–OCH3
–OCH3
–OCH3
–H
3e
90
6
3f
82
7
3g
88
8
3h
90
9
3i
94
10
11
12
13
14
15
16
17
18
H
3j [32]
3k
83
m-NO2
H
–H
59
–H
3l [32]
3m [33]
3n
52
H
–H
47
p-CF3
m-Br
H
–H
91
–H
piperidine
3o
91
–OCH3
–H
piperidine
3p
89
m-NO2
p-CF3
piperidine
3q
90
–OCH3
piperidine
3r
90
a) Isolated yield based on chalcone 1.
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