Mechanochemical michael reactions of chalcones and azachalcones with ethyl acetoacetate catalyzed by K2CO3 under solvent-free conditions

Article abstract of DOI:10.1246/cl.2004.168

Michael addition reactions of chalcones and azachalcones with ethyl acetoacetate have been successfully performed in the presence of catalytic amount of K₂CO₃ (10 mol %) and under the high-speed vibration milling conditions. The reac

Full text of DOI:10.1246/cl.2004.168

168
Chemistry Letters Vol.33, No.2 (2004)
Mechanochemical Michael Reactions of Chalcones and Azachalcones with Ethyl Acetoacetate
Catalyzed by K2CO3 under Solvent-Free Conditions
Ze Zhang, Ya-Wei Dong, Guan-Wu Wang,ꢀ and Koichi Komatsuy
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
yInstitute for Chemical Research, Kyoto University, Uji 611-0011
(Received November 20, 2003; CL-031123)
Michael addition reactions of chalcones and azachalcones
with ethyl acetoacetate have been successfully performed in
the presence of catalytic amount of K2CO3 (10 mol %) and under
the high-speed vibration milling conditions. The reactions take
place at ambient temperature without any solvent and full com-
pletion can be achieved in very short time (20–40 min). In most
cases, conventional side reactions were avoided and thus high
chemoselectivity and quantitative yields were achieved. The de-
sired Michael adducts were exclusively obtained consisting of
two diastereoisomers anti and syn, which were determined and
assigned by 1H NMR spectroscopy.
urated ketone, ethyl acetoacetate and K2CO3 in a molar ratio of
1:1:0.1 was introduced, together with a stainless-steel ball of 6.0-
mm diameter, into a stainless-steel capsule (9:0 ꢁ 26:0 mm).
The reaction capsule was fixed on the vibration arm of a
home-built ball-milling apparatus, and was vibrated vigorously
at a rate of 3500 rounds per minute at room temperature. The re-
sulting powder was collected and washed with 10 mL of water to
remove K2CO3 completely and then dried to afford the desired
product 2. This protocol does not require the use of any organic
solvent and only 10% molar equivalent of K2CO3 is enough to
promote the reaction efficiently. The yield and reaction time
for the Michael addition of ethyl acetoacetate to various chal-
cones and azachalcones 1 are summarized in Table 1.
As can be seen from Table 1, the yields obtained were good
to excellent. Compared with previous methodologies, the main
advantages of the present procedure are milder reaction condi-
tion, higher yield, shorter reaction time and occurrence of no
Mechanical alloying via high-energy ball-milling is a scala-
ble experimental technique, which is broadly used for the prep-
aration and modification of metals, metal hydrides, and other in-
organic solids in materials science in recent years.1–3 However,
mechanochemistry is seldom attempted in organic synthesis.
Even if attempted, mechanical processing of organic reactants
is sometimes followed by additional treatment (usually heat-
ing),4,5 or occasionally it is carried out in the presence of a sol-
vent.6 During the past two decades, solvent-free organic synthe-
sis has received considerable attention owing to growing
worldwide concerns over chemical wastes and future resources.
From these points of view, we applied a recently developed me-
chanical and environmentally benign technique called ‘high-
speed vibration milling’ (abbreviated as HSVM) to promote
the Michael addition of chalcones and azachalcones with ethyl
acetoacetate catalyzed by K2CO3 under the solvent-free condi-
tion. Traditionally, these reactions were performed in organic
solvents and catalyzed by strong bases such as NaOH, KOH,
Ba(OH)2, and NaOEt. Under these drastic conditions, the trans-
formation is sometimes complicated by side-reactions such as
bis-additions, auto-condensations, rearrangements, subsequent
condensation, retro Michael reaction, and so on.7 These undesir-
able side reactions decrease the yield and make the purification
of the products very tedious, and thus make it unsuitable for the
synthesis of desired compounds. However, in our present proto-
col, the Michael addition reactions were found to proceed effi-
ciently at ambient temperature in very short reaction time under
the HSVM conditions (Scheme 1).
Table 1. Michael addition of ethyl acetoacetate to chalcones
and azachalcones catalyzed by 10 mol % K2CO3 under the
HSVM conditions
1a
2b Reaction
time
Yield
/%c
Ar
X
/min
(anti:syn)d
1a
1b
1c
1d
1e
1f
4-NO2C6H4
CH 2a
CH 2b
CH 2c
CH 2d
CH 2e
30
40
35
40
40
20
25
30
40
40
98
(88:12)
96
(84:16)
99
(93:7)
99
(72:28)
99
(86:14)
97
(88:12)
92
(92:8)
97
(83:17)
94
3-NO2C6H4
4-NCC6H4
4-ClC6H4
3,4-ClC6H4
4-NO2C6H4
3-NO2C6H4
4-NCC6H4
3,4-ClC6H3
N
N
N
N
N
2f
2g
2h
2i
1g
1h
1i
In a typical experimental procedure, a mixture of an unsat-
(88:12)
86e
(84:16)
1j 3,4-CH2O2C6H3
2j
O
Ar
O
O
Ar
O
O
CH3COCH2COOEt
Ar
Me
Me
+
X
CO2Et
X
CO2Et
X
K2CO3 (0.1 equiv.) HSVM
aPrepared according to the recently reported method.8
bCharacterized by IR, 1H NMR, 13C NMR, and HRMS spec-
tral data.9 cIsolated yield from three runs on a 0.1 mmol scale.
anti
syn
1
2
1
e
dBased on H NMR analysis. Isolated by column chroma-
Scheme 1.
tography (silica gel, petroleum ether:ethyl acetate, 5:1).
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.2 (2004)
169
(KBr) 1740, 1717, 1693, 1512, 1350 cmꢂ1
;
1H NMR
side reactions. For example, compound 2d was previously pre-
pared in 85% yield, which was catalyzed by activated Ba(OH)2
in EtOH at room temperature for 8 h,7c whereas under our sol-
vent-free HSVM conditions, it was obtained in 99% yield at
room temperature for 40 min. The high efficiency of the current
procedure may be ascribed to the increased reaction rate result-
ing from ultimately high concentrations of reactants with no use
of solvent. Furthermore, common side reactions such as aldol
cyclizations and ester solvolysis are avoided owing to the use
of only catalytic amount of weak base K2CO3 and the solvent-
free conditions, hence high chemoselectivity was achieved.
In all the examples listed in Table 1, each product consists
of two diastereoisomers, anti and syn isomers. Interestingly, this
diastereoselectivity has not been investigated in previous
work,7b–d,10 Herein, the anti/syn ratio was determined by 1H
NMR spectrscopy, in which the diastereoisomer with the singlet
CH3CO at lower field and the CH3 in ethoxy group at higher
field was assigned as anti isomer.11 The anti isomer is the major
one in all cases. For these two diastereoisomers, the average dif-
ferential chemical shifts (ꢀꢀ) for the CH3CO and the CH3 in
ethoxy group are 0.26 and 0.24 ppm, respectively. They cannot
be separated by column chromatography. Even after crystalliza-
tion for several times, their ratio has no noticeable change. Prob-
ably the two diastereoisomers were in equilibrium via the corre-
sponding enol form even under the present heterogeneous
reaction conditions.11
(300 MHz, CDCl3) ꢀ 8.63 (d, J ¼ 4:2 Hz, 1H), 8.11 (d, J ¼
8:3 Hz, 2H), 7.90 (d, J ¼ 7:8 Hz, 1H), 7.80 (t, J ¼ 7:6 Hz,
1H), 7.51 (d, J ¼ 8:3 Hz, 2H), 7.45 (m, 1H), 4.34 (td, J ¼
10:0, 3.9 Hz, 1H), 4.04 (d, J ¼ 10:7 Hz, 1H), 3.93 (q, J ¼
7:0 Hz, 2H), 3.81 (dd, J ¼ 18:0, 9.5 Hz, 1H), 3.49 (dd, J ¼
18:0, 3.8 Hz, 1H), 2.33 (s, 3H), 1.01 (t, J ¼ 7:0 Hz, 3H); 13C
NMR (75 MHz, CDCl3) ꢀ 201.09, 198.67, 167.63, 152.92,
149.06, 147.08, 137.13, 129.67 (2C), 127.60, 123.82, 123.62
(2C), 121.98, 65.22, 61.82, 41.77, 39.86, 29.64, 13.94; HRMS
(EI–TOF) m=z calcd for C20H20N2O6 (Mþ): 384.1321, found:
384.1317. 2g: IR (KBr) 1734, 1714, 1695, 1532, 1350 cmꢂ1
;
1H NMR (300 MHz, CDCl3) ꢀ 8.63 (d, J ¼ 4:5 Hz, 1H), 8.19
(t, J ¼ 1:8 Hz, 1H), 8.03 (dd, J ¼ 8:2, 1.3 Hz, 1H), 7.90 (d,
J ¼ 7:8 Hz, 1H), 7.78 (td, J ¼ 7:7, 1.7 Hz, 1H), 7.71 (d, J ¼
7:7 Hz, 1H), 7.45 (dd, J ¼ 7:6, 1.1 Hz, 1H), 7.42 (t, J ¼
7:9 Hz, 1H), 4.33 (td, J ¼ 10:1, 4.1 Hz, 1H), 4.04 (d, J ¼
10:7 Hz, 1H), 3.92 (q, J ¼ 7:2 Hz, 2H), 3.82 (dd, J ¼ 17:9,
9.5 Hz, 1H), 3.51 (dd, J ¼ 17:9, 4.2 Hz, 1H), 2.33 (s, 3H),
1.00 (t, J ¼ 7:2 Hz, 3H); 13C NMR (75 MHz, CDCl3) ꢀ
201.15, 198.75, 167.66, 152.95, 149.08, 148.34, 143.59,
137.10, 135.46, 129.30, 127.57, 123.36, 122.24, 121.96,
65.34, 61.81, 41.80, 39.72, 29.72, 13.92; HRMS (EI–TOF)
m=z calcd for C20H20N2O6 (Mþ): 384.1321, found:
384.1338. 2h: IR (KBr) 2229, 1740, 1716, 1694 cmꢂ1 1H
;
NMR (300 MHz, CDCl3) ꢀ 8.62 (m, J ¼ 4:2 Hz, 1H), 7.90
(dt, J ¼ 8:0, 1.1 Hz, 1H), 7.79 (td, J ¼ 7:6, 1.5 Hz, 1H), 7.54
(d, J ¼ 8:3 Hz, 2H), 7.46 (m, 1H), 7.44 (d, J ¼ 8:3 Hz, 2H),
4.24 (m, 1H), 4.01 (dd, J ¼ 10:7, 4.1 Hz, 1H), 3.92(q, J ¼
7:2 Hz, 2H), 3.78 (dd, J ¼ 18:1, 9.5 Hz, 1H), 3.46 (dd, J ¼
18:1, 4.1 Hz, 1H), 2.32 (s, 3H), 1.00 (t, J ¼ 7:2 Hz, 3H); 13C
NMR (75 MHz, CDCl3) ꢀ 201.19, 198.72, 167.69, 152.96,
149.04, 147.01, 137.11, 132.21 (2C), 129.59 (2C), 127.56,
121.97, 118.82, 111.06, 65.26, 61.76, 41.72, 40.12, 29.59,
13.91; HRMS (EI–TOF) m=z calcd for C21H20N2O4 (Mþ):
364.1423, found: 364.1418. 2i: IR (KBr) 1732, 1714,
In summary, Michael reactions of chalcones and azachal-
cones with ethyl acetoacetate mechanically induced under com-
pletely solvent-free and K2CO3-catalyzed conditions have been
developed for the first time. The use of the HSVM technique and
catalytic amount of K2CO3 can give very high chemoselectivity
and thus high product yield. Furthermore, it is fast, clean and of
low cost, and work-up procedure is very simple. These advantag-
es indicate that solvent-free mechanochemistry has a potential to
become an alternative to conventional organic synthesis.
1694 cmꢂ1
;
1H NMR (300 MHz, CDCl3) ꢀ 8.63 (d, J ¼
3:5 Hz, 1H), 7.92 (d, J ¼ 7:6 Hz, 1H), 7.79 (td, J ¼ 7:7,
1.4 Hz, 1H), 7.45 (m, 1H), 7.41 (d, J ¼ 2:1 Hz, 1H), 7.30 (d,
J ¼ 8:2 Hz, 1H), 7.17 (dd, J ¼ 8:2, 2.1 Hz, 1H), 4.17 (td,
J ¼ 9:6, 4.2 Hz, 1H), 3.96 (q, J ¼ 7:0 Hz, 2H), 3.94 (d,
J ¼ 10:7 Hz, 1H), 3.73 (dd, J ¼ 17:5, 9.5 Hz, 1H), 3.42 (dd,
J ¼ 17:5, 4.3 Hz, 1H), 2.31 (s, 3H), 1.04 (t, J ¼ 7:0 Hz, 3H);
13C NMR (75 MHz, CDCl3) ꢀ 201.45, 198.74, 167.73,
152.93, 149.01, 141.59, 137.11, 132.34, 131.07, 130.63,
130.34, 128.17, 127.55, 122.00, 65.50, 61.79, 41.81, 39.20,
29.65, 13.93; HRMS (EI–TOF) m=z calcd for C20H19NO4Cl2
(Mþ): 407.0691, found: 407.0692. 2j: IR (KBr) 1732, 1709,
We are grateful to financial support from the National Sci-
ence Fund for Distinguished Young Scholars (20125205), Anhui
Provincial Bureau of Personnel Affairs and Anhui Provincial
Natural Science Foundation (00045306).
References and Notes
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1698 cmꢂ1
;
1H NMR (300 MHz, CDCl3) ꢀ 8.63 (d,
3
4
5
6
7
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J ¼ 4:2 Hz, 1H), 7.91 (d, J ¼ 8:3 Hz, 1H), 7.77 (td, J ¼ 7:7,
1.3 Hz, 1H), 7.43 (m, 1H), 6.79 (d, J ¼ 1:4 Hz, 1H), 6.75
(dd, J ¼ 8:0, 1.8 Hz, 1H), 6.65 (d, J ¼ 8:0 Hz, 1H), 5.87 (s,
2H), 4.14 (td, J ¼ 9:6, 4.0 Hz, 1H), 3.95 (q, J ¼ 7:2 Hz, 2H),
3.91 (d, J ¼ 10:7 Hz, 1H), 3.72 (dd, J ¼ 17:5, 9.5 Hz, 1H),
3.38 (dd, J ¼ 17:5, 4.3 Hz, 1H), 2.31 (s, 3H), 1.04 (t,
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199.17, 168.12, 153.17, 148.96, 147.54, 146.46, 137.01,
134.83, 127.34, 121.99, 121.76, 108.93, 108.18, 101.00,
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Selected spectral data for the anti isomer of product 2. 2f: IR
8
9
11 J. Christoffers, J. Chem. Soc., Perkin Trans. 1, 1997, 3141.
Published on the web (Advance View) January 14, 2004; DOI 10.1246/cl.2004.168