Solvent-free crossed aldol condensation of cyclic ketones with aromatic aldehydes assisted by microwave irradiation

Article abstract of DOI:10.1007/s00706-004-0256-9

A fast alumina-promoted crossed aldol-condensation reaction of aldehydes and cyclic ketones under microwave irradiation is described. This process is simple, efficient, and environmentally benign and proceeds in fairly high yield without any self-condensation. Springer-Verlag 2005.

Full text of DOI:10.1007/s00706-004-0256-9

Monatshefte f €u r Chemie 136, 571–576 (2005)
DOI 10.1007/s00706-004-0256-9
Solvent-Free Crossed Aldol Condensation
of Cyclic Ketones with Aromatic Aldehydes
Assisted by Microwave Irradiation
1
;ꢀ
1
1
Abbas A. Esmaeili , Mehri Salimi Tabas , Mohammad A. Nasseri ,
2
and Foad Kazemi
1
Department of Chemistry, University of Birjand, Birjand, Iran
2
Department of Chemistry, University of Shahid Chamran, Ahvaz, Iran
Received May 27, 2004; accepted (revised) August 26, 2004
Published online January 18, 2005 # Springer-Verlag 2005
Summary. A fast alumina-promoted crossed aldol-condensation reaction of aldehydes and cyclic
ketones under microwave irradiation is described. This process is simple, efficient, and environmen-
tally benign and proceeds in fairly high yield without any self-condensation.
Keywords. Alumina; Aldol reactions; Catalysts; Microwave irradiation; Cyclohexanone;
Cyclopentanone.
Introduction
0
Due to the importance of ꢀ,ꢀ -bis(substituted benzylidene)cycloalkanones as use-
ful precursors for potentially bioactive pyrimidine derivatives, condensation of
0
cycloalkanones with aldehydes to give the corresponding ꢀ,ꢀ -bis(substituted
benzylidene)cycloalkanones is of special interest [1].
Usually, this condensation can be performed using strong acid or base catalysts.
However, the presence of strong acid or base often induces side reactions and thus
gives the corresponding products in low yields [2]. Several metal complexes, such
as Mn (II), Fe (II), Co (II), Ni (II), Cu (II), and Zn (II), have also been reported as
catalysts for these reactions [3].
Among these metal complexes, Co (II)-bipyridyl is the most reactive one, but the
yield of the condensation product starting from cyclopentanone and benzaldehyde
is only 38%. Rh (III) porphyrin was also applied for this aldol condensation but
similar to other metal complexes the yields of the reaction are low [4]. Cp TiPh2
2
and anhydrous RuCl have also been used to catalyze the crossed aldol condensa-
3
tion [5, 6]. Good yields of the products can only be obtained at high temperature
ꢀ Corresponding author. E-mail: aa_esmaeili@yahoo.com

5
72
A. A. Esmaeili et al.
Scheme 1
in sealed tubes. The methods reported so far have serious limitations. There is a
need to develop more convenient and efficient methods for this type reaction.
In recent years, microwave-assisted reactions have attracted great interest
because of the simplicity of the process, enhanced reaction rates, and greater selec-
tivity. Particularly, solvent-free reactions have gained popularity as they provide an
opportunity to work with open vessels. This avoids the risks when working under
high pressure conditions and provides an easy opportunity to scale-up the reaction.
Thus microwave irradiation, which has become a powerful synthetic tool for the
rapid synthesis of a variety of biologically active compounds under solvent-free
conditions, is used to enhance the rates of many classical organic reactions [7–10].
Furthermore, microwave promoted solid-phase heterogeneous reactions are
environmentally benign. Among the various heterogeneous catalysts alumina is
attractive because it can be reused, it is environmentally compatible, its costs are
low, it is non-toxic, and it is experimentally simple to apply [11–13].
We report here that acidic alumina efficiently catalyzes the crossed aldol con-
densation reaction between different cycloalkanones and aromatic aldehydes under
microwave irradiation (Scheme 1).
Results and Discussions
Several classes of solids have commonly been used to catalyze organic transfor-
mations at their surface including alumina, silica gels, and clays. Acidic alumina,
the material used commonly for column chromatography, is certainly one of the
most interesting of these solids. Its surface properties allow many different organic
transformations to occur [14–15].
We report here our results on the alumina catalyzed, fast, solvent-free conden-
sations of cyclic ketones with different aromatic aldehydes under microwave irra-
diation (Table 1).
Green chemistry asks for the development of environmentally improved routes
and the use of sustainable resources. The recovery and the reuse of the catalyst and
the solvent is an important asset. After having separated the product by eluting with
a suitable solvent such as CH Cl , the catalyst (Al O ) could be recovered easily
2
2
2 3
ꢁ
by drying at 100 C for several hours. Investigations using benzaldehyde and cyclo-
pentanone as model substrates showed that the recovered alumina could be suc-
cessfully reused several times. The recovered Al O could be used five times and
2
3
similar yields were obtained in all runs (Table 2, entry 5).
The aldol condensation of different substituted benzaldehydes and cyclopenta-
none were carried out in the presence of acidic, neutral, and basic alumina. The
results are summarized in Table 3.

Solvent-Free Crossed Aldol Condensation
573
0
Table 1. Preparation of ꢀ,ꢀ -bis(substituted benzylidene)cycloalkanones in solvent-free conditions
under microwave irradiation
a
ꢁ
Entry Ar
n Time=sec
Products Alu-
mina=g
Power=% Isolated mp= C
Yield=%
1
2
C H
6
1 60-60-60-60
1 30-30-60-60
3a
3b
4
80
98
92
189
Ref. [5] 188.5)
164–166 (Ref.
16] 160–162)
5
(
2-furyl
4
100
[
3
4
5
p-CH OC H 1 30-30-60-60-60 3c
3 6 5
6.5
4
100
100
60
95
95
99
212 (Ref. [5] 212)
144–146
m-CH OC H 1 130-60-60-30
3 6 5
3d
3e
p-BrC H
6
1 180-30
3
251–253 (Ref.
5
[5] 212)
6
7
8
p-CH C H
6 5
1 60-120-60-60
3f
5.5
6.5
4
80
60
98
97
95
233–235
3
C H CH¼CH 1 60-120
3g
3h
225 (Ref. [5] 223)
175–176 (Ref.
6
5
m-ClC H
6
1 120-120-60
100
5
[18] 177)
9
0
o-ClC H
6
1 120-120-60
2 180-30
3i
3j
4
80
98
97
160–163
5
1
C H
6
4.5
100
116–117 (Ref.
5
[5] 116–117)
1
1
1
2
p-CH OC H 2 40-40-60
3 6 5
3k
3l
8
6
100
100
94
89
205 (Ref. [5] 204)
167–169 (Ref.
p-CH C H
6 5
2 60-120-60-60
3
[5] 170)
1
1
3
4
p-BrC H
6
2 30-30-60-120-60 3m
2 120-120-120-120 3n
3
6
80
96
87
163–165
159 (Ref.
5
p-NO C H
6 5
100
2
[5] 158.5)
15
16
17
m-ClC H
6
2 120-120-120-120 3o
4
7
2
80
100
100
72
95
98
105–107
5
C H CH¼CH 2 120-30
3p
3q
180 (Ref. [5] 179)
143–145 (Ref.
6
5
2-furyl
2 30-30-60-30
[16] 140–141)
a
1 13
Products were characterized by H NMR, C NMR, IR, and by comparison of their physical
properties with those reported in the literature
Table 2. Studies on the reuse of Al O
2
3
Round
Yield=%
Al O recovered=%
2 3
1
2
3
4
5
92
90
88
88
86
99
98
98
99
98
Table 3. Condensation reaction of benzaldehyde and cyclopentanone in different alumina
Entry
Type of alumina
Time=min
Isolated yield=%
1
2
3
Acidic alumina
Neutral alumina
Basic alumina
4 min
10 min
10 min
98
–
10

5
74
A. A. Esmaeili et al.
Table 4. Comparison of some results obtained from using acidic alumina under MW irradiation, that
listed in Table 1 (Method A), with other methods (Method B) [19] and (Method C) [16]
Entry
Product
Reaction time (yield=%)
Method A
Method B
Method C
1
6
7
9
3a
3f
4 min (98)
5 min (98)
3 min (97)
5 min (98)
4 min (97)
5 min (89)
8 min (87)
2.5 min (95)
6 h (92)
6 h (90)
10 h (80)
6 h (87)
6 h (90)
6 h (94)
6 h (91)
10 h (82)
5 min (84.5)
–
3g
3i
5 min (93.4)
–
1
1
1
1
0
2
4
6
3j
7 min (64.5)
–
3l
3n
3p
7 min (71.4)
7 min (71)
Only acidic alumina gave high yields of product under microwave irradiation
98%, Table 3, entry 1). When neutral alumina was used, the reaction could not be
observed after 10 min microwave irradiation. Using basic alumina under similar
(
conditions the desired product 3a was obtained but in a disappointingly low yield
(
10%). Therefore acidic alumina was selected as solid catalyst for the subsequent
reactions.
A comparison of our results with those reported in the literature clearly shows
the advantage of using microwave irradiation in the presence of acidic alumina as
catalyst (Table 4) [16, 19]. Employing our method (Method A) only 2.5–8 min
were needed for almost complete transformation, whereas the condensation cata-
lyzed by FeCl ꢂ 6H O (Method B) [19] needs 6–10 hours. It has also been found
3
2
that lower yields were obtained using acetonitrile as solvent and bis(p-methoxy-
phenyl)teluroxide (BMPTO) as catalyst under microwave irradiation (Method C)
[
16].
In summary, microwave-assisted solvent-free reactions were employed to
0
synthesize ꢀ,ꢀ -bis(benzylidene)cycloalkanone derivatives. The method not only
offers substantial improvement in yield over conventional heating methods but also
eliminates the use of hazardous solvents. Other advantages of this method include
the fact that it is environmentally benign and an economical procedure. The short
reaction time and the simplicity of the performance using a non-aqueous work-up
are further advantages of our method.
Experimental
Melting points were measured on an Electro thermal 9100 apparatus and are uncorrected. IR spectra
1
13
were measured on a Perkin-Elmer 783 Infrared spectrophotometer. H and C NMR spectra were
measured with a Bruker DRX-250 Avance spectrometer at 250 and 62.90 MHz, respectively. Alde-
hydes and ketones were obtained from Fluka (Buchs, Switzerland) and Merck and were used without
further purification. An unmodified domestic household microwave oven (Philco, MTO8E29, 1250W)
equipped with inverter technology, which provides a realistic control of the microwave power to the
desired level (20–100%) was used for microwave heating. The MW oven was operated at reduced
MW-power level of 60% (750 W), 80% (1000 W), and total power level 100% (1250 W).

Solvent-Free Crossed Aldol Condensation
575
General Procedure
Ketone (1mmol), aromatic aldehyde (2mmol), and 2–7 g of acidic alumina (Table 1) were added in a
3
Pyrex beaker (20 cm ). The mixture was stirred for 30 s until a free flowing powder was obtained. The
whole mixture was then irradiated in the microwave oven for appropriate times. The sample was
thoroughly mixed outside for 30 s and again irradiated for another time period. This intermittent
heating-stirring cycle was repeated for the total irradiation time as required to complete the reaction
3
TLC, Table 1). The reaction mixture was then eluted with CH Cl (20 cm ) and the extract was dried
(
2
2
over Na SO and the solvent was evaporated to leave the crude product which was further purified by
2
4
recrystallization from ethanol.
ꢁ
1
3
d: Yellow crystal, yield 95%, mp 212 C; H NMR (CDCl ): ꢁ ¼ 3.04 (s, 2CH ), 3.78 (s, 2OCH ),
3
2
3
13
.37–7.49 (m, 6CH ), 7.38 (s, CH ) ppm; C NMR (CDCl ): ꢁ ¼ 26.93 (CH ), 55.70 (OMe),
6
furyl
vinyl
3
2
1
15.48, 116.38, 123.69, 130.10, 134.21 (5CH), 137.51, 137.92, 160 (3C), 190.01 (C¼O) ppm; IR
ꢃ1
(
KBr): ꢂꢀ ¼ 3020 (¼C-H ), 2995 (C-H ), 2915 (C-H ), 1780 (C¼O) cm
.
Str
Str
Str
ꢁ
1
3
i: Yellow crystal, yield 98%, mp 159–167 C; H NMR (CDCl ): ꢁ ¼ 2.92 (s, 2CH ), 6.90–7.85
3
2
13
(
m, 8CH ), 8.17 (s, 2CH ) ppm; C NMR (CDCl ): ꢁ ¼ 26.93 (CH ), 127.00, 130.43, 130.50,
arom
vinyl
3
2
1
30.60 (4CH), 134.23, 136.44, 137.50 (3C), 139.68 (CH), 191.01 (C¼O) ppm; IR (KBr): ꢂꢀ ¼ 3020
ꢃ1
ꢁ
(
¼C-H ), 2920 (C-H ), 1780 (C¼O) cm
.
Str
Str
1
3
k: Yellow crystal, yield 97%, mp 205 C; H NMR (CDCl ): ꢁ ¼ 1.82 (quin, J ¼ 5.7 Hz, CH ),
3
2
13
C
2
.93 (t, J ¼ 5.7 Hz, 2CH ), 3.86 (s, 2OCH ), 6.95 (d, J ¼ 8.6 Hz, 4CH ), 8.10 (s, CH ) ppm;
2
3
arom
vinyl
NMR (CDCl ): ꢁ ¼ 23.43 (CH ), 28.92 (CH ), 55.70 (OMe), 114.29 (CH), 129.13 (C), 132.63 (CH),
3
2
2
1
34.73 (C), 136.89 (CH), 160.31(C), 190.55 (C¼O) ppm; IR (KBr): ꢂꢀ ¼ 3020 (¼C-H ), 2910
Str
ꢃ1
(
C-H ), 1650 (C¼O) cm
.
Str
ꢁ
1
3
m: Yellow crystal, yield 97%, mp 164 C; H NMR (CDCl ): ꢁ ¼ 1.69 (quin, J ¼ 6.2 Hz, CH ),
3
2
13
), 7.22–7.61 (m, 10H) ppm; C NMR (CDCl ): ꢁ ¼ 24.55 (CH ), 30.15
2
.78 (t, J ¼ 6.2Hz, 2CH
2
allyl
3
2
(
(
(
CH
), 124.73 (C-Br), 133.41 (CH meta to Br), 133.57 (C ortho to Br), 136.48 (C ), 137.60
allyl ipso
2
CHvinyl), 138.27 (C¼CH), 191.53 (C¼O) ppm; IR (KBr): ꢂꢀ ¼ 3020 (C-H ), 2920 (C-H ), 2820
Str
Str
ꢃ1
C-H ), 1720 (C¼O), 1600 (C¼C), 830 (C-H ) cm
.
Str
OOP
1
ꢁ
3
o: Yellow crystal, yield 72%, mp 106 C; H NMR (CDCl ): ꢁ ¼ 1.83 (quin, J ¼ 6.5 Hz, CH ),
3
2
13
.91 (t, J ¼ 6.5 Hz, 2CH ), 7.34–7.44 (m, 8H), 7.72 (s, CH ) ppm; C NMR (CDCl ): ꢁ ¼ 23.15
2
2
vinyl
3
(
CH ), 28.72 (2CH
2
), 128.88, 128.99, 130.05, 130.29, 134.73, 135.96 (6C), 137.43 (¼CH ),
2 allyl
vinyl
1
38.01 (C¼CH), 190.04 (C¼O) ppm; IR (KBr): ꢂꢀ ¼ 3050 (C-H ), 2935 (C-H ), 2860 (C-H ), 2830
Str
Str
Str
ꢃ1
.
(
C-H ), 1720 (C¼O) cm
Str
ꢁ
1
3
q: Brown crystal, yield 98%, mp 145 C; H NMR (CDCl ): ꢁ ¼ 1.79 (quin, J ¼ 6.2 Hz, CH ), 2.91
3
2
13
(
t, J ¼ 6.2 Hz, 2CH ), 6.42–7.46 (m, 8H) ppm; C NMR (CDCl ): ꢁ ¼ 22.04 (CH ), 28.36 (2CH ),
2
3
2
2
1
12.70, 116.43, 123.73, 144.90 (4CH), 133.42, 153.15 (2C), 189.34 (C¼O) ppm; IR (KBr): ꢂꢀ ¼ 3125
ꢃ1
(
C-H ), 2925 (C-H ), 1680 (C¼O) cm
.
Str
Str
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A. A. Esmaeili et al.: Solvent-Free Crossed Aldol Condensation
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