Highly selective claisen-schmidt condensation catalyzed by silica chloride under solvent-free reaction conditions

Article abstract of DOI:10.1080/00397910903340637

Silica chloride serves as a useful catalyst in the cross-aldol condensation, leading to the synthesis of a wide variety of bisarylidene cycloalkanones and chalcones. The catalyst showed high selectivity; self-condensation of ketones was not observed.

Full text of DOI:10.1080/00397910903340637

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Highly Selective Claisen–Schmidt
Condensation Catalyzed by Silica
Chloride Under Solvent-Free Reaction
Conditions
Hassan Hazarkhani a , Pradeep Kumar a , Kadam Sachin Kondiram a
Ikhlas M. Shafi Gadwal a
&
a Division of Organic Chemistry, National Chemical Laboratory ,
Pune, India
Published online: 25 Aug 2010.
To cite this article: Hassan Hazarkhani , Pradeep Kumar , Kadam Sachin Kondiram & Ikhlas M. Shafi
Gadwal (2010) Highly Selective Claisen–Schmidt Condensation Catalyzed by Silica Chloride Under
Solvent-Free Reaction Conditions, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:19, 2887-2896, DOI: 10.1080/00397910903340637
To link to this article: http://dx.doi.org/10.1080/00397910903340637
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Synthetic Communications1, 40: 2887–2896, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903340637
HIGHLY SELECTIVE CLAISEN–SCHMIDT
CONDENSATION CATALYZED BY SILICA CHLORIDE
UNDER SOLVENT-FREE REACTION CONDITIONS
Hassan Hazarkhani, Pradeep Kumar,
Kadam Sachin Kondiram, and Ikhlas M. Shafi Gadwal
Division of Organic Chemistry, National Chemical Laboratory, Pune, India
Silica chloride serves as a useful catalyst in the cross-aldol condensation, leading to the
synthesis of a wide variety of bisarylidene cycloalkanones and chalcones. The catalyst
showed high selectivity; self-condensation of ketones was not observed.
Keywords: Aldol reaction; arylidene cycloalkanone; Claisen–Schmidt; condensation; silica chloride
INTRODUCTION
The Claisen–Schmidt condensation is an important reaction for the
preparation of a,a0-bisarylidene and alkylidene cycloalkanones and chalcones.
Arylidende and alkylidene cycloalkanones are important precursors for potentially
bioactive pyrimidine derivatives;[1] agrochemicals, pharmaceuticals, and perfumes;[2]
cytotoxic analogs;[3] and units of liquid-crystalline polymers.[4] They also serve as key
starting materials for the synthesis of a new class of spiropyrrolidines as antimicro-
bial and antifungal agents,[5] tetraazadispiro[4.1.4.3]tetradeca-2,9-dien-6-ones,[6] tri-
cyclic thiazolo[3,2-a]thiapyrano[4,3-d]pyrimidines as potentially anti-inflammatory
agents,[7] and other novel heterocycles.[8]
Chalcones are useful groups of natural products[9] that are potentially impor-
tant synthetic intermediates for preparation of flavonoids[10] and a series of hetero-
cyclic compounds. They have been recently used as simple building blocks for the
synthesis of dihydropyridones[11] and preparation of novel bridged bicyclic products
via intermolecular electrocyclization reactions.[12] In addition, they mostly display
anticancer activity,[13] as well as anti-inflammatory and analgesic properties.[14]
For example, curcumin (also known as diferuloylmethane), a carotenoid pigment
isolated from the spice turmeric having a chalcone moiety, shows a wide range of
biological properties including anti-oxidant, anti-inflammatory, and anti-HIV
properties.[15] Therefore, the synthesis of bisarylidene cycloalkanones and chalcones
have attracted the attention of synthetic organic chemists worldwide. These com-
pounds are classically prepared from cross-aldol condensation (Claisen–Schmidt
Received July 20, 2009.
Address correspondence to Hassan Hazarkhani, Division of Organic Chemistry, National
Chemical Laboratory, Pune 411 008, India. E-mail: hazarkhani@gmail.com
2887

2888
H. HAZARKHANI ET AL.
condensation) catalyzed by strong protic acids,[16] bases,[17] and variety of metal(II)
ions such as Zn(II) and Ni(II).[18] However, these reactions suffer from side reactions
(such as self-condensation of ketones) and thus give poor yields of the desired pro-
ducts. Subsequently, more modified procedures have been developed that used Lewis
acids and several other reagents such as Cp2TiPh2,[19] BMPTO,[20] RuCl3,[21]
SmI3,[22] TMSCl=NaI,[23] TiCl3(CF3SO3),[24] Yb(OTf)3,[25] [(Me3Si)2N]3Ln(m-
Cl)Li(THF)3,[26] Al2O3=KF,[27] PEG400=K2CO3,[28] HT-OBU,[29] Mg(HSO4)2,[30]
InCl3,[31] FeCl3,[32] BF3 ꢀ OEt2,[33] molecular iodine (I2),[34] Et3N in the presence of
LiClO4,[35] LiOH,[36] trichlorotriazine (TCT),[37] NaOAc=HOAc,[38] and SOCl2=
EtOH.[39] In spite of high-yielding products, many disadvantages such as the use
of costly catalyst, hazardous agents like LiClO4 and silica sulfuric acid, stoichio-
metric amounts of catalyst, and complicated purification operations have been
encountered.
Chlorinated silica gel, known as silica chloride, was first introduced as an
efficient catalyst for thioacetalization of carbonyl compounds by Kamitori et al.[40]
Later, Firouzabadi’s group modified the preparation of silica chloride and used
the same in several functional-group transformations.[41] Subsequently, silica chlor-
ide was extensively used as a reagent or a catalyst for various organic transforma-
tions.[42] As a part of our ongoing research program on solid catalyst–mediated
organic transformations,[43] we now report a new application of silica chloride for
the highly selective Claisen–Schmidt condensation reaction.
RESULTS AND DISCUSSION
Synthesis of a,a’-Bisarylidene and Alkylidene Cycloalkanones
To check the feasibility of this condensation reaction, initially the
self-condensation reaction of cyclohexanone in the presence of 5 mol% of silica
chloride under solvent-free reaction condition was examined. When the reaction
mixture was heated for 12 h at 100–110 ꢁC, it was a failure, and we could not observe
the formation of any product. Increasing the reaction time and catalyst amount to
10 mol% had no effect on the course of the reaction (Scheme 1).
Similarly, when 4-chloro acetophenone was treated with silica chloride under
identical reaction conditions, the 1H NMR spectrum of the reaction mixture showed
that there was no reaction and the starting material almost remained intact
(Scheme 2).
Interestingly, the self-condensation reaction of 3-phenylpropanal as an ali-
phatic aldehyde smoothly proceeded in the presence of silica chloride. Thus, when
a mixture of 5 mmol of 3-phenyl propanal and 0.5 g silica chloride was heated at
Scheme 1. Self-condensation reaction of cyclohexanone.

ALDOL CONDENSATION CATALYZED BY SILICA CHLORIDE
Scheme 2. Self-condensation reaction of 4-chloro acetophenone.
Scheme 3. Self-condensation reaction of 3-phenylpropanal.
2889
100–110 ꢁC for 12 h, it produced 2-benzyl-5-phenylpent-2-enal (1) in 65% yield
(Scheme 3).
With these results in hand, we then examined the cross-aldol condensation of
cyclohexanone and cyclopentanone with different aldehydes. We first attempted the
reaction of cyclohexanone with benzaldehyde as a model reaction to optimize the
reaction condition. When 2 mmol of cyclohexanone was allowed to react with
4.1 mmol of PhCHO in the presence of 400 mg of silica chloride at 100–110 ꢁC under
neat reaction conditions, 2,6-dibenzylidenecyclohexanone was obtained in almost
quantitative yield. Recrystallization from ethanol gave the pure product in 92% yield
(Scheme 4).
Increasing the catalyst amount and reducing the reaction time, or vice versa,
did not have any pronounced effect in terms of the yield of the product obtained.
Encouraged by this finding, we next attempted the cross-aldol condensation reaction
of several types of substituted aldehydes with cyclohexanone or cyclopentanone
(Scheme 5; Table 1).
As shown in Table 1, the aromatic aldehydes with electron-withdrawing substi-
tutions (entries 2, 3, and 6–10) as well as electron-donating groups (entries 4, 11, and
12) reacted smoothly with cyclohexanone=cyclopentanone to afford the correspond-
ing a,a0-bisarylidene and alkylidene cycloalkanones in good to excellent yields.
Cinnamaladehyde as an a,b-unsaturated aldehyde was successfully reacted with
Scheme 4. Claisen–Schmidt condensation of cyclohexanone and benzaldehyde.

2890
H. HAZARKHANI ET AL.
Scheme 5. Synthesis of bisarylidenecycloalkanones.
cyclohexanone under similar reaction conditions to produce 2,6-bisphenylallylidene-
cyclohexanone in 85% yield (Table 1, entry 13). Reaction of freshly distilled 2-pyr-
idinecarbaldehdye as a heteroaromatic aldehyde with cyclohexanone in the
presence of 10 mol% of silica chloride at 70–80 ꢁC proceeded smoothly to afford
desired product in 60% yield. We also examined the reaction of aliphatic aldehyde
such as 3-phenylpropanal with cyclohexanone under similar reaction conditions.
To avoid the self-condensation reaction of aldehdye, 4.1 mmol of 3-phenylpropanal
was added dropwise to a mixture of 2 mmol of cyclohexanone and 400 mg of silica
chloride in ethylene dichloride (EDC) with stirring under reflux condition to give
2o in 70% yield.
Synthesis of Chalcones
Prompted by this finding, we then proceeded toward the cross-aldol conden-
sation reactions of 4-chloroacetophenone, benzalacetone, tetralone, acetone, and
Table 1. Synthesis of bisarylidenecyclohexanones and cyclopentanones
Entry
R
N
Producta
Time (h)
Yieldb (%)
Mp (ꢁC)
Mp (lit.)
1
2
Ph
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2a
2b
2c
2d
2e
2f
4
3
3
5
2
2
2
2
2
2
5
6
5
7
6
92
93
92
90
92
93
95
90
92
89
91
90
85
65
70
187–189
175–177
152–154
211–212
116–117
105–106
104–105
97–98
188–190[37]
175–176[38]
152–153[37]
211–212[37]
117–118[37]
102–104[37]
103–105[38]
Not reported[44]
157–159[36]
187–188[36]
Not reported[44]
—
3-Cl-C6H4
2-Cl-C6H4
4-MeO-C6H4
Ph
3
4
5
6
2-Cl-C6H4
3-Cl-C6H4
2-F-C6H4
7
2g
2h
2i
8
9
4-F-C6H4
158–159
187–188
136–138
193–194
179–180
70–71
10
11
12
13
14
15
3-NO2-C6H4
2,5-di(MeO)C6H4
4-PhCH2O-C6H4
2j
2k
2l
2m
2n
2o
177–178[37]
Not reported[36]
=
Ph-CH CH
C5H4N
Ph-CH2CH2
Liquid
1
aProducts were characterized by H NMR, 13C NMR, and mass spectroscopy and also by comparison
with authentic samples.
bIsolated yield.

ALDOL CONDENSATION CATALYZED BY SILICA CHLORIDE
2891
Scheme 6. Synthesis of chalcones.
3-penatanone (as ketones having enolizable methyl and methylene groups) with
substituted aromatic aldehydes. Accordingly, several chalcones were prepared
under the catalysis of silica chloride and solvent-free reaction condition
(Scheme 6). We first examined the reaction of 4-chloro acetophenone with that
of benzaldehyde under similar reaction conditions. The reaction of 4-chloro acet-
ophenone with benzaldehyde proceeded smoothly in the presence of silica chloride
and produced 1-(4-chloro-phenyl)-3-phenyl-propane in excellent yields (Table 2,
entry 1).
In a similar manner, 4-chlorobenzaldehyde and 4-methoxybenzaldehyde were
reacted with 4-chloro acetophenone to obtain the corresponding chalcones in excel-
lent yields. Subsequently, when benzalacetone was allowed to react with PhCHO,
dibenzalacetone (1,5-diphenyl-penta-1,4-dien-3-one) was formed in 88% yield
(Table 2, entry 6).
4-Chlorobenzaldehyde and cinnamaldehyde were condensed with benzal acet-
one, and the desired products were obtained in moderate yield (Table 2, entry 5).
However, the cross-aldol condensation of acetone with 3-chlorobenzaldehyde pro-
ceeded slowly and 1,5-bis-(3-chloro-phenyl)-penta,1,4-dien-3-one was obtained after
15 h in only 60% yield (Table 2, entry 7). Moreover, reaction of a-tetralone with ben-
zaldehyde and 4-benzyloxy benzaldehdye under similar reaction conditions afforded
the desired product in good yields (Scheme 7; Table 2, entries 8 and 9).
Table 2. Synthesis of chalcones
Time Yield
(%)b
Entry
R1
R2
Producta
(h)
Mp (ꢁC)
Mp (lit.)
1
2
3
4
5
6
7
8
9
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
=
PhCH CH
=
PhCH CH
Ph
3a
3b
3c
3d
3e
3f
6
5
92
91
90
90
91
88
65
85
87
99–101
156–157
120–121
113–114
128–130
Liquid
100–101[39]
156–157[39]
121–122[39]
113–114[46]
129–131[46]
4-Cl-C6H4
4-MeO-C6H4
Ph
4
9
4-Cl-C6H4
=
PhCH CH
3-Cl-C6H4
8
=
PhCH CH
10
15
10
12
H
3g
3h
3i
125–127
105–106 Not reported[29]
125–126[46]
ketone¼tetralone Ph
ketone¼tetralone 4-PhCH2O-C6H4
190–191
—
aProducts were characterized by 1H NMR, 13C NMR, and mass spectroscopic data and also by
comparison with authentic samples.
bIsolated yield.

2892
H. HAZARKHANI ET AL.
Scheme 7. Reaction of tetralone with benzaldehyde and 4-benzyloxybenzaldehyde.
CONCLUSION
In conclusion, we have demonstrated a new application of silica chloride as an
efficient catalyst for the large-scale synthesis of bisarylidene cycloalkanones and
chalcones. The catalyst showed high selectivity and ketones remained almost intact
under the reaction conditions. The high selectivity, easy availability and low cost of
catalyst, and excellent yield of products are the noteworthy features of our pro-
cedure. Currently, some new applications of silica chloride for carbon–carbon
bond-forming reactions are in progress in our group.
EXPERIMENTAL
Melting points were recorded on a Fisher-Jones melting-point apparatus and
are uncorrected. Infrared spectra (IR) were recorded using KBr pellets for solids
and neat for liquids on a Perkin-Elmer Fourier transform (FT)–IR spectrometer.
Nuclear magnetic resonance (NMR) spectra were recorded using a Bruker
200-MHz spectrometer (200 MHz for 1H NMR and 50 MHz for 13C NMR) or
Bruker 400-MHz spectrometer (400 MHz for 1H NMR and 100 MHz for 13C
NMR), and d values are reported in parts per million (ppm). Cyclohexanone, cyclo-
pentanone, and 2-pyridinecarbaldehyde were redistilled before the reaction. Mass
spectra (MS) were recorded on an LCQ advantage-trap mass spectrometer.
General Procedure for Synthesis of 2,6-Bis(4-benzyloxybenzylidene)
Cyclohexanone (2l)
A mixture of cyclohexanone (2 mmol, 0.19 g), 4-benzyloxy benzaldehdye
(4.2 mmol, 0.89 g), and 200 mg silica chloride was heated at 100–110 ꢁC. After com-
pletion of the reaction (thin-layer chromatography [TLC], 6 h), the reaction mixture
was allowed to cool to room temperature, treated with a saturated aqueous solution
of sodium bisulfite (NaHSO3), and extracted with CH2Cl2 (2 ꢂ 15 mL). The organic
layer was separated and dried over anhydrous Na2SO4. Evaporation of solvent gave
the crude product, which was recrystallized from ethanol to give compound 2l in
90% yield. Light green needles, 0.87 g, mp ¼ 193–194 ꢁC. IR (KBr): 1660, 1600,
1
1559, 1250, 831 cmꢃ1. H NMR (CDCl3, 200 MHz): d ¼ 7.77–7.27 (m, 18 H), 7.02
(d, J ¼ 10 Hz, 2H), 5.12 (s, 4H), 2.93 (t, 4H), 1.71 (m, 2H) ppm. 13C NMR (CDCl3,
100 MHz): d ¼ 190.2, 159.1, 136.5, 134.4, 132.2, 128.9, 128.6, 128.4, 128.2, 128.1,

ALDOL CONDENSATION CATALYZED BY SILICA CHLORIDE
2893
127.4, 70.0, 28.5, 22.9 ppm. 13C NMR (CDCl3, 100 MHz, Dept): d ¼ 136.4, 132.2,
128.6, 128.1, 127.4, 114.7, 70.0, 28.4, 22.9 ppm.
General Procedure for Synthesis of 2-(4-Benzyloxybenzylidene)-
3,4-dihydronaphthalen-1-(2H)-one (3i)
A mixture of tetralone (2 mmol, 0.29 g), 4-benzyloxybenzaldehdye (2.1 mmol,
0.44 g), and 100 mg silica chloride was heated at 100–110 ꢁC. After completion of
the reaction (TLC, 10 h), the reaction mixture was allowed to cool to room tempera-
ture, treated with saturated aqueous solution of sodium bisulfite, and extracted with
CH2Cl2 (2 ꢂ 15 mL). The organic layer was separated and dried over anhydrous
Na2SO4. Evaporation of solvent gave the crude product. Pure 3i was obtained from
recrystallization from EtOH in 85% yield. Cream white powder, 0.57 g, mp ¼ 190–
1
191 ꢁC. IR (KBr): 1667, 1602, 1550, 1248, 837 cmꢃ1. H NMR (CDCl3, 200 MHz):
d ¼ 8.07–7.18 (m, 13H), 6.96 (d, J ¼ 12 Hz, 2H), 5.06 (s, 2H), 3.07 (t, 2H), 2.87 (t,
2H) ppm. 13C NMR (CDCl3, 50 MHz): d ¼ 187.7, 159.1, 136.5, 133.6, 133.1, 131.7,
128.6, 128.1, 127.4, 126.9, 114.8, 70.0, 28.7, 27.1 ppm.13C NMR (CDCl3, 50 MHz,
Dept): d ¼ 136.5, 133.0, 131.7, 128.5, 128.1, 127.4, 114.7, 69.9, 28.7, 27.1 ppm.
Large-Scale Synthesis of
2,6-Bis(3-chlorobenzylidene)cyclohexanone (2f)
A
mixture of cyclohexanone (10 mmol, 0.98 g), 3-chlorobenzaldehyde
(21 mmol, 2.95 g), and 1 g silica chloride was heated at 100–110 ꢁC. After completion
of the reaction (TLC, 1 h), the reaction mixture was allowed to cool to room tem-
perature, treated with a saturated aqueous solution of sodium bisulfite, and extracted
with CH2Cl2 (2 ꢂ 25 mL). The organic layer was separated and dried over anhydrous
Na2SO4. Evaporation of the solvent gave the crude product. Pure 2,6-bis(3-
chlorobenzylidene) cyclohexanone was obtained with recrystallization from EtOH
in 95% yield. Yellow plates, 3.25 g, mp ¼ 106–107 ꢁC. IR (KBr): 1664, 1604, 1552,
1
1244, 825 cmꢃ1. H NMR (CDCl3, 200 MHz): d ¼ 7.70 (s, 2H), 7.42–7.25 (m, 8H),
2.89 (t, 4H), 1.80 (m, 2H) ppm.
2-Benzyl-5-phenylpent-2-enal (1)
1
Colorless liquid. H NMR (CDCl3, 200 MHz): d ¼ 9.37 (s, 1H), 7.25–7.11 (m,
10H), 6.56 (t, 1H), 3.53 (s, 2H), 2.96 (m, 4H) ppm. 13C NMR (CDCl3, 50 MHz):
d ¼ 194.7, 155.1, 142.8, 140.6, 139.2, 128.7, 128.6, 128.5, 128.3, 126.5, 126.2, 34.5,
31.2, 29.8 ppm.13C NMR (CDCl3, 50 MHz, and Dept): d ¼ 194.8, 155.1, 128.7,
128.5, 128.4, 126.5, 126.3, 126.2, 34.8, 31.2, 29.7 ppm.
ACKNOWLEDGMENTS
H. Hazarkhani is thankful to the director of NCL, Pune, for allowing him to
work as a guest worker. We are grateful to Dr. G. Pandey, head of the Organic
Division, for his support and encouragement.

2894
H. HAZARKHANI ET AL.
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