Solvent-free, cross-aldol condensation reaction using silica-supported, phosphorus-containing reagents leading to α,α′-Bis(arylidene) cycloalkanones

Article abstract of DOI:10.1080/00397910903457282

This article describes an efficient, simple, and clean method for the synthesis of α,α′-bis(arylidene, furylidene and cinnamylidene)cycloalkanones under solvent-free conditions. The cross-aldol condensation of cycloalkanones with aldehydes in the presence of silica-supported phosphorus pentoxide (P₂O₅/SiO ₂) or silicaphosphinoxide (silphox, [POCl_3-n(SiO ₂)_n]) as heterogeneous reagents produces the title compounds in good to excellent yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903457282

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Solvent-Free, Cross-Aldol Condensation
Reaction Using Silica-Supported,
Phosphorus-Containing Reagents Leading
to α,α′-Bis(arylidene)cycloalkanones
a
b
b
Alireza Hasaninejad , Abdolkarim Zare , Laleh Balooty , Hadis
b
a
Mehregan & Mohsen Shekouhy
a
Department of Chemistry, Faculty of Sciences , Persian Gulf
University , Bushehr, Iran
b
Department of Chemistry , Payame Noor University (PNU) ,
Bushehr, Iran
Published online: 05 Nov 2010.
To cite this article: Alireza Hasaninejad , Abdolkarim Zare , Laleh Balooty , Hadis Mehregan & Mohsen
Shekouhy (2010) Solvent-Free, Cross-Aldol Condensation Reaction Using Silica-Supported, Phosphorus-
Containing Reagents Leading to α,α′-Bis(arylidene)cycloalkanones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:23, 3488-3495,
DOI: 10.1080/00397910903457282
To link to this article: http://dx.doi.org/10.1080/00397910903457282
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1
Synthetic Communications , 40: 3488–3495, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903457282
SOLVENT-FREE, CROSS-ALDOL CONDENSATION
REACTION USING SILICA-SUPPORTED,
PHOSPHORUS-CONTAINING REAGENTS LEADING
TO a,a’-BIS(ARYLIDENE)CYCLOALKANONES
1
Alireza Hasaninejad, Abdolkarim Zare, Laleh Balooty,
2
2
2
Hadis Mehregan, and Mohsen Shekouhy
1
1
Department of Chemistry, Faculty of Sciences, Persian Gulf University,
Bushehr, Iran
2
Department of Chemistry, Payame Noor University (PNU), Bushehr, Iran
0
This article describes an efficient, simple, and clean method for the synthesis of a,a -
bis(arylidene, furylidene and cinnamylidene)cycloalkanones under solvent-free conditions.
The cross-aldol condensation of cycloalkanones with aldehydes in the presence of silica-
supported phosphorus pentoxide (P
SiO ]) as heterogeneous reagents produces the title compounds in good to excellent
yields.
2 5 2
O /SiO ) or silicaphosphinoxide (silphox, [POCl3-n-
(
2 n
)
0
Keywords: a,a -Bis(arylidene)cycloalkanone; cross-aldol condensation; green chemistry;
silphox; solvent-free
2 5 2
P O =SiO ;
The aldol condensation reaction has been widely applied for carbon-carbon bond
[1]
formation in organic synthesis. Among them, the cross-aldol condensation of
0
arylaldehydes with cycloalkanones leads to a,a -bis(arylidene)cycloalkanones, which
have attracted much attention due to their use as precursors for the synthesis of
[2]
pyrimidine derivatives, and their intriguing biological activities such as antiangio-
[
genic, quinine reductase inducer, cytotoxic, and cholesterol-lowering proper-
3]
[4]
[5]
[
6]
ties. The aldol condensation reaction has been originally catalyzed by strong
[
acids, and more likely by bases. However, in these conditions, the reactions suffer
7]
[8]
[9]
from reverse and=or side reactions. Moreover, some metal (II) ions such as Mn(II),
Fe(II), Co(II), Ni(II), Cu(II) and Zn(II), with different ligands have been
introduced as catalysts to replace acids or bases, but the yields were not satisfactory
[10]
in most cases. Continuing efforts to find new catalysts have resulted in the intro-
[
11]
[12]
[13]
[14]
duction of several reagents such as RuCl
[16]
SmI3,
Pd=C-(TMSCl),
Cp ZrH ,
2
Cp TiPh
2 2,
3
,
2
[17]
[15]
[18]
TiCl -(SO CF ),
3
Rn(III)-porphyrin,
KF=Al O ,
2
and
3
3
3
Received June 29, 2009.
Address correspondence to Alireza Hasaninejad, Department of Chemistry, Faculty of Sciences,
Persian Gulf University, Bushehr 75169, Iran. E-mail: ahassaninejad@yahoo.com or Abdolkarim Zare,
Department of Chemistry, Payame Noor University (PNU), Bushehr 1698, Iran. E-mail: abdolkarimzare@
yahoo.com
3
488

CROSS-ALDOL CONDENSATION REACTION
19]
3489
[
bis(p-ethoxyphenyl)telluroxide. Nevertheless, most of these methods are associated
with the following drawbacks: (i) long reaction times, (ii) low yields, and (iii)
Unwanted side reactions. Moreover, in some cases, high temperatures in sealed
ampoules or tubes are needed and=or the cost of the catalysts or toxic reagents
makes general use impractical. Therefore, it is important to develop more convenient
and efficient methods for the preparation of aldol-condensation products, especially
0
a,a -bis(arylidene)cycloalkanones.
Recently, the use of catalysts and reagents supported on solid supports as well
as solvent-free conditions has been extensively developed because such reagents not
only simplify the purification processes, but also help to prevent the release of toxic
[
20,21]
reaction residues into the environment.
some reagents, their application of them in organic reactions is difficult. This prob-
Moreover, due to moisture sensitivity of
[
20,21]
lem can be solved by their immobilization onto solid supports.
Handling of
solid-supported reagents is also easy. In addition, these reagents can be easily
removed from the reaction mixture by filtration. Silica-supported phosphorus-
containing reagents are among the most interesting solid-supported reagents, and
are inexpensive, commercially available and environmentally benign, allowing them
[
21]
to be used in various organic transformations.
In this article, we report a new, green, and highly efficient method for the
0
synthesis of a,a -bis(arylidene, furylidene and cinnamylidene)cycloalkanones via
the cross-aldol condensation of aldehydes with cycloalkanones using P O =SiO or
silphox as non-toxic, readily producible, and heterogeneous reagents under solvent-
2
5
2
ꢀ
free conditions at 80 C (Scheme 1).
To find the optimized reaction conditions for the synthesis of a,a -bis-
arylidene)cycloalkanones, the condensation of cyclopentanone (2 mmol) with
0
(
benzaldehyde (4.2 mmol) was chosen as a model reaction (Scheme 1), and its beha-
vior was studied in the presence of different amounts of some phosphorus-
ꢀ
containing reagents under solvent-free conditions at 80 C. The results are shown
in Table 1. As it can be seen in Table 1, P O =SiO (1 g) and silphox (1 g) were
2
5
2
the best reagents for the reaction. The condensation of cyclopentanone with benzal-
dehyde was also examined using only SiO ; however, in these conditions, the product
2
was obtained in 48% yield after 5 h (Table 1, Entry 12). Increasing the reaction time
did not improve the yield.
In another study, the model reaction was examined at different temperatures in
the presence of P O =SiO and silphox under solvent-free conditions (Table 2). As
2
5
2
ꢀ
Table 2 indicates, the best results were obtained at 80 C using both reagents.
To compare the efficiency as well as capacity of the solvent-free conditions with
respect to solution conditions, the reaction of cyclopentanone (2 mmol) with benzal-
dehyde (4.2 mmol) was also tested in the presence of silica-supported P O and sil-
2
5
phox in several solvents (10 mL), such as MeCN, CH Cl , CHCl , THF, EtOH,
2
2
3
Scheme 1. The condensation of cyclopentanone with benzaldehyde.

3490
A. HASANINEJAD ET AL.
Table 1. The condensation of cyclopentanone (2 mmol) with benzaldehyde
(4.2 mmol) using different amounts of some reagents under solvent-free
conditions at 80 C
ꢀ
a
Yield (%)
Entry
Reagent
–
(0.4 g)
Time (h)
1
24
4
No reaction
2
3
4
5
6
7
8
9
0
1
2
3
P
P
P
P
2
2
2
2
O
O
O
O
5
50
90
81
90
36
29
26
95
88
94
69
48
5
5
5
=SiO
=SiO
=SiO
2
2
2
(1 g)
(0.8 g)
(1.2 g)
2.5
3
2.5
3
3
POCl (0.2 mL)
PCl
PCl
3
(0.2 mL)
(0.2 g)
4
5
3.5
0.5
0.75
0.5
3
Silphox (1 g)
Silphox (0.8 g)
Silphox (1.2 g)
Silphoz (1 g)
1
1
1
1
SiO
2
(1 g)
5
a
Isolated yield.
and toluene under reflux conditions. However, a mixture of products was obtained in
poor yields under these conditions.
After optimization of the reaction conditions, different types of aromatic alde-
hydes (including aromatic aldehydes possessing electron-releasing substituents,
electron-withdrawing substituents and halogens on their aromatic rings, furfural
and cinnamaldehyde) were condensed with cycloalkanones (cyclopentanone, cyclo-
hexanone, and cycloheptanone) in the presence of the silica-supported phosphorus-
ꢀ
containing reagents under solvent-free conditions at 80 C. The results are
summarized in the Table 3. As it is shown in Table 3, the reactions were completed
within 2.5–10 and 0.5–2.5 h in the presence of P O =SiO and silphox, respectively;
2
5
2
and the desired cross-aldol condensation products were obtained in good to excellent
yields. Under the reactions conditions, no self-condensation of the starting materials
was observed. Attempts to achieve mono-condensation from one side of the
Table 2. The reaction of cyclopentanone with benzaldehyde using P
silphox at different temperatures under solvent-free conditions
2
5 2
O =SiO or
ꢀ
a
Yield (%)
Entry
Reagent
Temperature ( C)
Time (h)
1
2
3
4
5
6
7
8
9
P
P
P
P
P
2
2
2
2
2
O
O
O
O
O
5
5
5
5
5
=SiO
=SiO
=SiO
=SiO
=SiO
2
2
2
2
2
r.t.
50
70
80
90
r.t.
50
70
80
90
12
4
No reaction
49
75
3.5
2.5
2.5
10
3.5
1
90
88
Silphox
Silphox
Silphox
Silphox
Silphox
Trace
65
78
0.5
0.5
95
92
1
0
a
Isolated yield.

CROSS-ALDOL CONDENSATION REACTION
3491
0
Table 3. Synthesis of a,a -bis(arylidene)cycloalkanones from aldehydes and cycloalkanones in the
ꢀ
presence of P
2
5
O =SiO
2
as well as silphox under solvent-free conditions at 80 C
P
2
O
5
=SiO
2
Silphox
ꢀ
Mp ( ) (lit.)
Entry
N
R
Time (h)=Yield (%)
Time (h)=Yield (%)
[
19]
19]
22]
23]
22]
18a]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
C
p-CH
6
H
5
2.5=90
4=92
0.5=95
0.5=93
1=92
187–189 (188–189)
[
3
OC
C
6
H
4
207–209 (210–211)
[
p-CH
3
6
H
4
5.5=89
10=74
8=71
243–245 (244–246)
[
p-NO
m-NO
p-ClC
m-ClC
o-ClC
2-Furyl
CH=CH
2
C
6
H
4
1=85
228–230 (229–231)
[
2
C
6
H
4
0.5=83
0.5=89
2=87
225–227 (226–227)
[
6
H
4
4=78
9=83
227–229 (224–226)
[24]
6
H
4
173–175 (177)
155–157 (152–153)
[
14]
19]
25]
6
H
4
10=90
4=89
3=84
2.5=92
1=93
[
162–164 (160–162)
[
1
1
1
1
1
1
1
1
1
1
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
C
6
H
5
0.5=92
0.5=95
0.5=93
1=95
217–219 (215–216)
[10]
116–118 (117)
C
6
H
5
3=93
3=87
[19]
161–163 (160–162)
p-CH
p-CH
p-NO
m-NO
p-ClC
m-ClC
o-ClC
2-Furyl
CH=CH
3
OC
6
H
4
[14]
3
C
6
H
4
6=86
4=82
169–171 (170)
156–158 (159)
180–182 (181–182)
[10]
2
C
6
H
4
1.5=90
2=86
2=91
[
22]
25]
26]
22]
26]
19]
2
C
6
H
4
6=76
3=89
[
6
H
4
147–149 (147–148)
[
6
H
4
7=84
6=88
2.5=94
1=92
1=90
108–110 (105–107)
[
6
H
4
103–105 (102–104)
[
7=85
2.5=90
3=84
140–142 (143–145)
[
C
6
H
5
2.5=90
1=87
176–178 (179–180)
105–107
162–164
6 5
C H
3,4-(CH
3
O)
2
C
6
H
3
4.5=76
2.5=88
1.5=82
0.5=94
p-ClC
6
H
4
131–133
a
Isolated yield.
cycloalkanones, in the presence of lower amounts of the aldehydes, was not success-
ful, and only bis-aldol products were produced.
In conclusion, the presented method is a highly efficient, green, inexpensive,
clean, and selective protocol for the cross-aldol condensation of cycloalkanones with
0
aldehydes to provide a,a -bis(arylidene)cycloalkanones in high yields and with rela-
tively short reaction times.
EXPERIMENTAL
All chemicals were purchased from Merck or Fluka Chemical Companies. The
13
H NMR (500 MHz) and C NMR (125 MHz) were run on a Bruker Avance
1
DPX-250, FT-NMR spectrometer (d in ppm). Mass spectra were recorded on a
Shimadzu GC MS-QP 1000 EX apparatus. Microanalyses were performed on a
Perkin-Elmer 240-B microanalyzer. Melting points were recorded on a B u¨ chi
B-545 apparatus in open capillary tubes.

3492
A. HASANINEJAD ET AL.
Preparation of P O /SiO (30% w/w)
2
5
2
A mixture of SiO [silica gel 60, 0.063–0.200 mm (70–230 mesh ASTM), 3.5 g]
2
and P O (1.5 g) was ground vigorously to give the reagent, P O =SiO , as a white
2
2
5
2
5
powder (5.0 g). This reagent can be stored for months in a capped bottle without
deterioration.
Preparation of Silphox
Under a nitrogen atmosphere, we added POCl (64.0 g, 0.5 mol) at room tem-
3
perature to a flask containing dry plate silica gel (6.0 g) and stirred slowly with a
ꢀ
mechanical stirrer for 30 min. The mixture was then heated to 60 C while it was stir-
ring under pressure of nitrogen for 3 h to remove all produced HCl. Afterward, the
reaction mixture was cooled to room temperature, filtered, and the resulting precipi-
tate washed with dry CH Cl (50 mL) to give silphox as a white solid (9.1–9.3 g),
2
2
[21j]
which was stored in a capped bottle.
any change.
The reagent can be stored for month without
General Procedure for the Preparation of
a,a’-Bis(arylidene)cycloalkanones Using P O /SiO or Silphox
2
5
2
A mixture of cycloalkanone (2 mmol), aldehyde (4.2 mmol), and the silica-
supported phosphorus containing reagent (1.0 g) was added in a 25 mL round-
ꢀ
bottomed flask connected to a reflux condenser. The mixture was stirred at 80 C
for the appropriate time (Table 3). Afterward, the reaction mixture was cooled to
room temperature, EtOAc (60 mL) was added and heated for 5 minutes. The reagent
was removed by filtration, and the filtrate was concentrated. The solid residue was
recrystallized from ethanol to afford pure product.
Selected Spectral Data of the Products
2
,5-Bis(3-chlorobenzylidene)cyclopentanone (Table 3, Entry 7). Yellow
[24]
ꢀ
ꢀ
1
needles; mp 173–175 C (lit.
4
177 C); H NMR (CDCl , 500 MHz): d ¼ 3.01 (s,
3
H), 7.29–7.33 (m, 4H), 7.39–7.42 (m, 2H), 7.43 (s, 2H), 7.51 (t, J ¼ 1.2 Hz, 2H);
1
3
C NMR (CDCl , 125 MHz): d ¼ 27.0, 128.6, 129.6, 130.5, 130.7, 132.5, 135.3,
3
1
6
37.1, 138.6, 196.0; Anal. calcd. for C H Cl O: C, 69.32; H, 4.29. Found: C,
2
1
9
14
9.58; H, 4.48.
2
,6-Bis(3-chlorobenzylidene)cyclohexanone (Table 3, Entry 17). Yellow
[26]
ꢀ
ꢀ
1
needles; mp 108–110 C (lit. 105–107 C); H NMR (CDCl , 500 MHz): d ¼ 1.69
3
(
quintet, J ¼ 5.7 Hz, 2H), 2.78 (t, J ¼ 5.7 Hz, 4H), 7.30–7.37 (m, 6H), 7.41 (s, 2H),
1
3
7
1
6
.62 (t, J ¼ 1.2 Hz, 2H); C NMR (CDCl , 125 MHz): d ¼ 23.7, 27.9, 126.3, 127.9,
3
29.3, 130.4, 130.9, 133.2, 135.8, 137.8, 188.9; Anal. calcd. for C H Cl O: C,
2
0
16
2
9.98; H, 4.70. Found: C, 69.76; H, 4.87.
2
,6-Bis(2-chlorobenzylidene)cyclohexanone (Table 3, Entry 18). Yellow
[22]
ꢀ
ꢀ
1
needles; mp 103–105 C (lit. 102–104 C); H NMR (CDCl , 500 MHz): d ¼ 1.75
3
(
quintet, J ¼ 5.8 Hz, 2H), 2.78 (t, J ¼ 5.8 Hz, 4H), 7.28 (m, 4H), 7.34 (d, J ¼ 3.4,

CROSS-ALDOL CONDENSATION REACTION
3493
1
3
2
H), 7.45 (d, J ¼ 3.3 Hz, 2H), 7.89 (t, J ¼ 1.2 Hz, 2H); C NMR (CDCl , 125 MHz):
3
d ¼ 23.2, 28.7, 126.8, 130.8, 130.9, 131.0, 134.5, 135.0, 135.5, 138.3, 189.2; Anal.
calcd. for C H Cl O: C, 69.98; H, 4.70. Found: C, 69.80; H, 4.56.
2
2
0
16
(2E,6E)-2,6-Bis((E)-3-phenylallylidene)cyclohexanone (Table 3, Entry 20).
Yellow solid; mp 176–178 C (lit. 179–180 C); H NMR (CDCl , 500 MHz):
ꢀ
[19]
ꢀ
1
3
d ¼ 1.85 (quintet, J ¼ 5.8 Hz, 2H), 2.81 (t, J ¼ 5.8 Hz, 4H), 6.97 (d, J ¼ 15.4 Hz,
2
6
H), 7.10 (dd, 2H, J ¼ 15.4, 1.2 Hz), 7.28 (m, 2H), 7.36 (m, 4H), 7.48–7.54 (m,
1
3
H); C NMR (CDCl , 125 MHz): d ¼ 22.5, 27.8, 124.7, 124.8, 127.5, 129.3,
3
135.9, 136.8, 137.3, 141.4, 188.3; Anal. calcd. for C H O: C, 88.31; H, 6.79. Found:
2
C, 88.52; H, 6.63.
4
22
(
2E,7E)-2,7-Dibenzylidenecycloheptanone (Table 3, Entry 21). Pale yellow
1
ꢀ
solid; mp 105–107 C; H NMR (CDCl , 500 MHz): d ¼ 2.03 (br, s, 4H), 2.75 (br, s,
3
1
3
4
H), 7.37 (t, J ¼ 7.2 Hz, 2H), 7.43 (s, 2H), 7.45 (m, 4H), 7.51 (d, J ¼ 7.5 Hz, 4H);
C
NMR (CDCl , 125 MHz): d ¼ 28.5, 29.3, 128.7, 128.9, 129.9, 136.1, 136.4, 142.2,
3
þ
1
C, 87.69; H, 6.84.
99.9; MS: m=z ¼ 288 (M ); Anal. calcd. for C H O: C, 87.46; H, 6.99. Found:
2
1
20
(2E,7E)-2,7-Bis(3,4-dimethoxybenzylidene)cycloheptanone (Table 3,
Entry 22). Pale yellow solid; mp 162–164 C; H NMR (CDCl , 500 MHz):
ꢀ
1
3
d ¼ 2.05 (br, s, 4H), 2.77 (br, s, 4H), 3.91 (s, 6H), 3.96 (s, 6H), 6.94 (d, J ¼ 8.5 Hz,
1
3
2
1
H), 7.05 (s, 2H), 7.12 (d, J ¼ 8.5 Hz, 2H), 7.39 (s, 2H); C NMR (CDCl ,
3
25 MHz): d ¼ 28.7, 29.1, 56.3, 56.4, 111.5, 113.3, 123.1, 129.2, 135.9, 140.5, 149.2,
þ
1
Found: C, 73.32; H, 6.80.
49.7, 199.9; MS: m=z ¼ 408 (M ); Anal. calcd. for C H O : C, 73.51; H, 6.91.
2
5
28
5
(
2E,7E)-2,7-Bis(4-chlorobenzylidene)cycloheptanone (Table 3, Entry 23).
1
ꢀ
Pale yellow solid; mp 131–133 C; H NMR (CDCl , 500 MHz): d ¼ 2.00 (br, s, 4H),
3
1
.71 (br, s, 4H), 7.38 (s, 2H), 7.41–7.45 (m, 8H); C NMR (CDCl , 125 MHz):
3
2
3
þ
d ¼ 28.4, 29.1, 129.2, 131.1, 134.6, 134.7, 135.0, 142.4, 199.3; MS: m=z ¼ 357 (M );
Anal. calcd. for C H Cl O: C, 70.60; H, 5.08. Found: C, 70.87; H, 4.93.
1
2
18
2
ACKNOWLEDGMENTS
We appreciate the Persian Gulf University and Payame Noor University
PNU) Research Councils for the financial support of this work.
(
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