Copper triflate-catalyzed cross-aldol condensation: A facile synthesis of α,α′-bis(substituted benzylidene) cycloalkanones

Article abstract of DOI:10.1080/00397910500278735

A facile, efficient, and clean procedure is described for synthesis of α,α′-bis(substituted benzylidene) cycloalkanones with good yields by the reaction of cycloalkanones with aromatic aldehydes using Cu(OTf)₂ as catalyst. The catalyst was easily recovered and reused without loss of activity. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500278735

Synthetic Communicationsw, 35: 3037–3043, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500278735
Copper Triflate–Catalyzed Cross-Aldol
Condensation: A Facile Synthesis of
a,a0-Bis(Substituted Benzylidene)
Cycloalkanones
Jianjun Li, Weike Su, and Ning Li
Zhejiang Key Laboratory of Pharmaceutical Engineering,
College of Pharmaceutical Sciences, Zhejiang
University of Technology, Hangzhou, China
Abstract: A facile, efficient, and clean procedure is described for synthesis of a,a0-
bis(substituted benzylidene) cycloalkanones with good yields by the reaction of
cycloalkanones with aromatic aldehydes using Cu(OTf)2 as catalyst. The catalyst
was easily recovered and reused without loss of activity.
Keywords: Catalyst, condensation, copper triflate, cross-aldol, cycloalkanone
The a,a0-bis(substituted benzylidene) cycloalkanones, as useful precursors of
biologically active pyrimidine compounds, have drawn considerable attention
in organic synthesis.[1] Various methods for synthesis of this type of
compounds have been developed. The typical methods for the preparation
of a,a0-bis(substituted benzylidene) cycloalkanones generally involve the
cross-aldol condensation of cycloalkanone with aldehydes under strong
acids or bases.[2] However, traditional acid- or base-catalyzed reactions
resulted in some reverse and side reactions, and thereby the yields of the
desired product were decreased. There are other methods performed in
Received in Japan May 6, 2005
Address correspondence to Weike Su, Zhejiang Key Laboratory of Pharmaceutical
Engineering, College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou 310014, China. Fax: (0086)57188320752; E-mail: suweike@zjut.edu.cn
3037

3038
J. Li, W. Su, and N. Li
neutral conditions using some metal salts to reduce side reactions, and
different complex metal ions, such as Mn (II), Fe (II), Co (II), Ni (II), Cu
(II), and Zn (II), and different ligands were used in these reactions.[3]
[5]
[6]
RuCl3,[4] InCl3 4H2O, and Cp2Tiph2 were reported to give good yields
of enone products, but these reactions need long reaction times and high
temperatures (120 8C) in sealed tubes. Cp2ZrH2,[7] in combination with
metal salts such as NiCl2 under strict conditions, was also reported. In the
course of this reaction, it was found that self-condensation as a side
.
reaction occured. The catalysts of Ti(OR)4 and TiCl3(SO3CF3)[9] have
[8]
been reported for synthesis of a,a0-bis(substituted benzylidene) cycloalk-
anones. However, they can be hydrolyzed in the presence of water, which
may result in the aldol-condensation reaction.
Microwave-assisted synthesis[10] has been reported using bis
(p-ethoxyphenyl) telluroxide (BMPTO) as catalyst for cross-condensation of
cyclohexanone or cyclopentanone with aromatic aldehydes. More recently,
ultrasound irradiation[11] has also been used in cross-condensation. With
these methods, the obtained yields are not high in most cases. Also, the
catalyst system of TMSCl/NaI[12] or TMSCl/SmI3
[13]
can promote cross-
condensation in mild conditions. After the completion of the reaction, the
catalyst system cannot be recycled. Metal triflates[14] have been widely used
in organic synthesis as an all-purpose Lewis acid over the past decades. It
can activate the formation of new carbon–carbon and carbon–heteroatom
bonds.[14,15] Wang et al.[16] reported that Yb(OTf)3 could promote the
condensation reaction efficiently.
Because of the importance for the preparation of a,a0-bis(substituted
benzylidene) cycloalkanones and some disadvantages in the current
reported methods, it is important to exploit a simple, efficient, and clean
procedure for cross-condensation from the views of environmental and
green chemistry. In continuation of our interest on the use of metal triflate
for several efficient organic transformations,[17] we found that Cu(OTf)2 as
a recyclable and reused catalyst was a suitable alternative catalyst. Herein,
we report our results as shown in Scheme 1.
Initially, we tested the reaction effects catalyzed by some metal triflates
using cyclohexanone and benzaldehyde as reactants. The results are summa-
rized in Table 1. Cu(OTf)2 showed the best catalytic effects. When using other
metal triflates (Table 1, entries 1–3), the results were unsatisfactory and some
Scheme 1.

Cross-Aldol Condensation
3039
Table 1. Cross-aldol condensation of cyclohexanone with benzaldehyde under
different reaction conditionsa
Cat.
amount
(mol%)b
Yield
(%)c
Entry
Solvent
CH3CN
CH3CN
Catalyst
1
2
3
4
5
6
7
8
9d
Zn(OTf)2
Sm(OTf)3
Sr(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
10
10
10
1
48
39
CH3CN
CH3CN
52
94
CH3CH2OH
CH3COOEt
Cyclohexane
THF
1
66
1
48
90
1
1
56
None
1
94, 92,
92, 93, 92
95
10
11
None
None
Cu(OTf)2
Cu(OTf)2
5
0.2
67
aReaction conditions: cyclohexanone (5 mmol), benzaldehyde (10 mmol), catalyst
(given amount), solvent (10 mL, entries 1–8), 6 h, refluxed temperature (808C for
entries 9–11).
bCat. amount based on cyclohexanone 1.
cIsolated yields based on cyclohexanone 1.
dCatalyst was reused for five times.
side reactions could be observed even if the amount of the catalyst increased.
From Table 1, it seemed that acetonitrile and cyclohexane are much
better (yielding 94% and 90% respectively) than other solvents tested by
Cu(OTf)2. From the view of green chemistry, the best results were achieved
by carrying out the reaction at 808C for 6 h in the presence of a catalytic
amount of Cu(OTf)2 under solvent-free conditions. The reactions proceeded
smoothly with 1 mol% of Cu(OTf)2 and excessive amounts of catalyst
cannot greatly increase the yields. Attempts were made to recover the
catalyst in the course of our study. Using cyclohexanone and benzaldehyde
as reactants, we observed that it was possible to recover Cu(OTf)2. From
the experiment (Table 1, entry 9), the reactions were run five times by
using recovered Cu(OTf)2 under the same conditions. We recovered around
97% yield of the catalyst every time and obtained the desired product with
94, 92, 92, 93, and 92% isolated yields, respectively.
The cross-aldol condensation of cyclohexanone or cyclopentanone with
a series of aromatic aldehydes affored a,a0-bis(substituted benzylidene)
cycloalkanones in good yields catalyzed by Cu(OTf)2 at 808C. The results
are listed in Table 2. The reactions were completed in 6–12 h and good
yields of desired products were obtained. In the course of our study, we
found that Cu(OTf)2 is an efficient catalyst for the condensation reaction

3040
J. Li, W. Su, and N. Li
Table 2. Cross-aldol condensation of cycloalkanones with aldehydes catalyzed by
Cu(OTf)2 at 808C (Scheme 1)a
Reaction
time (h)
Yield
(%)b
Entry
Ar
n
Products
1
2
C6H5
2
2
2
2
2
2
2
1
1
1
1
1
1
1
6
8
3a
3b
3c
3d
3e
3f
94
93
96
95
88
90
87
92
93
91
90
90
87
86
p-NO2C6H4
m-NO2C6H4
p-ClC6H4
3
8
4
8
5
p-Me2NC6H4
p-CH3OC6H4
2-Furyl
8
6
10
12
8
7
3g
3h
3i
8
C6H5
p-NO2C6H4
p-ClC6H4
9
8
10
11
12
13
14
8
3j
p-Me2NC6H4
o-ClC6H4
8
3k
3l
8
p-CH3OC6H4
2-Furyl
10
12
3m
3n
aAll the products were characterized by 1H NMR, IR.
bIsolated yields based on cycloalkanones.
of cycloalkanones with aromatic aldehydes without any ketones self-
condensing. Attempts to obtain selective mono-condensation from only
one side of cycloalkanone were not successful. When the mole ratio of
cyclohexanone or cyclopentanone to benzaldehyde was 1 : 1 or even less,
a trace of mono-adduct was detected and only di-adduct was isolated in
our experiment.
In conclusion, the present method provides an efficient procedure for
synthesis of a,a0-bis(substituted benzylidene) cycloalkanones in the
presence of Cu(OTf)2 with good yields under mild and simple conditions.
More important, the catalyst can be easily recovered after the reactions are
completed, and does not lose activity. The possibility of cross-aldol conden-
sation and easily recovered catalyst made this method an attractive addition
to the present methodologies in the literature.
EXPERIMENTAL
All reagents were used as received. The melting points were determined on a
digital melting-point apparatus, WRS-1B, and are uncorrected. 1H NMR
spectra were recorded on a Varian 400-MHz instument using CDCl3 as the
solvent, and chemical shifts were expressed in ppm using TMS as an
internal standard. IR measurements were carried out with a Nicolet Aviatar-
370 instrument.

Cross-Aldol Condensation
3041
General Procedure for the Preparation of a,a0-Bis(Substituted
Benzylidene) Cycloalkanones
A mixture of cycloalkanone 1 (5 mmol), aldehyde 2 (10 mmol), and Cu(OTf)2
(0.05 mmol) was added to a round-bottomed flask. The mixture was stirred at
808C for a indicated time to complete the reaction (monitored by TLC). After
cooling to room temperature, the reaction was quenched by water (5 mL) and
stirred for 10 min. The solid product 3 was isolated with high purity by fil-
tration, and rinsed with water and a little amount of cool alcohol. The
catalyst can be recovered from the liquid under reduced pressure, drying
under reduced pressure at 1508C for 2 h gives a white solid, which could be
reused without loss of activity.
Data
1
3a: Mp 117–1188C. H NMR (400 MHz, CDCl3): d ¼ 7.81 (s, 2 H, 55CH),
7.46–7.24 (m, 10H, ArH), 2.92 (t, 4H, J ¼ 5.6 Hz, CH2), 1.80–1.74
(m, 2H, CH2). IR (KBr): 3072, 3023, 1658, 1570, 1445, 1271, 1415, 1271,
1145, 770 cm21
.
3b: Mp 160–1618C. 1H NMR (400 MHz, CDCl3): d ¼ 8.28 (d, 4H,
J ¼ 8.8 Hz, ArH), 7.80 (s, 2H, 55CH), 7.60 (d, 4H, J ¼ 8.8 Hz, ArH), 2.95
(t, 4H, J ¼ 6.0 Hz, CH2), 1.89–1.83(m, 2H, CH2). IR (KBr): 3108, 2928,
1669, 1591, 1514, 1490, 1343, 1267, 856 cm21
.
3c: Mp 188–1908C. 1H NMR (400MHz, CDCl3): d ¼ 8.33 (s, 2 H,55CH),
8.22 (d, 2H, J ¼ 8.0 Hz, ArH), 7.81–7.60 (m, 6H), 2.98 (t, 4 H, J ¼ 5.6 Hz,
CH2), 1.90–1.84 (m, 2H, CH2). IR (KBr): 3108, 2928, 1669, 1591, 1514,
1490, 1343, 1267, 856 cm21
.
1
3d: Mp 148–1498C. H NMR (400MHz, CDCl3): d ¼ 7.73 (s, 2 H,
55CH), 7.41–7.36 (m, 8H, ArH), 2.90 (t, 4H, J ¼ 6.0 Hz, CH2), 1.83–1.79
(m, 2H, CH2). IR (KBr): 2927, 1664, 1608, 1579, 1270, 833 cm21
.
3e: Mp 250–2528C. 1H NMR (400MHz, CDCl3): d ¼ 7.75 (s, 2H,55CH),
7.62–6.85 (m, 8H, ArH), 2.94 (t, 4H, J ¼ 6.0 Hz, CH2), 1.83–1.80 (m, 2H,
CH2). IR (KBr): 2930, 2852, 1646, 1580, 1516, 1359, 1155, 815 cm21
.
3f: Mp 203–2058C. 1H NMR (400MHz, CDCl3): d ¼ 7.76 (s, 2 H,55CH),
7.46 (d, 4 H, J ¼ 8.6 Hz, ArH), 6.93 (d, 4H, J ¼ 8.6 Hz, ArH), 3.84 (s, 6H,
OCH3), 2.92 (t, 4H, J ¼ 5.6 Hz, CH2),1.86–1.73 (m, 2H, CH2). IR (KBr):
3008, 2938, 1658, 1596, 1507, 1248, 1023, 832 cm21
.
3g: Mp 140–1428C. 1H NMR (400 MHz, CDCl3): d ¼ 7.63–6.95
(m, 8H, Furyl H and 55CH), 2.95–2.72 (m, 4H, CH2), 2.05–1.90 (m, 2H,
.
CH2). IR (KBr): 3183, 2903, 1643, 1594, 752 cm21
3h: Mp 188–1898C. 1H NMR (400 MHz, CDCl3): d ¼ 7.60–7.58
(m, 6H, ArH and 55CH), 7.45–7.36 (m, 6H, ArH), 3.13 (s, 4H, CH2). IR
.
(KBr): 3053, 3018, 1690, 1626, 1602 cm21

3042
J. Li, W. Su, and N. Li
3i: Mp 230–2318C. 1H NMR (400 MHz, CDCl3): d ¼ 8.32–8.30 (m, 4H,
ArH), 7.76–7.65 (m, 6H, ArH and55CH2), 3.20 (s, 4H, CH2). IR (KBr): 3105,
.
2843, 1706, 1605, 1522 cm21
1
3j: Mp 227–2298C. H NMR (400 MHz, CDCl3): d ¼ 7.47–7.45 (m, 6
H, ArH and 55CH), 7.36–7.33 (m, 4H, ArH), 3.02 (s, 4H, CH2). IR (KBr):
.
2912, 1693, 1620, 1604, 1587 cm21
3k: Mp 152–1538C. 1H NMR (400MHz, CDCl3): d ¼ 7.79 (s, 2H,55CH),
7.43–7.40 (m, 2H, ArH), 7.32–7.32 (m, 2H, ArH), 7.20–7.13 (m, 4H, ArH),
.
2.83 (s, 4H, CH2). IR (KBr): 3047, 2917, 1687, 1621, 1600, 1587cm21
3l: Mp .2508C. 1H NMR (400 MHz, CDCl3): d ¼ 7.55 (s, 2 H, 55CH),
7.52–6.73 (m, 8H, ArH), 3.06 (s, 4H, CH2), 3.02(s, 12H, Me2N). IR (KBr):
.
2898, 1671, 1588, 1521, 1362, 1163, 812 cm21
1
3m: Mp 210–2118C. H NMR (400 MHz, CDCl3): d ¼ 7.59 (d, 4H,
J ¼ 8.0 Hz, ArH), 7.58 (s, 2H, 55CH), 6.98 (d, 4H, J ¼ 8.0 Hz, ArH), 3.88
(s, 6H, CH3), 3.07(s, 4H, CH2). IR (KBr): 3080, 2851, 1684, 1590 cm21
.
3n: Mp 162–1638C. 1H NMR (400MHz, CDCl3): d ¼ 7.60 (s, 2H,55CH),
7.36 (s, 2H, Furyl H), 6.71 (d, 2H, J ¼ 3.2 Hz, Furyl H), 6.54 (s, 2H, Furyl H),
3.09 (s, 4H, CH2). IR (KBr): 3135, 3115, 2917, 1681, 1620, 1600cm21
.
ACKNOWLEDGMENTS
The authors are grateful to the National Basic Research Program (No.
2003CB114402) and National Natural Science Foundation of China (No.
20276072) for financial support.
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