Simple and effective protocol for Claisen-Schmidt condensation of hindered cyclic ketones with aromatic aldehydes

Article abstract of DOI:10.1055/s-2007-983746

A simple and effective methodology for Claisen-Schmidt condensation of (-)-menthone and other hindered cyclic ketones with aromatic aldehydes under highly basic conditions using a polar aprotic solvent and a strong base (alkali metal hydroxide or an alkoxide) is described and discussed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983746

PAPER
2125
Simple and Effective Protocol for Claisen–Schmidt Condensation of Hindered
Cyclic Ketones with Aromatic Aldehydes
Claisen–Schmidt
C
a
ondensatio
l
n of
H
e
indere
d
Cyc
r
lic
K
eto
i
nes y Vashchenko,* Lidiya Kutulya, Alexander Krivoshey
STC ‘Institute for Single Crystals’, National Academy of Sciences of Ukraine, Lenin Avenue 60, Kharkov 61001, Ukraine
Fax +38(057)3409343; E-mail: valeravv@isc.kharkov.com
Received 9 January 2007; revised 7 May 2007
Dedicated to the memory of Professor Ludmila Yanovskaya
arylidene menthanones 3 in good yields.10-12 These com-
Abstract: A simple and effective methodology for Claisen–
pounds have found practical application as chiral compo-
Schmidt condensation of (–)-menthone and other hindered cyclic
ketones with aromatic aldehydes under highly basic conditions us-
nents for liquid crystal materials.13–17 The stereochemistry
of the major product of the condensation, 3 (cis-E,1R,4R-
configuration), has been exhaustively studied by different
methods18,19 including X-ray diffraction for compounds
3h,3k,3n and 3o.19 Compounds of the same configuration
at C-4 as in 1, trans-E,1R,4S-diastereomers 4o and
4x (R = 4-COOMe), have been synthesized indirectly,
and their stereochemistry has been proved by X-ray crys-
tallographic and NMR spectroscopic data.20 The Z-iso-
mers of 1R,4R-2-arylidene derivatives have been obtained
by photochemical isomerization of the corresponding E-
isomers 3 and studied by NMR and molecular simula-
tion.18c,d
Thus, the most pronounced differences in 1H NMR spec-
tra of diastereomeric compounds 3 and 4 were found to be
the lower field chemical shifts of protons at C-4, C-6 and
C-8 adjacent to the C-4 chiral center in 1R,4R-diastere-
omers 3 when compared to corresponding 1R,4S-diastere-
omers 4. Moreover, it was shown experimentally that
trans-E,1R,4S-diastereomers 4o21 and 4y (R = 4-OH)14b
are thermodynamically less stable than corresponding cis-
diastereomers 3o and 3y, and the equilibrium mixture of 3
and 4 forms in approximately a 70:30 ratio under condi-
tions (both basic and acidic) which allow the epimeriza-
tion of 3. In the case of Z-isomers of 3, the arylidene
proton is observed in the range of 6.2–6.3 ppm18c,d that is
about 1 ppm upfield when compared to the corresponding
E-isomers (6.9–7.2 ppm) in the 1H NMR spectra.
ing a polar aprotic solvent and a strong base (alkali metal hydroxide
or an alkoxide) is described and discussed.
Key words: aldehydes, a,b-unsaturated ketones, condensation,
diastereoselectivity, super basic conditions
(–)-Menthone (1) has been widely used in organic synthe-
sis as an inexpensive chiral synthon.1 One of the ways of
modifying 1 is to introduce an arylidene moiety by
Claisen–Schmidt condensation with aromatic aldehydes 2
to produce chiral a,b-unsaturated ketones 3 and 4
(Scheme 1). However, a poor reactivity of 1 under com-
mon reaction conditions (alkali metal hydroxides or
alkoxides in alcohol media2) has been found (Table 1, en-
tries 1,2,12,14,31).3 The use of stronger bases such as
3
NaNH2 or NaH4,5 in low-polar solvents has not improved
the result substantially, and moderate yields of 3a have
been obtained at best (entries 3,4).5 The acid-catalyzed re-
action is complicated due to migration of the benzylidene
double bond in cyclohexane ring (compounds 5a and 5b,
Scheme 1),6,7 and only in rare cases has acid catalysis
been reported (entry 5).3
These obstacles have been successfully overcome by ap-
plying the so-called super-basic media8 (the combination
of an alkali hydroxide and a polar aprotic solvent).9 Such
an approach has allowed us to synthesize a number of
Ar
Ar
7
However, the detailed synthetic procedure for compounds
of type 3 and discussion on its features have hitherto been
published in sources which are difficult to access.10–12,21–23
Apparently, it sometimes results in applying the simplest
and non-optimized procedure,24,25 or even in repeated
studies on the reaction optimization.5 Applications of su-
perbasic media to Claisen–Schmidt condensation26,27 and
to subsequent transformations of a,b-unsaturated
ketones28,29 were also reported.
B:
1
4
2
+
O
O
O
H
8
4
3
Ar
+
H
O
Ar
2
Ar
H
1
and/or
O
O
Here we summarize our work on Claisen–Schmidt con-
densation of (–)-menthone with aromatic aldehydes pro-
moted by hydroxides and alkoxides of alkali metals and
tetrabutylammonium in polar aprotic solvents. We also
extend the approach on the reactions to some other cyclic
ketones and discuss the scope and limitation of the syn-
thetic methodology proposed.
5b
5a
Scheme 1
SYNTHESIS 2007, No. 14, pp 2125–2134
Advanced online publication: 03.07.2007
DOI: 10.1055/s-2007-983746; Art ID: T00307SS
x
x.
x
x
.
2
0
0
7
© Georg Thieme Verlag Stuttgart · New York

2126
V. Vashchenko et al.
PAPER
We have failed to obtain any 2-arylidenementhanones 3 basic media, alkali hydroxides or alkoxides (KOH,
apart from 2-benzylidene derivative (3a) following the CsOH·H2O, Bu4NOH, t-BuOK) in combination with po-
method described in reference 3 (acid catalysis with dry lar aprotic solvents (DMSO, DMF, DMA) (Table 1)
HCl, Table 1, entry 5). However, the use of the super- solved the problem.
Table 1 Reaction of (–)-Menthone (1) with Aromatic Aldehydes 2
Entry
Aldehyde
Methoda Catalyst
(equiv per 1)
Solvent
Reaction Product Yield
time (h)
(%)
O
R
5
5
3
5
3
1
2
R = H, 2a
–
–
–
–
–
50% aq NaOH
15% NaOEt
H2O
–
3a
3a
3a
3a
3a
3a
10
14
18
32
37
52
2a
EtOH
–
3
2a
NaNH2 (1.0)
NaH (1.0)
Et2O
–
4
2a
Et2O
–
5
2a
dry HCl
neat
–
6
2a
A
C
C
C
A
C
A
A
A
A
A
A
A
C
A
A
A
A
A
B
B
A
KOH (1.0)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
MeOH
4
7
2a
CsOH·H2O (0.25)
CsOH·H2O (0.25)
CsOH·H2O (0.20)
KOH (1)
16
16
24
2
3a:4a 84b
8
R = 2-F, 2b
3b
3c:4c
3d
3d
3e
3e
3f
82
70c
49
72
15
56
11
64
72
81
80
84
65
40
57
61
–
9
R = 3-F, 2c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
R = 4-F, 2d
2d
CsOH·H2O (0.25)
KOH (0.7)
16
96
3
R = 4-Cl, 2e
2e
KOH (1.0)
DMSO
MeOH
R = 4-Br, 2f
50% aq KOH (0.7)
NaOH (0.5)
96
3.5
3.5
3.5
2
2f
2f
2f
2f
2f
2f
2f
2f
2f
DMSO
DMSO
DMSO
DMSO
DMSO
DMA
3f
KOH (0.5)
3f
CsOH·H2O (0.25)
Bu4NOH (0.11)d
t-BuOK (0.1)
KOH (0.5)
3f
3f
2.5
3.5
3.5
3.5
3.5
3
3f
3f
KOH (0.5)
DMF
3f
CsOH·H2O (0.25)
Bu4NOH (0.11)d
KOH (0.7)
DMF
3f
DMF
3f
R = 3-NO2, 2g
2g
DMSO
3:1 DMF–MeOH
4:1 DMSO–MeOH
3:1 DMF–MeOH
3g
3g
3h
3i
KOH (0.4)
5
47
62
31
R = 4-NO2, 2h
R = 4-CN, 2i
N
KOH (0.3)
3
KOH (0.36)
3.5
O
H
28
29
B
C
KOH (0.4)
KOH (0.4)
4:1 DMSO–MeOH
1:1 DMSO–MeOH
3.5
3.5
3j
3j
21
48
N
2j
Synthesis 2007, No. 14, 2125–2134 © Thieme Stuttgart · New York

PAPER
Claisen–Schmidt Condensation of Hindered Cyclic Ketones
2127
Table 1 Reaction of (–)-Menthone (1) with Aromatic Aldehydes 2 (continued)
Entry
Aldehyde
Methoda Catalyst
(equiv per 1)
Solvent
Reaction Product Yield
time (h)
(%)
3
30
31
32
33
34
35
36
37
38
39
40
41
R = 4-OMe, 2k
–
NaNH2 (1.0)
50% aq KOH (1.0)
NaOH (1)
Et2O
3k
3k
3k
3k
3k
3k
3l
5
17
35
51
78
46
74
4
2k
A
A
A
A
A
C
A
A
A
B
C
MeOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
6
4
2k
2k
KOH (1.0)
2.5
24
24
2.5
19
120
5
2k
KOH (0.9)
2k
CsOH·H2O (0.4)
CsOH·H2O (1.0)
KOH (1.0)
R = 2-OMe, 2l
R = 4-OEt, 2m
3m
3n
3o
3o
3o
R = 4-NMe2, 2n
KOH (1.0)
15
64
72
75
R = 4-Ph, 2o
KOH (0.5)
2o
KOH (0.5)
3
2o
CsOH·H2O (0.25)
5
R = 4-(4-CnH2n+1OC6H4)
42
43
44
45
46
47
48
49
50
51
52
53
n = 1, 2p
A
A
A
C
C
C
C
A
KOH (0.5)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
5
5
5
5
5
5
3
5
5
5
5
5
3p
3q
3q
3q
3q
3r
3r
3s
3s
3s
3t
64
18
26
38
61
38
50
8
n = 4, 2q
KOH (0.5)
2q
CsOH. H2O (0.25)
CsOH·H2O (0.25)
Bu4NOH (0.11)d
KOH (0.5)
2q
2q
n = 5, 2r
2r
CsOH·H2O (0.25)
KOH (0.5)
n = 7, 2s
2s
KOH/dibenzo-18-crown-6 (0.5)
Bu4NOH (0.11)d
KOH (0.5)
24
51
–
2s
C
A
C
n = 9, 2t
2t
Bu4NOH (0.25)d
3t
29
R = 4-(4-XC6H4CH2O)
X = H, 2u
54
55
56
C
C
C
KOH (0.8)
DMSO
DMSO
DMSO
16
2.5
3
3u
3v
3w
48
52
13
X = Me, 2v
CsOH·H2O (0.25)
CsOH·H2O (1.0)
X = OMe, 2w
a Addition of a powdered base to the mixture of reactants in an appropriate solvent at r.t. (Method A); pre-treatment of ketone solution with
small KOH portion prior to dropwise addition of aldehyde solution followed by addition of the rest of the base (Method B); vacuum degassing
and flushing of the mixture of reactants with argon prior to the addition of an appropriate base (Method C) or according to described in the
literature. See also the experimental section.
b Mixture of cis-3a:trans-4a diastereomers was formed as an oil in 74:26 ratio.
c Mixture of cis-3c:trans-4c diastereomers formed as an oil in 77:23 ratio was further separated by
HPLC.
d 30% aqueous solution.
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2128
V. Vashchenko et al.
PAPER
1
6
B:
B:
B:
B:
O
O
O
7a
7b
7c
2
2
Ar
Ar
O
Ar
B:
B:
H
O
O
Figure 1 X-ray crystal structure of compound 3b
4
3
Scheme 2
days are needed to obtain reasonable yields (entry 38). If
structural features of the type 3 compound do not allow
precipitation, then lowering of conversion of starting ma-
terials is observed in the case of low-reactive aldehydes
(entries 37,56). In the case of reactive aldehyde 2a or 2c,
the mixture of diastereomers 3 and 4 in a ratio, similar to
the equilibrium, forms after neutralization (entries 7 and
9, respectively).
The simplest reaction protocol consists in the addition of
a powdered base to a mixture of reactants in an appropri-
ate solvent at room temperature (Method A).10 Spontane-
ous heating of the reaction mixture up to 45 °C occurs on
addition of KOH, which often accelerates unwanted side
reactions, and consequently, leads to lower yields of target
compounds. It could be prevented if the base is introduced
portionwise. Initially, 1 is pre-treated with small portions
of KOH prior to dropwise addition of the aldehyde solu-
tion followed by the addition of the rest of the base (Meth-
od B).11,21,23
Stereochemical assignment of the new products as major
diastereomers 3 were made based on typical chemical
shift values in their 1H NMR spectra as it is shown above.
Additionally, the structure of compound 3b was proved
by X-ray crystallography (Figure 1).30
Moreover, it is believed that the pre-treatment of a (–)-
menthone promotes its epimerization to an equilibrium
mixture of 1 and its epimer (+)-isomenthone (6) through
the enolate 7b (Scheme 2) and, in such a way, also favors
the reaction to proceed in the desirable manner.
Minor components 4a and 4c were isolated by preparative
HPLC and assigned using NMR as well. The 1H and 13C
spectra for diastereomeric pair 3a and 4a were interpreted
with the aid of COSY and HSQC experiments.
As one can see from Table 1, the yields of the products de-
crease in the same order as solvent basicity: DMSO >
DMA > DMF31 for each base studied (cf. entries 16,20,21
and 17,22). The amount of the base is varied depending on
aromatic aldehyde reactivity amenable to the principles
known for the traditional protocol.2 Indeed, for halogen-,
alkyl-, or aryl-substituted aromatic aldehydes the optimal
amount of KOH lies within a range of 50–70 mol% per
starting menthone and it increases up to 100 mol% for al-
dehydes possessing electron-donating groups, such as 2k
or 2n (entries 33,34 and 38). In the case of aldehydes with
electron-withdrawing groups 2g–j, the basicity of the me-
dium should be reduced both by addition of methanol and
by reducing the base amount in order to prevent tarring
(entries 24–29).
According to HPLC data, full consumption of the alde-
hyde occurs in several minutes after addition of the base
in the case of reactive aryl aldehydes (e.g. halogen-substi-
tuted benzaldehydes), but for 4-methoxybenzaldehyde,
which has poor reactivity, it takes a minimum of four to
five hours. At the beginning of the reaction, a diastereo-
meric mixture of 3 and 4 forms in about 75:25 ratio almost
independently of the aldehyde nature (Schemes 1 and 2).
In most cases, 2-arylidene derivatives 3, being of cis-
1R,4R-configuration, are considerably less soluble than
trans-1R,4S-diastereomers 4, and precipitation of 3 in the
bulk usually causes the reaction mixture to thicken into a
slurry. This feature is believed to be an additional factor
of the stereoselectivity of the reaction towards products 3
of 4R-configuration. Normally, precipitation is complete
in three to four hours, however, sometimes prolongation
up to 24 hours is needed (entries 7–11, 33, 34). Further ex-
tension of the reaction, with or without precipitation of 3,
usually leads to the formation of essential amounts of by-
products. The major ones have been identified by HPLC
The influence of the alkali cation nature is illustrated in
entries 10–11, 15–18, 21–23, 32–33, 40–41, 43–53
(Table 1). A smaller alkali cation (Na+ vs. K+, Cs+ or
Bu4N+) lowers the yield of the reaction. This effect mani-
fests slightly for the reaction with quite reactive alde-
hydes, e.g., for 2f (entries 15 vs. 16–18) or 2o (entry 40 vs.
41), but becomes considerable for poor reactive ones (2k).
In the last case, when NaOH is used, the yield of the target
compound 3k drops down to 35% (entry 32), and anisic
acid is isolated as the main product of the reaction. The
blank experiment (treatment of anisic aldehyde with
1
and H NMR spectra as the corresponding benzoic acids
and benzylic alcohols obviously arising from the Canniz-
zaro reaction of the starting aromatic aldehydes. An ex-
ception is the reaction of 1 with low-reactive aldehydes
such as 2n where much higher reaction times up to several
Synthesis 2007, No. 14, 2125–2134 © Thieme Stuttgart · New York

PAPER
Claisen–Schmidt Condensation of Hindered Cyclic Ketones
2129
NaOH in DMSO) has resulted in the formation of anisic with several aromatic aldehydes containing long terminal
acid in 60% yield. Therefore, the use of the bases with cat- alkyl or alkyloxy chains. It is clearly pronounced (see
ions smaller than K+ is inappropriate. On the contrary, use Table 1) when passing from 3k to 3m (entries 34 and 37)
of alkalies with cations larger than K+, such as Cs+ or or 3v to 3w (entries 55 and 56) but less pronounced for the
Bu4N+,12 or an alkoxide base (t-BuOK) essentially en- series of alkoxybiphenyl derivatives 3p–t, cf. entries 42
hances the effectiveness of the superbasic media. This ef- and 45–48,53. Derivatives of 4-hydroxy-, 4-carboxy-, 4-
fect became apparent for the reaction of 1 with 4- amino-, and long-chain 4-alkyloxy-substituted com-
biphenylcarboxaldehyde derivatives 2q–t bearing long- pounds of type 3w have been obtained indirectly.17,32
chain alkyl substituents (entries 43–53). Total amount of
The applicability of the superbasic media has also been
the base can be reduced without any loss of effectiveness
demonstrated for Claisen–Schmidt condensation of some
in these cases. Thus, the optimal amount of CsOH was
other cyclic ketones 8–10,14 (Scheme 3). In the case of
non-hindered cycloalkanones with both reactive a-meth-
ylene groups 8–10 formation of bis-arylidene derivatives
11–13 in DMSO proceeds even under unoptimized condi-
tions in almost the same yields (Table 2, entries 2,3,5,7,8),
and, in some cases, in less time, as compared to the tradi-
found to be 25 mol%. For Bu4NOH and t-BuOK it should
not exceed 20 mol%, whereas the optimum is about 10
mol%. The exothermic character of the reaction, as well
as yields dependent on temperature, becomes weaker
when optimal amounts of CsOH, Bu4NOH or t-BuOK are
used in comparison to KOH. Thus, compound 3t, com-
pletely unavailable by KOH/DMSO methodology, was
obtained with a satisfactory yield (entry 53) by the use of
CsOH and at 35 °C. It has also been found that maximum
yield and reproducibility of the reaction are improved and
the amount of side-products is reduced if the mixture of
starting materials was thoroughly degassed and flushed
with argon before addition of the base. The reaction was
then carried out under inert atmosphere as well. This pro-
cedure (Method C) appears to be noticeably simpler than
Method B. It turned out to be especially useful for the re-
action of aldehydes almost insoluble in DMSO (e.g., 2q–
t) to be added to the reaction mixture dropwise in DMSO
solution, as is required for Method B.
tional protocol (entries 1,3,6).33,34 Although numerous ef-
fective methods for synthesis of bis-arylidene derivatives
11–13 have been reported recently, they often require the
use of rather complex equipment and/or chemicals.35
Therefore, even if the protocol proposed here generates
some loss in yields compared to those methods, it may be
considered as a simpler and cheaper alternative.
H
O
H
O
2
R'
R
R'
R
n
n
8, R = H, n = 0
9, R = H, n = 1
10, R = Me, n = 1
11, R = R' = H, n = 0
12, R = R' = H, n = 1
13, R = Me, R' = Cl, n = 1
There are several limitations of the methodology pro-
posed. Thus, all attempts to use aldehydes with highly
acidic protons (4-carboxy- and 4-hydroxybenzaldehydes)
in the condensation have failed, probably, due to partial
neutralization of the base and, therefore, reduction of me-
dium basicity. In the case of 4-hydroxybenzaldehyde, the
lowering of the carbonyl group reactivity under basic con-
ditions must be an additional factor of the reaction inhibi-
tion. A drastic decrease in yields was also found in
attempts to use (–)-menthone in condensation reactions
2
15a, R = H,
15b, R = Br
15c, R = OMe
R
O
O
14
H
Scheme 3
Bis-arylidenecyclopentanones 11 have been shown to un-
dergo retro-aldol reaction followed by further deep trans-
Table 2 Synthesis of Diarylidenecycloalkanones 11–13
Entry
Ketone
Aldehyde Methoda Base
(equiv per ketone)
Solvent
Reaction time Product Yield
Mp
(°C)
(h)
(%)
33a
1
2
3
4
5
6
7
8
8
2a
–
50% aq KOH (0.7)
KOH (0.8)
MeOH
DMSO
EtOH
24
11
12
77
189
A
0.3
79
189–190
116–117
–
33b
9
2a
–
NaOH (0.6)
CsOH (0.06)
KOH (0.7)
0.5
1.5
0.8
62
C
A
DMSO
DMSO
MeOH
DMSO
DMSO
no reaction
62
73
59
77
115–116
–
34
10
2e
–
KOH (–)
24
13
A
C
KOH (0.6)
0.8
150–151
150–151
KOH (0.4)
0.14
a See footnotes in Table 1.
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2130
V. Vashchenko et al.
PAPER
Table 3 Synthesis of 3-Arylidene Derivatives of Camphor
Entry
1
Aldehyde
Methoda
Base (equiv per ketone) Solvent
Reaction time (h) Product
Yield (%)
Mp (°C)
5
2a
–
NaOH
H2O
6
22
6
15a
16
–
36b
2
–
Na
benzene
Et2O
50–70
56
97
5
3
–
NaH
–
4
A
C
KOH (1.0)
t-BuOK (0.35)
NaNH2
DMSO
DMSO
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
benzene
DMSO
1.5
42
94–96
95–96
13136b
–
5
3
63
38a
6
2f
–
–
15b
50
b
7
A
C
C
C
C
KOH (1)
CsOH (1)
Bu4NOH (0.35)a
t-BuOK (1)
t-BuOK (0.35)
Na
8.5
4
–
8
18c
–
d
9
72
–
–
10
11
12
13
3
3
18.5e
62.6
–
130-131
12636b
124–125
36c
2k
–
22
15c
50–70
52.5
C
t-BuOK (0.35)
7f
a See footnotes for Table 1.
b 4-Bromobenzoic acid is isolated in 16.5% yield.
c 1:1 Mixture of 15b and benzoic acid is formed; yield is estimated by 1H NMR spectroscopy.
d Mixture of 10% 2f, 20% benzylic alcohol, 20–25% 15b and 45–50% 4-bromobenzoic acid as is estimated by 1H NMR spectroscopy.
e Mixture of 9% benzylic alcohol, 70–78% of 15b and 10–20% of 4-bromobenzoic acid as it is estimated by 1H NMR spectroscopy.
f According to HPLC, reaction was complete in 8 min.
formations in the super-basic media at elevated to be a more effective base than alkali hydroxides. How-
temperatures.28 Nevertheless, carrying out the reaction in ever, the amount of t-BuOK should be reduced to 35% (cf.
a KOH/DMSO mixture at milder conditions (Table 2, en- entries 10 and 11) to obtain higher yield of 15b. More-
try 2) produces 11a in high yields. Moreover, no detect- over, when alkali hydroxides are used (entries 4,6–8), for-
able amounts of side products were found in this case by mation of substantial amounts of the corresponding
HPLC analyses. Cyclohexanone (9) and its 3-methyl de- benzoic acids and benzyl alcohols were detected by NMR
rivative 10 also appear to be not too sensitive towards su- and HPLC, similarly to the case of using NaOH for men-
per-basic media (entries 5,7,8). Moreover, a catalytic thone condensation (see above). This fact could be ratio-
amount of the base does not promote the reaction of 9 at nalized in terms of the further lowering of camphor
all (cf. entries 4 and 5).
reactivity in comparison to menthone in the Claisen–
Schmidt condensation, while the rate of the Cannizzaro
reaction of the aromatic aldehydes obviously remains the
same.
Camphor (14) (Scheme 3), being a sterically hindered and
low-reactive ketone, has been shown to be almost unable
to react with aromatic aldehydes under the traditional pro-
tocol (see, e.g., Table 3, entry 1).5,36,37 More effective ap- The effectiveness of the superbasic media is believed to
proaches to the synthesis of 3-arylidenecamphors 15 be clearly described in terms of the HSAB principle.39,40
described before are in fact variations of Haller’s meth- More effective solvation of soft Lewis acids (alkali cat-
od,36a and represent two-step procedure: camphor enoliza- ions) with softly basic solvent molecules occurs as com-
tion with NaH,5 Na,36a,c t-BuOK,36b NaNH2
in a pared to hardly basic hydroxyl anions. Consequently,
38a
nonpolar solvent under reflux followed by the addition of these anions become more active with proton abstraction
an appropriate aldehyde. Haller’s protocol36a,c,38a provides from the substrate (Scheme 2). Decrease in self-associa-
the highest yields of compounds 15 (50–70%) known to tion of hydroxide anion in a polar aprotic solvent, when
date.
the cation radius increases from Na+ to Bu4N+, should also
be considered, which is again consistent with the HSAB
principle.
As it could be seen from Table 3, the use of superbasic
media produces arylidenecamphors 15 in high yields,
which are comparable to the best known results (cf. en- Thus, it is reasonable to suppose that all elementary steps
tries 1–3,6,12 and 5,11,13), but carrying out the reaction in the epimerization of 1 (see above, Scheme 2),41 where
as a simpler one-step procedure, in a shorter reaction time, proton abstraction occurs, are accelerated substantially in
and at a lower temperature. In these cases t-BuOK appears superbasic media, which provides faster accomplishment
Synthesis 2007, No. 14, 2125–2134 © Thieme Stuttgart · New York

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Claisen–Schmidt Condensation of Hindered Cyclic Ketones
2131
lowed by the rest of the base. The rest of the procedure was as above
for Method A.
of the equilibrium of the desired reaction (e.g., between 3
and 4, see Scheme 2), than for any side reactions.
Method C: Equimolar amounts of a ketone and an aromatic alde-
hyde are mixed in an appropriate solvent (see Tables 1– 3) at con-
centrations of 0.5–0.9 mmol/mL, vacuum degassed and flushed
with argon (3–5 cycles). Then a powdered base (for amount, see
Tables 1– 3) was added with vigorous stirring and external cooling
and the degassing procedure was repeated. Further as above for
Method A.
In conclusion, an effective protocol for Claisen–Schmidt
condensation of sterically hindered ketones, such as men-
thone and camphor, in the superbasic media consisting of
a strong base (KOH, CsOH, Bu4NOH or t-BuOK) and a
polar aprotic solvent (DMSO, DMF or DMA) is proposed
to produce the corresponding arylidene derivatives in
good to high yields. The t-BuOK/DMSO combination ap-
pears to be the most effective for these reactions. In the
case of more reactive ketones, such as cyclopentanone
and some cyclohexanones, the method proposed substan-
tially reduces reaction times without lowering product
yields.
Product Data
The identification of the following compounds described before,
3a,3d,3f,3g,3o;18a 3e,3h,3i,3k,3m–o;18b 3p;18c 3q,3r;32 3v and 3w32c
11;45 12;33 13;34 15a;36c 15b and 15c,36b,c,38a was made by HPLC or/
and comparison of their melting points, and, in several cases, using
1H NMR spectroscopy. For compound 3a, high-resolution NMR
spectra are given for comparison.46 For all the new compounds, data
confirming their structure are given below:
1H NMR spectra were recorded on a Bruker Avance DRX-500 (200
MHz) or Varian Mercury VX-200 (200 MHz) spectrometer. Mass
spectra were recorded on a Varian 1200 L GC-MS instrument either
in GC-MS mode or with the use of direct exposure probe (DEP)
method with EI at 70 eV. HPLC analyses were performed using a
Bischoff HPLC system equipped with Prontosil 120-5-C18H re-
verse-phase column (70–100 vol% MeCN–H2O mixtures served as
eluents). Elemental analyses were performed with EA-3000 analyz-
er (Eurovector, Italy). X-ray crystal structure analysis was made on
the Xcalibur-3 diffractometer (graphite monochromated MoKa ra-
diation, CCD detector, w-scanning, 2Qmax = 60°). (–)-Menthone
(1), KOH, CsOH·H2O and Bu4NOH (as 30% aq solution), cyclo-
pentanone (8), cyclohexanone (9), d-camphor (14), aldehydes 2a–o
are commercially available. DMSO, DMF and DMA were dried
over MgSO4, vacuum-distilled and stored over molecular sieves.
The following compounds were obtained as described in the litera-
ture: 3-methylcylohexanone (10),42 5-formyl-2-phenylpyrimidine
(2j),43 arylmethyleneoxybenzaldehydes 2v–x.32c Aldehydes 2p–t
were obtained by reduction of corresponding nitriles with Ni-Al
alloy21 similarly to the methods described in the literature.44
(3R,6R)-2-Benzylidene-6-isopropyl-3-methylcyclohexanone
(3a)
An oil obtained after flash chromatography on silica gel with hex-
ane as eluent contained 96% of mixture of diastereomers 3a and 4a
in 74:26 ratio. The oil was diluted with MeOH (1:1) and chilled at
–15 °C for 12 h. Crystals formed were collected by filtration to fur-
nish cis-(3R,6R)-diastereomer 3a; mp 49–50 °C (Lit.3 mp 51 °C).
1H NMR (500 MHz, DMSO-d6): d = 7.43–7.37 (m, 4 H), 7.36–7.32
(m, 1 H), 6.98 (s, 1 H), 3.36 (m, 1 H, overlapped with H2O), 2.40
(sept d, J = 3.4, 6.8 Hz, 1 H), 2.25 (m, 1 H), 1.88–1.76 (m, 3 H),
1.74–1.69 (m, 1 H), 1.11 (d, J = 6.8 Hz, 3 H), 0.91 (d, J = 7.1 Hz, 3
H), 0.82 (d, J = 6.8 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 17.6, 18.2, 19.3, 19.9, 26.1,
29.6, 31.0, 54.9, 128.1, 128.5, 129.2, 131.4, 135.1, 144.4, 203.3.
(3R,6S)-2-Benzylidene-6-isopropyl-3-methylcyclohexanone
(4a)
The mother liquor after separation of crystalline 3a consisted of a
mixture of diastereomers 3a:4a in 1:1 ratio. From 6 mL of this so-
lution, diastereomer 4a was isolated by preparative HPLC using a
mixture of MeCN–H2O (87:13) as eluent. After evaporation of the
eluate to dryness, the oil solidified; mp 46–47 °C; [a]D20 –207 (c =
0.9, toluene).
Claisen–Schmidt Condensation in Super-Basic Media; General
Procedures
Method A: To a solution of equimolar amounts of a ketone and an
aromatic aldehyde in an appropriate solvent (see Tables 1– 3) at
concentrations of 0.5–0.9 mmol/mL, was added a powdered base
(for amount see Tables 1– 3) with vigorous stirring. After a short
period of exothermic reaction, the mixture became red-brownish
and often thickened. The resulting mixture was stirred until the re-
action was complete as monitored by TLC or HPLC. In the case of
well-crystallizing compounds (3, 11–13, 15, except 3a, 3c, 3d, 3g,
3m), the mixture was diluted with slight excess of alcoholic AcOH,
the precipitate formed was filtered, washed with alcohol, thorough-
ly washed with warm H2O, then with alcohol again, and dried. The
obtained crude material usually had more than 90% purity (HPLC)
and could be used in further transformations without additional pu-
rification. Analytically pure sample could be obtained by crystalli-
zation from EtOH, MeCN or hexane. Otherwise, oily material
formed after neutralization with aqueous acid was extracted with
CH2Cl2 (3 × 10 mL per 1 mmol of 3), the combined extracts were
washed with H2O, dried (Na2SO4), and evaporated to dryness. The
residue was purified by flash chromatography on silica gel using
CH2Cl2 or hexane as eluent or extracted with hot hexane via short
plug of silica gel in a modified Soxhlet apparatus.
IR (KBr): 3053, 2956, 2931, 2868, 1682, 1611 cm–1.
1H NMR (500 MHz, DMSO-d6): d = 7.47–7.38 (m, 4 H), 7.37–7.31
(m, 1 H), 6.91 (s, 1 H), 3.36 (m, 1 H), 2.13–2.01 (m, 2 H), 1.96–1.89
(m, 2 H), 1.74–1.63 (m, 1 H), 1.40–1.31 (m, 1 H), 1.10 (d, J = 7.1
Hz, 3 H), 0.84 (d, J = 7.1 Hz, 3 H), 0.83 (d, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 19.4, 20.9, 21.0, 21.2, 28.0,
28.1, 31.6, 55.2, 128.8, 129.1, 129.9, 132.4, 145.2, 206.2, 220.2.
MS: m/z (%) = 243 (16), 242 (M+, 100), 241 (26), 227 (16), 214
(12), 200 (63), 171 (75), 144 (23), 131 (13), 129 (56), 115 (16), 91
(18).
Anal. Calcd for C17H22O: C, 84.25; H, 9.15; O, 6.60. Found: C,
84.56; H, 9.45.
(3R,6R)-2-(2-Fluorobenzylidene)-6-isopropyl-3-methylcyclo-
hexanone (3b)
Mp 88–89 °C; [a]D20 –165 (c 2.0, toluene).
IR (KBr): 3061, 2959, 2929, 2868, 1675, 1621 cm–1.
Method B: To a solution of a ketone in an appropriate solvent (see
Table 1) at concentrations of 0.5–0.9 mmol/mL, was added about a
third of the needed base (for total amount see Table 1) with vigorous
stirring and external cooling. The mixture was stirred for 30–40 min
and then aldehyde (1 equiv per menthone) was added dropwise fol-
1H NMR (500 MHz, C6D6): d = 7.37 (s, 1 H), 7.09 (td, J = 7.8, 1.7
Hz, 1 H), 6.85 (d, J = 5.1, 1.7 Hz, 1 H), 6.81–6.76 (m, 2 H), 3.11–
3.06 (m, 1 H), 2.62 (sept d, J = 3.4, 7.1 Hz, 1 H), 1.60–1.42 (m, 3
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2132
V. Vashchenko et al.
PAPER
H), 1.39–1.31 (m, 1 H), 0.92 (d, J = 6.8 Hz, 3 H), 0.88 (d, J = 7.1
Hz, 3 H), 0.84 (d, J = 6.6 Hz, 3 H).
H), 1.45–1.36 (m, 1 H), 1.17 (d, J = 7.1 Hz, 3 H), 0.90 (d, J = 6.4
Hz, 3 H), 0.90 (d, J = 6.5 Hz, 3 H).
13C (125 MHz, C6D6): d = 18.1, 19.1, 19.5, 20.4, 26.8, 30.6, 32.5,
56.1, 115.8 (d), 124.0 (d), 124.3 (d), 129.8 (d), 130.3 (d), 131.4,
147.7, 161.1 (d), 202.8.
13C (75 MHz, CDCl3): d = 19.2, 20.7, 20.8, 21.3, 27.8, 31.8, 55.7,
114.9 (d), 115.9 (d), 125.3 (d), 129.9 (d), 131.2 (d), 137.9 (d), 146.2,
162.5 (d), 207.5.
MS: m/z (%) = 260 (M+, 78.7), 245 (29.2), 232 (19.1), 219 (24.8),
218 (100.0), 203 (20.4), 190 (15.3), 189 (95.9), 162 (33.2), 161
(16.6), 149 (18.6), 148 (16.2), 147 (92.6), 146 (55.6), 133 (20.8),
109 (24.1).
GC-MS (minor component, 1st on retention, 4c): m/z (%) = 260
(M+, 35.9), 245 (21.2), 219 (14.0), 218 (100.0), 217 (12.7), 203
(12.4), 190 (11.2), 189 (65.5), 162 (17.4), 161 (23.9), 148 (13.0),
147 (70.5), 146 (24.6), 133 (15.8), 109 (16.8).
Anal. Calcd for C17H21FO: C, 78.43; H, 8.13; Found: C, 78.13; H,
8.21.
Anal. Calcd for C17H21FO: C, 78.43; H, 8.13; Found: C, 78.61; H,
8.32.
X-ray Crystal Data
(3R,6R)-6-Isopropyl-3-methyl-2-[(2-phenylpyrimidin-
5-yl)methylene]cyclohexanone (3j)
Crystals of 3b are monoclinic. At 293 K: a = 9.570(1), b = 7.684(1),
c = 10.184(1) Å, b = 95.58(1)°, V = 745.35(7) Å3, Mr = 260.34,
Z = 2, space group P21, dcalc = 1.160 g/cm3, m (MoKa) = 0.079 mm–1,
F(000) = 280. Intensity of 6343 reflections (3794 independent,
Rint = 0.029) were collected. The structure was solved by direct
method using SHELXTL package. Positions of hydrogen atoms
were located from electron density difference maps and refined by
‘riding’ model with Uiso = nUeq of non-hydrogen atom bonded with
given hydrogen atom (n = 1.5 for methyl groups and n = 1.2 for oth-
er hydrogen atoms). Full-matrix least-squares refinement against F2
in anisotropic approximation using 3721 reflections was converged
to wR2 = 0.160 [R1 = 0.057 for 2161 reflections with F > 4s(F),
S = 0.908].
Mp 131–133 °C; [a]D20 –192 (c 1.2, toluene).
IR (KBr): 3049, 2956, 2868, 1682, 1603, 1574 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.79 (s, 2 H), 8.45 (m, 2 H), 7.50
(t, J = 6.3 Hz, 3 H), 6.99 (s, 1 H), 3.37 (m, 1 H), 2.54 (sept d,
J = 7.0, 3.4 Hz, 1 H), 2.26 (m, 1 H), 1.99–1.87 (m, 3 H), 1.86–1.81
(m, 1 H), 1.23 (d, J = 7.1 Hz, 3 H), 0.98 (d, J = 7.1 Hz, 3 H), 0.91
(d, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 17.9, 18.8, 19.7, 20.3, 26.6, 30.4,
32.3, 56.1, 125.1, 127.4, 128.2, 128.7, 131.0, 137.0, 148.0, 157.2,
163.3, 203.9.
MS: m/z (%) = 320 (M+, 100.0), 306 (16.2), 305 (15.2), 292 (10.4),
279 (13.1), 278 (58.5), 277 (21.1), 263 (11.8), 250 (30.9), 249
(88.8), 222 (20.8), 221 (13.7), 207 (15.6), 105 (7.2).
(3R,6R)-2-(3-Fluorobenzylidene)-6-isopropyl-3-methylcyclo-
hexanone (3c) and (3R,6S)-2-(3-Fluorobenzylidene)-6-isopro-
pyl-3-methylcyclohexanone (4c)
An oil obtained after flash chromatography on silica gel with hex-
ane as eluent was a mixture of diastereomers 4c and 3c in a 27:73
ratio (according to HPLC) or in a 30:70 ratio (according to GC-MS).
The mixture was separated by preparative HPLC using a mixture of
MeCN–H2O (7:13) as eluent.
Anal. Calcd for C21H24N2O: C, 78.71; H, 7.55; N, 8.74. Found: C,
78.93; H, 7.49; N, 8.82.
(3R,6R)-2-(2-Methoxybenzylidene)-6-isopropyl-3-methylcyclo-
hexanone (3l)
Mp 80–81 °C; [a]D20 –254 (c 1.2, toluene).
IR (KBr): 3061, 2959, 2868, 1683, 1606 cm–1.
3c
1H NMR (500 MHz, DMSO-d6): d = 7.34 (td, J = 7.8, 1.4 Hz, 1 H),
7.26 (dd, J = 7.6, 1.4 Hz, 1 H), 7.05 (s, 1 H) 7.04 (dd, J = 7.8, 0.7
Hz, 1 H), 6.98 (td, J = 7.6, 0.8 Hz, 1 H), 3.78 (s, 3 H), 3.21 (m, 1
H), 2.40 (sept d, J = 3.2, 7.0 Hz, 1 H), 2.25 (m, 1 H), 1.86–1.75 (m,
3 H), 1.71 (m, 1 H), 1.07 (d, J = 7.0 Hz, 3 H), 0.91 (d, J = 7.1 Hz,
3 H), 0.82 (d, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 17.6, 18.2, 19.5, 19.9, 26.1,
29.8, 31.1, 54.8, 55.3, 111.0, 120.1, 123.7, 126.9, 128.8, 129.8,
144.1, 157.5, 203.6.
Oil; [a]D20 –169 (c 1.2, toluene).
IR (neat): 3066, 2960, 2872, 1685, 1609, 1581 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.4 (ddd, J = 5.8, 8.1, 7.6 Hz, 1
H), 7.13 (d, J = 7.7 Hz, 1 H), 7.14–7.04 (m, 2 H), 7.11 (s, 1 H),
3.52–3.40 (m, 1 H), 2.62 (sept d, J = 3.3, 6.9 Hz, 1 H), 2.36–2.26
(m, 1 H), 1.99–1.83 (m, 3 H), 1.25 (d, J = 7.1 Hz, 3 H), 1.04 (d,
J = 6.4 Hz, 3 H), 0.98 (d, J = 6.5 Hz, 3 H).
13C (75 MHz, CDCl3): d = 17.7, 18.6, 19.6, 20.3, 26.5, 30.3, 31.6,
55.9, 114.9 (d), 115.8 (d), 125.2, 129.8 (d), 130.9 (d), 138.0 (d),
145.7, 162.6 (d), 204.8.
MS: m/z (%) = 272 (M+, 5), 242 (19.4), 241 (100.0), 201 (13.1), 159
(15.4), 121 (6.1).
GS-MS (major component, 2nd on retention, 3c): m/z (%) = 260
(M+, 82.9), 245 (35.7), 219 (12.5), 218 (91.0), 203 (26.5), 190
(14.4), 189 (88.9), 175 (13.8), 162 (42.7), 161 (26.9), 159 (11.0),
149 (15.0), 147 (100.0), 146 (32.7), 133 (26.5), 123 (20.0), 109
(28.6).
Anal. Calcd for C18H24O2: C, 79.37; H, 8.88. Found: C, 79.29; H,
8.93.
(3R,6R)-2-[1-(4¢-Heptyloxybiphenyl-4-yl)methylene]-6-isopro-
pyl-3-methylcyclohexanone (3s)
Mp 90–91 °C; [a]D20 –214 (c 1.2, toluene).
Anal. Calcd for C17H21FO: C, 78.43; H, 8.13; Found: C, 78.55; H,
8.40.
IR (KBr): 3058, 2948, 2853, 1682, 1606, 1575 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.57 (d, J = 8.4 Hz, 2 H), 7.54 (d,
J = 8.4 Hz, 2 H), 7.43 (d, J = 8.4 Hz, 2 H), 7.17 (s, 1 H), 6.98 (d,
J = 8.4 Hz, 2 H), 4.00 (t, J = 6.6 Hz, 2 H), 3.49 (m, 1 H), 2.59 (sept
d, J = 7.0, 3.2 Hz, 1 H), 2.25 (m, 1 H), 1.97–1.85 (m, 3 H), 1.85–
1.77 (m, 3 H), 1.48 (quint, J = 7.8 Hz, 2 H), 1.41–1.30 (m, 6 H),
1.24 (d, J = 7 Hz, 3 H), 0.98 (d, J = 7 Hz, 3 H), 0.93 (d, J = 6.9 Hz,
3 H), 0.91 (t, J = 7.1 Hz, 3 H).
4c
Oil; [a]D20 –216 (c 0.9, toluene).
IR (neat): 3067, 2961, 2871, 1686, 1608, 1581 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.32 (ddd, J = 5.9, 8.2, 7.5 Hz, 1
H), 7,13 (dd, J = 7.5, 1.4 Hz, 1 H), 7.06 (dt, J = 9.9, 2.4, 1.4 Hz, 1
H), 6.99 (tdd, J = 2.4, 8.1, 8.2, 0.9 Hz, 1 H), 6.94 (s, 1 H), 3.41–3.31
(m, 1 H), 2.18–2.07 (m, 2 H), 2.07–1.96 (m, 2 H), 1.86–1.74 (m, 1
Synthesis 2007, No. 14, 2125–2134 © Thieme Stuttgart · New York

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Claisen–Schmidt Condensation of Hindered Cyclic Ketones
2133
13C NMR (125 MHz, CDCl3): d = 14.0, 17.8, 18.6, 19.8, 20.4, 22.6,
26.0, 26.7, 29.0, 29.3, 30.5, 31.7, 31.7, 55.8, 68.1, 114.8, 126.5,
127.9, 130.1, 132.5, 132.6, 134.1, 140.6, 144.4, 159.0, 204.7.
MS: m/z (%) = 432 (M+, 100.0), 431 (19.3), 390 (17.4), 361 (17.2),
334 (16.6), 263 (10.6), 221 (15.2), 207 (9.9), 183 (9.3), 181 (7.0).
References
(1) Recent selected papers: (a) Elguero, J.; Shimizu, B. An.
Quim. Real Soc. Esp. Quim. 1988, 183; Chem. Abstr. 1989,
111, 153745. (b) Shanmugam, P.; Srinivasan, R.;
Rajagopalan, K. Tetrahedron 2001, 57, 673. (c) Malkov, A.
V.; Baxendale, I. R.; Langer, V.; Fawcett, J.; Russell, D. R.
Organometallics 2001, 20, 673. (d) Kashima, C.
Heterocycles 2003, 47, 959.
Anal. Calcd for C30H40O2: C, 83.28; H, 9.32. Found: C, 83.19; H,
9.25.
(2) Nielsen, A. T.; Houlihan, W. T. Org. React. 1968, 16, 444.
(3) Martine, M. C. Ann. Chim. Phys. 8 Ser. 1904, 49.
(4) Metge, C.; Bertrand, C. C. R. Hebd. Seances Acad Sci., Ser.
C 1971, 272, 318.
(5) Ozarslan, O.; Ertan, M.; Sayrac, T.; Akgun, H.;
Demirdamar, R.; Gumusel, B. Arch. Pharm. (Weinheim)
1994, 327, 525.
(6) Hassner, A.; Mead, T. C. Tetrahedron 1964, 20, 2201.
(7) Vashchenko, V. V.; Pivnenko, N. S.; Kutulya, L. A.;
Petrenko, A. S.; Iksanova, S. V.; Goodby, J. W. Russ. Chem.
Bull. 2000, 1218; Izv. Akad. Nauk, Ser. Khim. 2000, 1221;
Chem. Abstr. 2001, 134, 29564.
(3R,6R)-2-[1-(4¢-Nonyloxybiphenyl-4-yl)methylene]-6-isopro-
pyl-3-methylcyclohexanone (3t)
Mp 86–87 °C; [a]D20 –184 (c 1.9, toluene).
IR (KBr): 3060, 2951, 2853, 1679, 1606, 1575 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.57 (d, J = 8.3 Hz, 2 H), 7.54 (d,
J = 8.3 Hz, 2 H), 7.43 (d, J = 8.3 Hz, 2 H), 7.17 (s, 1 H), 6.98 (d,
J = 8.4 Hz, 2 H), 4.00 (t, J = 6.6 Hz, 2 H), 3.49 (m, 1 H), 2.59 (sept
d, J = 7.0, 3.2 Hz, 1 H), 2.25 (m, 1 H), 1.97–1.85 (m, 3 H), 1.85–
1.77 (m, 3 H), 1.48 (quint, J = 7.8 Hz, 2 H), 1.41–1.26 (m, 10 H),
1.24 (d, J = 7 Hz, 3 H), 0.98 (d, J = 7 Hz, 3 H), 0.92 (d, J = 6.9 Hz,
3 H), 0.90 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 14.1, 17.8, 18.7, 19.8, 20.4, 22.6,
26.0, 26.7, 29.2, 29.3, 29.4, 29.5, 30.5, 31.7, 31.9, 55.8, 68.1, 114.8,
126.5, 127.9, 130.1, 132.5, 132.6, 134.1, 140.6, 144.4, 159.0, 204.7.
MS: m/z (%) = 460 (M+, 100.0), 459 (17.1), 418 (15.4), 389 (14.3),
362 (9.2), 347 (11.5), 333 (8.4), 306 (6.2), 292 (11.8), 263 (12.1),
241 (6.7), 236 (5.4), 235 (6.1), 222 (5.2), 221 (15.2), 207 (9.5), 183
(11.1), 181 (8.1).
(8) (a) Bates, R. B.; Ogle, C. A. Carbanion Chemistry; Springer-
Verlag: Berlin, 1983. (b) Dolman, D.; Stewart, R. Can. J.
Chem. 1967, 45, 911.
(9) A similar approach had been proposed first for the reactions
of formaldehyde with ketones: Wesslen, B. Acta Chem.
Scand. 1967, 21, 713.
(10) Kutulya, L. A.; Nemchenok, I. B.; Tishchenko, V. G.; Shnol,
V. Y.; Yanovskaya, L. A.; Semenkova, G. P. SU 1098210,
1986; Chem. Abstr. 1986, 105, 190665.
(11) Kutulya, L. A.; Krivosheeva, N. F.; Vashchenko, V. V.;
Khandrimailova, T. V.; Cherkashina, R. M.; Protsenko, L. I.
SU 1617881, 1988; Chem. Abstr. 1995, 122, 240069.
(12) Vashchenko, V. V.; Kutulya, L. A. Ukrainian Patent
33753A, 2001.
Anal. Calcd for C32H44O2: C, 83.43; H, 9.63. Found: C, 83.50; H,
9.71.
(3R,6R)-2-[4-(Phenylmethyleneoxy)benzylidene]-6-isopropyl-3-
methylcyclohexanone (3u)
Mp 93–94.5 °C; [a]D20 –225 (c 1.9, toluene).
(13) (a) Nemchenok, I. B.; Tolmachev, A. V.; Kutulya, L. A.;
Tishchenko, V. G. Zh. Fiz. Khim. 1986, 635; Chem. Abstr.
1986, 105, 15749. (b) Kutulya, L. A.; Nemchenok, I. B.;
Khandrimailova, T. V. Kristallografiya 1990, 1234; Chem.
Abstr. 1991, 114, 92280. (c) Kutulya, L. A.; Nemchenok, I.
B.; Oleiniik, S. S. Kristallografiya 1990, 1242; Chem. Abstr.
1991, 114, 92281. (d) Tishchenko, V. G.; Kutulya, L. A.;
Nemchenok, I. B.; Tolmachev, A. V.; Rusalovich, A. I. SU
1167887, 1984; Chem. Abstr. 1994, 120, 121381.
(14) (a) Van de Witte, P.; Brehmer, M.; Lub, J. J. Mater. Chem.
1999, 9, 2087. (b) Lub, J.; Hoeve, T. W.; Nijssen, W. P. M.;
Wegh, R. T. Liq. Cryst. 2002, 29, 71.
IR (KBr): 1664, 1572, 1600, 1542 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.44 (d, J = 7.3 Hz, 2 H), 7.40 (t,
J = 7.3 Hz, 2 H), 7.37–7.32 (m, 3 H), 7.13 (s, 1 H), 6.98 (d, J = 8.5
Hz, 2 H), 5.09 (s, 2 H), 3.44 (m, 1 H), 2.58 (sept d, J = 7.0, 3.4 Hz,
1 H), 2.23 (m, 1 H), 1.95–1.83 (m, 3 H), 1.83–1.75 (m, 1 H), 1.22
(d, J = 7.1 Hz, 3 H), 0.97 (d, J = 7.1 Hz, 3 H), 0.91 (d, J = 7.1 Hz,
3 H).
13C NMR (125 MHz, CDCl3): d = 17.8, 18.5, 19.7, 20.3, 26.8, 30.4,
31.5, 55.6, 70.0, 114.8, 127.4, 128.0, 128.6, 128.6, 131.3, 132.8,
136.7, 142.7, 158.8, 204.6.
Anal. Calcd for C24H28O2: C, 82.72; H, 8.10. Found: C, 82.79; H,
8.17.
(15) Popova, E. V.; Fedoryako, A. P.; Vashchenko, V. V.;
Kutulya, L. A. Zh. Fiz. Khim. 2000, 1967; Chem. Abstr.
2001, 134, 139582.
(16) Kutulya, L.; Vashchenko, V.; Semenkova, G.; Shkolnikova,
N.; Drushlyak, T.; Goodby, J. Mol. Cryst. Liq. Cryst. 2001,
361, 125.
(17) Vashchenko, V. V.; Kutulya, L. A.; Pivnenko, M. N.;
Shkol’nikova, N. I. Russ. Chem. Bull. 2003, 2406; Izv. Akad.
Nauk, Ser. Khim. 2003, 2276; Chem. Abstr. 2004, 140,
383456.
(18) (a) Kutulya, L. A.; Pivnenko, N. S.; Nemchenok, I. B.;
Handrimailova, T. V.; Semenkova, G. P.; Biba, V. I.;
Tishchenko, V. G. Zh. Obshch. Khim. 1987, 57, 397; Chem.
Abstr. 1988, 108, 22054. (b) Yarmolenko, S. N.; Chepeleva,
L. V.; Kutulya, L. A.; Vashchenko, V. V.; Drushlyak, T. G.;
Ponomarev, O. A. Zh. Obshch. Khim. 1995, 65, 145; Chem.
Abstr. 1995, 123, 284996. (c) Yarmolenko, S. N.; Kutulya,
L. A.; Vashchenko, V. V.; Chepeleva, L. V. Liq. Cryst. 1994,
21, 877. (d) Pivnenko, N. S.; Vashchenko, V. V.; Kutulya,
L. A.; Doroshenko, A. O.; Chepeleva, L. V. Russ. Chem.
Acknowledgment
The authors thank Dr. V. Kravets for assistance with some synthetic
experiments, Dr S. Shishkina (STC ISC, Ukraine) for providing X-
ray crystal structure analysis for compound 3b, Dr. V. Averin and
Dr. T. Drushlyak (STC ISC, Ukraine) for carrying out some HPLC
analyses, Dr. Th. Gurley (USA) and Dr. M. Pivnenko (University of
Cambridge, UK) for useful discussion on the manuscript.
Synthesis 2007, No. 14, 2125–2134 © Thieme Stuttgart · New York

2134
V. Vashchenko et al.
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Synthesis 2007, No. 14, 2125–2134 © Thieme Stuttgart · New York