Solvent-free Claisen and Cannizzaro reactions

Article abstract of DOI:10.1016/S0040-4039(01)01562-3

Claisen and Cannizzaro reactions were found to proceed efficiently under solvent-free conditions. The solvent-free Claisen reactions were especially effective for the ester substituted with sterically bulky groups, which does not react in solution.

Full text of DOI:10.1016/S0040-4039(01)01562-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7983–7985
†
Solvent-free Claisen and Cannizzaro reactions
Kazuhiro Yoshizawa, Shinji Toyota and Fumio Toda*
Department of Chemistry, Okayama University of Science, Ridai-cho, Okayama 700-0005, Japan
Received 7 June 2001; revised 16 July 2001; accepted 21 August 2001
Abstract—Claisen and Cannizzaro reactions were found to proceed efficiently under solvent-free conditions. The solvent-free
Claisen reactions were especially effective for the ester substituted with sterically bulky groups, which does not react in solution.
©
2001 Elsevier Science Ltd. All rights reserved.
t
We have been studying how molecules move quite
easily and even selectively in the solid state. When the
The same treatment of 1b and 1c with BuOK for 2 h
1
and 10 min, respectively, gave 2b in 60% and 2c in 73%
yields, respectively. In contrast, reactions of 1b and 1c
in solution for 16 and 6 h, respectively, gave 2b and 2c
molecular movements in the solid state are applied to
organic reactions, selective and efficient solvent-free
1
3
organic reactions can be designed. Recently, we found
in 47 and 55% yields, respectively. These data clearly
that the title reactions also proceed efficiently under
solvent-free conditions. In particular, the solvent-free
Claisen reactions of the ester substituted with a steri-
cally bulky group proceeded very efficiently, although
these reactions did not occur in solution. These solvent-
free reactions are important not only for their efficiency
and simplicity, but also as green and sustainable
procedures.
show that solvent-free reactions are simpler and more
efficient than solution reactions. For the ester substi-
tuted with a sterically bulky group, the difference in
efficiency between solvent-free and solution reactions
becomes larger. Treatment of ethyl pentanoate (1d)
t
with BuOK for 1 h gave 2d in 61% yield, although its
solution reaction for 32 h gave 2d in 35% yield. Fur-
thermore, solvent-free reaction of ethyl 3-methylbu-
tanoate (1e) for 1 h gave 2e in 33% yield; however,
solution reaction for 48 h did not give any 2e, and 1e
was recovered unchanged. A plausible explanation of
2
Claisen condensation reactions
For example, after a mixture of ethyl acetate (1a) (3.52
t
g, 40 mmol) and powdered BuOK (3.68 g, 28 mmol)
Table 1. Solvent-free Claisen condensation reactions of 3
was kept at 80°C for 20 min, the reaction mixture was
neutralized by addition of dil. HCl and extracted with
ether. The oil left after evaporation of the solvent from
the dried ether solution was distilled in vacuo by Kugel-
rohr apparatus to give 2a (1.9 g, 73% yield). When the
same reaction was carried out in EtOH containing
EtONa for 8 h under reflux, 2a was obtained in 36–76%
R
Reaction conditions
Yield (%) of 4
Temperature (°C) Time (min)
a
b
c
H
100
30
60
30
20
75
66
64
84
Me 120
Et
Ph
120
90
3
yield. For example, when a solution of 1a (3.52 g, 40
d
mmol) and EtONa (1.9 g, 28 mmol) in EtOH (4 ml)
was heated under reflux for 8 h, 2a (1.17 g, 45%) was
obtained after the usual work up procedure.
O
O
O
tBuOK
R
R
OEt
OEt
R
Keywords: solvent-free reaction; Claisen reaction; Cannizzaro reac-
tion; green chemistry.
1
2
n
a : R=H
b : R=Me
c : R=Ph
d : R= Pr
i
*
Corresponding author. Fax: +81 86 256 9604; e-mail: toda@
chem.ous.ac.jp
This paper is dedicated to Professor Masazumi Nakagawa on the
occasion of his 85th birthday.
e : R=Pr
†
Scheme 1.
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01562-3

7
984
K. Yoshizawa et al. / Tetrahedron Letters 42 (2001) 7983–7985
O
O
O
tBuOK
R
R
O
O
R
3
4
a : R=H
b : R=Me
c : R=Et
d : R=Ph
Scheme 2.
the inefficiency of the reaction in solution is that the
reactant and reagent are solvated and their mutual
approach to the condensation reaction becomes
difficult for sterical reasons.
the ester, metal alkoxide and alcohol used as a solvent
should be identical. In the solvent-free reactions, how-
ever, a strong base such as BuOK can be used for any
kind of ester substrate, since such exchange does not
occur. This is also a considerable advantage (Schemes 1
and 2.
t
A similar steric effect was observed in the reaction of
benzyl carboxylate (3). When 3a–d were treated with
t
BuOK under solvent-free conditions at the reaction
Cross-condensation reaction of benzyl benzoate (5) and
benzyl carboxylate (6) was carried out under solvent-
free conditions. Treatment of a 1:1 mixture of 5 and 6
temperature and reaction time indicated in Table 1,
4
a–d were obtained in the moderate yields shown in
t
Table 1. When the same reactions of 3a–e were carried
with BuOK under the conditions indicated in Table 2
t
out in toluene and BuOH under reflux for 16 h, no
gave the cross-condensed product 7 in the yield shown
in Table 2. Although the cross-condensation between 5
and 6c did not occur, cross-condensation products 7a
and 7b were obtained in moderate yields. Because heat-
condensation product was obtained and 3a–e were
recovered unchanged. In solution reactions, exchange
of the alkoxy group occurs among the substrate,
reagent and solvent. Therefore, the alkoxy groups of
t
ing of 5, 6 and BuOK in toluene under reflux for 16 h
did not give any product, it is clear that the solvent-free
reaction is again effective even for the cross-condensa-
tion. In these cases, self-condensation of 6 itself did not
occur probably because of the high reactivity of 5
Table 2. Solvent-free cross-condensation reactions of 5
and 6
R
Reaction conditions
Temperature (°C) Time (h)
120
Yield (%) of 7
(
Scheme 3).
4
Cannizzaro reactions
a
b
c
H
1
1
1
42
45
0
Me 100
Ph 120
After a mixture of powdered 1-formylnaphthalene (8)
(4.68 g, 30 mmol) and powdered KOH (2.52 g, 45
mmol) was kept at 100°C for 5 min, water was added to
the reaction mixture, and was filtered to give 1-(hydroxy-
methyl)naphthalene (10), after Kugelrohr distillation,
Table 3. Solvent-free Cannizzaro reactions
(
0.485 g, 38% yield). The filtrate was acidified by conc.
HCl and filtered to give 1-naphthoic acid (9) (0.57 g,
1% yield). For liquid aldehydes, a similar method can
Aldehyde
Reaction conditions
Yield (%) of
4
Temperature Time (min)
Acid
Alcohol
be applied. When the alcohol formed by the solvent-
free reaction is an oily material, the product was
extracted with ether. Finally, treatment of aldehydes
11–18 by these procedures gave the corresponding alco-
hols and acids in the yields indicated in Table 3.
(
°C)
8
100
rt
5
10
3
5
5
30
10
10
10
41
43
51
46
49
46
48
53
40
38
39
18
38
41
27
45
33
36
11
12
13
14
15
16
17
18
80
80
100
100
rt
In the case of crystalline p-methylbenzaldehyde (16),
the yield of p-methylbenzoic acid exceeded 50%, proba-
bly due to air oxidation of 16 during the reaction at
rt
8
0°C. When the reaction was carried out at room
0
temperature in nitrogen atmosphere under ultrasound
O
O
O
O
O
R
tBuOK
O
O
+
R
5
6
7
a : R=H
b : R=Me
c : R=Ph
Scheme 3.

K. Yoshizawa et al. / Tetrahedron Letters 42 (2001) 7983–7985
COOH
CHO CH OH
7985
2
KOH
+
8
9
10
Scheme 4.
CHO
CHO
CHO
MeO
CHO
Me
MeO
MeO
11
12
13
14
CHO
CHO
CHO
MeO
Cl
CHO
NO2
O
MeO
15
16
17
18
Scheme 5.
irradiation, p-methylbenzoic acid and p-methylbenzyl
alcohol were obtained in 43 and 33% yield, respectively
Research from the Ministry of Education, Science,
Sports and Culture, Japan.
(
Table 3). In all cases shown in Table 3, solvent-free
Cannizzaro reactions proceeded efficiently under milder
conditions, and the products were obtained in moderate
yields by a simple separation method (Schemes 4 and 5).
References
The solvent-free Cannizzaro reaction has some advan-
tages. In addition to simplicity and cleanness of the
procedure, the solvent-free reaction proceeds much faster
1. (a) Toda, F. Synlett 1993, 302; (b) Toda, F. Acc. Chem.
Res. 1995, 28, 480; (c) Toda, F. Supramol. Sci. 1996, 3,
139; (d) Toda, F. Compr. Supramol. Chem. 1996, 6, 465;
(e) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025.
2. Hauser, C. R.; Hudson, Jr., B. E. Org. React. 1942, I,
266.
than a solution reaction. For example, reaction of 11 in
5
6
0% aq. KOH takes 24 h to complete, although the
solvent-free reaction is completed within 5 min. In all
other cases indicated in Table 3, all reactions are com-
pleted within 30 min.
3. (a) Spielman, M. A.; Schmidt, M. T. J. Am. Chem. Soc.
1937, 59, 2009; (b) Fisher, N.; Mcelvain, S. M. J. Am.
Chem. Soc. 1934, 56, 1766.
Acknowledgements
4. Geissman, T. A. Org. React. 1944, II, 94.
5. Cumming, W. M.; Hopper, I. V.; Wheeler, T. S. Syst.
This work was supported by a Grant-in-Aid for Scientific
Org. Chem. 1950, 190.