Benzoin reaction in water as an aqueous medium catalyzed by benzimidazolium salt

Article abstract of DOI:10.1016/j.tetlet.2006.07.153

Benzoin reactions are catalyzed by N,N-dialkylbenzimidazole to yield α-hydroxy ketones; the reaction proceeds in water as an aqueous medium under mild conditions. The utility of these salts as pre-catalysts in these reactions has been demonstrated.

Full text of DOI:10.1016/j.tetlet.2006.07.153

Tetrahedron Letters 47 (2006) 7175–7177
Benzoin reaction in water as an aqueous medium catalyzed
by benzimidazolium salt
Ken-ichi Iwamoto,* Masako Hamaya, Naoki Hashimoto, Hitomi Kimura,
Yumiko Suzuki and Masayuki Sato
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, Shizuoka, Japan
Received 23 June 2006; revised 28 July 2006; accepted 31 July 2006
Available online 17 August 2006
Abstract—Benzoin reactions are catalyzed by N,N-dialkylbenzimidazole to yield a-hydroxy ketones; the reaction proceeds in water
as an aqueous medium under mild conditions. The utility of these salts as pre-catalysts in these reactions has been demonstrated.
Ó 2006 Elsevier Ltd. All rights reserved.
Recently, N-heterocyclic carbenes have received consid-
erable attention in the catalysis of organic reactions.1
There have been several reports dealing with carbene-
catalyzed reactions due to their ability to produce acyl
anion equivalents.2 This feature has been successfully
exploited in numerous catalytic reactions. The a-
hydroxycarbonyl group is an important synthon for
the synthesis of natural products, industrial materials,
and pharmaceutical materials. Among the numerous
synthetic strategies for introducing this moiety, the ben-
zoin reaction and related additions remain, perhaps, the
most direct. The benzoin reaction is catalyzed by the
toxic cyanide ion in its traditional form.3 Several nucleo-
philic carbenes are derived from heterocyclic com-
pounds including thiazole,4 triazole,5 and imidazole,6
which are also employed in this reaction as acyl anion
synthons.
1-N-alkyl-3-methylimidazolium salt was demonstrated
to catalyze the benzoin reaction via a carbene intermedi-
ate.10 However, these pre-catalysts were ineffective for
the benzoin reaction in water as an aqueous medium.
However, we found that 1,3-dipropylbenzimidazolium
bromide 2a catalyzed the benzoin reaction in the pres-
ence of triethylamine (TEA) in water in 43% yield. This
result encouraged us to investigate the limit and scope of
benzimidazolium salts as pre-catalysts for the benzoin
reaction in water.
We report herein that N-heterocyclic carbenes derived
from benzimidazolium salts with one or two long ali-
phatic side chains at the nitrogen atoms in the imidazole
ring catalyze the benzoin reaction to give a-hydroxy
ketones 3 in water as an aqueous medium in moderate
to excellent yields (Scheme 1).
Breslow and Kool7 reported the effect of inorganic salts
on the rate of the cyanide-catalyzed benzoin reactions in
aqueous media. The reaction is 200 times faster in water
than in ethanol. Recently, the use of aqueous media in
organic reactions has been extensively investigated for
synthesis and also for exploiting hydrophobic effect.8
R1
Br
N
N
R2
2
O
O
Ar
OH
Base
2
Ar
H
Ar
H2O, r.t.
base
1
3
In our initial work,9 the benzoin reaction was found to
proceed efficiently when 1,3-dimethylbenzimidazolium
iodide was employed as pre-catalyst in THF or metha-
nol under basic condition. In another study, a simple
R1
N
2
N
R2
*
Scheme 1. Benzoin reaction catalyzed by benzimidazolium salts 2 in
Corresponding author. Tel./fax: +81 54 264 5756; e-mail:
water.
iwamotok@ys7.u-shizuoka-ken.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.153

7176
K. Iwamoto et al. / Tetrahedron Letters 47 (2006) 7175–7177
R1
N
Table 2. Benzoins 3b–k prepared by the self-condensation of aromatic
aldehydes 1b–k (20 mmol) in the presence of pre-catalyst 2e in water
Br
Basea
Time (h)
Yield (%)
N
1
Ar
2 (0.2 eq.)
R2
O
O
TEA
DBU
NaOH
20
20
20
39
79
76
TEA (3.6 mmol)
2
b
H
MeO
OH
3a
H2O (20 mL), r.t., 20 h
1a (20 mmol)
c
TEA
20
70
Me
Scheme 2. Benzoin reaction of 1a catalyzed by benzimidazolium salts 2
in water.
d
e
TEA
DBU
3
3
71
91
F
Table 1. Benzoin reaction catalyzed by benzimidazolium salts (2a–g)
in the presence of TEA in water
TEA
20
81
Cl
Catalyst
Yield (%)
1a: Recovery (%)
f
TEA
DBU
20
20
—
—
O2N
2
R1
R2
a
b
c
d
e
f
(CH2)2Me
Me
Me
Me
(CH2)11Me
Me
(CH2)2Me
(CH2)2Me
(CH2)3Me
(CH2)11Me
(CH2)11Me
Me
43
45
76
99
98
—
—
22
15
—
—
—
80
73
g
h
TEA
DBU
20
20
—
—
Me2N
DBU
2
78
O
S
g
Et
Et
i
DBU
1
62
First, we examined the benzoin reaction of benzalde-
hyde 1a in water with benzimidazolium salts 2 in the
presence of triethylamine (TEA) as a base; the reaction
produces N-heterocyclic carbenes from benzimidazo-
lium salt (Scheme 2). The results are summarized in
Table 1. Pre-catalysts 2a–g were easily prepared from
benzimidazole with a suitable alkyl halide in the usual
manner.
j
DBU
TEA
30
30
43
38
Me
k
Cl
a TEA: 3.6 mmol, DBU: 3.3 mmol, NaOH: 12.5 mmol.
shown in Table 2. The reaction of p-nitrobenzaldehyde
1f, possessing a strong electron-accepting group, and
p-N,N-dimethyl-aminobenzaldehyde 1g, possessing a
strong electron-donating group, failed to proceed in a
manner similar to that with the cyanide ion.12 In the
case of ortho-substituted benzaldehydes 1j and k, the
reaction proceeded with difficulty in comparison with
that of the para-substituted benzaldehydes because of
the steric hindrance, although benzoins were obtained
in low yields.
From the results, with an increase in the number of the
carbon atoms of the N-substituent, it is clear that the
benzoin yield improved. Between the two N-substituents
of the benzimidazole ring, a good correlation is observed
between the number of carbon atoms of the longer sub-
stituent and the benzoin yield. Based on the result, one
of the important factors that contribute to the construc-
tion of the reaction field in an aqueous medium is con-
sidered to be a hydrophobic long N-alkyl chain. The
hydrophobic tails in the pre-catalyst certainly play an
important role in the micelle formation.
The variation of the base required for the formation of
the carbene was also investigated. In this benzoin reac-
tion, TEA (pKa; 10.7), 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) (pKa; 12.0), and NaOH were employed as
bases. TEA and DBU were effective for deprotonating
the benzimidazolium salt in a self-condensation reaction
involving various aromatic aldehydes. NaOH was also
found to be effective. However, in the case where NaOH
is employed in a benzoin reaction in THF, it has been
reported that NaOH tends to cause the benzoins formed
in the reaction to precipitate as their sodium salts re-
tards any further reaction.13 In our examination, NaOH
proved to be an excellent base, and there was no indica-
tion that the reaction was retarded by NaOH under our
reaction conditions.
The preparation of various benzoins 3 by the self-con-
densation of aromatic aldehydes 1 catalyzed by benzim-
idazolium salt 2e was examined (Scheme 3).11
The results are summarized in Table 2. In the presence
of 2e, the benzoin reaction of fluoro, chloro, methyl,
and methoxy para-substituted benzaldehydes proceeded
to give the corresponding benzoins 3 in good yields, as
O
catalyst 2e (0.2 eq.)
base
O
Ar
Ar
Ar
H
H2O (20 mL), r.t.
OH
3b - k
1b - k
Next, we examined the turnover numbers (TONs) of 2e
in the self-condensation of 1a (20 mmol) in water
Scheme 3. Benzoin reaction catalyzed by benzimidazolium salts 2e in
water.

K. Iwamoto et al. / Tetrahedron Letters 47 (2006) 7175–7177
7177
Table 3. TONs of 1,3-didodecylbenzimidazolium pre-catalyst 2e in the
self-condensation reaction of 1a in water
the nitrogen atoms. a-Hydroxy ketones are obtained
throughout in moderate to excellent yields without fur-
ther purification. These catalysts are easy to prepare,
stable, and easy to handle. Benzimidazolium salt 2e is
currently the most efficient pre-catalyst for the synthesis
of a-hydroxy ketones in aqueous media under mild basic
conditions. Moreover, its utility aparently increases
from the viewpoint of green chemistry. This provides a
new insight for the catalytic utility of benzimidazolium
salts.
2e (mmol)
3a: Yield (%)
1a: Recovery (%)
Turnover
0.02
0.04
0.06
0.1
—
—
68
98
96
77
94
13
Trace
Trace
—
—
113
98
48
0.2
(20 ml). In this reaction, NaOH (12.5 mmol) was em-
ployed as the base. The results are summarized in Table
3. The benzoin reaction proceeded quantatively in the
case of 5 mol % loaded pre-catalyst 2e. Low loading
(0.3 mol %) of 2e resulted in a 68% yield of benzoin 3a
and 13% recovery of 1a. Moderate TONs suggest that
the partial decomposition of a pre-catalyst proceeds
concomitantly to yield an inactive catalyst. The so-called
‘Wanzlick equilibrium’14 demonstrates that benzimi-
dazolium salts having sterically less demanding substitu-
ents like methyl or ethyl moieties favor the formation of
tetraaminoethylene 4, whereas sterically demanding sub-
stituents shift the equilibrium toward free carbene 5.
This report suggests that benzimidazolium salt 2e tends
to exist as a free carbene and hence the free carbene is
likely to oxidize during a long reaction time (Scheme
4). In fact, the oxidized compound 1H-benzo[d]imi-
dazol-2(3H)-one 6 was obtained from the reaction mix-
ture of the benzoin reaction where pre-catalyst 2e was
used in water. The precise mechanism of the deactiva-
tion mechanism of the catalyst was not investigated.
References and notes
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The reusability of pre-catalyst 2e in water was briefly
investigated. The filtrate, obtained as described in a typ-
ical procedure for benzoin reactions11 was recycled. The
filtrate containing catalyst was employed for the next
reaction. In this reaction, NaOH was employed as the
base. The results are summarized in Table 4.
In conclusion, we have presented the first benzoin reac-
tion in water as an aqueous medium, catalyzed by N-
heterocyclic carbenzenes derived from the benzimidazo-
lium salts with one or two long aliphatic side chains at
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R
R
R
R
R
R
H
N
N
N
N
N
N
N
2
O
N
H
11. Typical procedure for benzoin reactions catalyzed by
benzimidazolium salts, as exemplified for using 2e as the
pre-catalyst: Benzaldehyde 1a (2.12 g, 20.0 mmol) was
added water (20 mL). To the mixture was added N,N-
dialkylbenzimidazolium pre-catalyst 2e (4.0 mmol) and
0.5 mL of triethylamine (3.6 mmol) was added under
vigorous stirring. The reaction mixture was stirred for 20 h
at room temperature. Benzoin 3a was filtered, washed with
water, and dried in open air. In the case of unsatisfied
purity, the purification by column chromatography (SiO2,
hexane–AcOEt = 5:1) was employed.
5
6
4
Scheme 4. The ‘Wanzlick equilibrium’ and the formation of 1H-
benzo[d]imidazol-2(3H)-one 6 as deactivated pre-catalyst 2e.
Table 4. Reuse of pre-catalyst 2e (4 mmol) in the benzoin reaction of
1a (20 mmol) in the presence of NaOH (12.5 mmol)
Reuse number
Time (h)
3a: Yield (%)
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14. Bohm, V. P. W.; Herrmann, W. A. Angew. Chem., Int. Ed.
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0
1
2
3
3
3
17
72
99
99
92
85