A catalytic aldol reaction and condensation through in situ boron "ate" complex enolate generation in water

Article abstract of DOI:10.1002/anie.200704293

(Chemical Equation Presented) Cooperation is key: N-Butyl-1-benzimidazole- 2-phenylboronic acid hydroxide complex catalyzes the aldol condensation and aldol addition between hydroxyacetone or acetone, and different aldehydes in water. The catalytic activity results from cooperative interactions between the boronate complex and the imidazole function. Aldol condensation gives the unsaturated methyl ketones of acetone, whereas aldol addition predominates with hydroxyacetone.

Full text of DOI:10.1002/anie.200704293

Communications
DOI: 10.1002/anie.200704293
Aqueous Catalysis
A Catalytic Aldol Reaction and Condensation through In Situ Boron
Ate” Complex Enolate Generation in Water**
“
Karel Aelvoet, Andrei S. Batsanov, Alexandrea J. Blatch, Christophe Grosjean,
Leonard G. F. Patrick, Christian A. Smethurst, and AndrewWhiting*
The development of new catalytic processes for CÀC bond
formation that can either be carried out in water or are water
tolerant is an important goal in the pursuit of environmentally
aldehyde, thus resulting in aldol products. Herein, we report
preliminary results to show that it is indeed possible to
demonstrate the cooperative effect of intramolecular amine
and boronate functions to generate boron enolate species in
water.
[1]
benign chemical synthesis. Of the water-tolerant catalytic
CÀC bond-forming reactions known, there are several
[
2]
examples of catalytic aldol reactions; however, very few of
A series of bifunctional aminoboronate systems of general
[
3]
[7]
these are mediated by boron enolates. Indeed, the in situ
type 1 were examined for their in situ effectiveness at
[
4]
generation of boron enolates in water is rare. Therefore, we
were interested in determining whether boron enolates could
be generated in situ under aqueous conditions and confirmed,
for example, by trapping with an aldol reaction.
Our goal was to develop a water-based catalytic system
that was capable of generating a boron enolate intermediate
in water. A possibility for generating the intermediate would
be through the cooperative intramolecular interaction
between a basic and a boronate function. The hypothesis is
that deprotonation of a ketone, for example, proximal to a
boronate group, would result in immediate trapping of the
boron enolate by esterification. The potential for success of
such a process is supported by reports from the 1960s in which
cooperation between intramolecular amino and boronic acid
functions was used to achieve catalytic effects. For example,
Letsinger et al. demonstrated rate enhancement in chloro-
enolization of hydroxyacetone and acetone through forma-
tion of the corresponding boron enolate. Ketone enolization
was initially demonstrated by reaction with benzaldehyde to
give the corresponding condensation product(s). Of the
several potential analogues for model aminoboronate catalyst
[
6a]
1 examined, benzimidazolylphenylboronic acid 2a
was
[
5]
[7d]
hydrin hydrolysis. The proposed mechanism involved an
equilibrium-mediated boronic acid esterification process,
inactive. However, its “ate” complex 2b
showed high
catalytic activity in water at 20 mol% for Equation (1); solely
[
6]
followed by intramolecular amine-assisted hydrolysis.
[
7]
Hence, we proposed that aminoboronates and their com-
[
7d]
plexes might have potential as bifunctional catalysts for a
range of reactions, such as in situ generation of boron enolates
and subsequent trapping of the enolate species with an
[
*] K. Aelvoet, Dr. A. S. Batsanov, A. J. Blatch, Dr. C. Grosjean,
L. G. F. Patrick, Dr. A. Whiting
Department of Chemistry
Durham University
Science Laboratories
South Road, Durham, DH1 3QZ (UK)
Fax: (+44)191-384-4737
E-mail: andy.whiting@durham.ac.uk
Dr. C. A. Smethurst
Discovery Research Systems Chemistry
GlaxoSmithKline Pharmaceuticals
Stevenage, Hertfordshire, SG1 2NY (UK)
[
**] We thank the EPSRC for research grants (GR/R24722/01, GR/
S85368/01, and GR/T22759/01) and GlaxoSmithKline Pharma-
ceuticals for a CASE award (to A.R.B.). We also thank Dr. M.
Crampton (Durham University) for helpful discussions and the
EPSRC MS service, Swansea.
aldol adducts 5 were produced with hydroxyacetone (4a) in
high conversion and moderate to high syn selectivity (Table 1,
entries 1–6). In contrast, reactions of aldehydes 3a–d with
acetone (4a; Table 1, entries 7–10) mainly gave condensation
products 6 (aldehydes 3e and 3 f resulted in a complex
mixtures of products). This observed activity of complex 2b
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
768
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Angew. Chem. Int. Ed. 2008, 47, 768 –770

Angewandte
Chemie
Table 1: Product ratios and yields for the aldol reactions outlined in
Equation (1).
cies in the aldol reactions was indeed the boronate complex
b, that is, that the complexdoes not simply act as a source of
2
Entry Aldehyde Ketone Catalyst t [h] Conv. Yield of
Yield of
6 [%]
hydroxide ions. The reactions of benzaldehyde with either
acetone or hydroxyacetone could be followed by HPLC over
time in the presence of either hydroxide ions or catalyst 2b.
Subsequent data analysis showed different kinetic effects
between the two catalysts. The observed rate constants for the
formation of aldol 5 from the reaction of benzaldehyde with
hydroxyacetone catalyzed by hydroxide ions and by complex
[
a]
[b]
[b]
[%]
5 [%]
syn:anti)
[
a]
(
[8]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
3a
3b
3c
3d
3e
3 f
3a
3b
3c
3d
3a
3a
3a
3a
3a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4a
4a
4a
4a
4b
2b
2b
2b
2b
2b
2b
2b
2b
2b
2b
7
7
9
7
7
7
7
7
9
7
7
7
7
7
7
>99 97(2.75:1)
>99 76(5.5:1)
ca. 70 46(2.2:1)
>99 64(1.3:1)
>99 68(2:1)
>99 62(1:0)
>99 19
0
0
0
0
0
À4 À1
À4 À1
2
b were (4.41 Æ 1.18) ” 10
s
and (1.54 Æ 0.27) ” 10 s ,
0
respectively, whereas those for the reaction of benzaldehyde
77
64
81
75
0
–
–
–
99
À4 À1
with acetone were (2.81 Æ 0.16) ” 10
s
and (5.54 Æ 0.53) ”
>99
0
À5 À1
>93 10
>85 10
>99 49(2.3:1)
10 s , respectively (all first order kinetics; see the
Supporting Information). These preliminary results show
that catalyst 2b not only behaves as a true catalyst, but acts
through the cooperative effect of both the boronate-hydrox-
ide complexand benzimidazole group, thus producing an
0
1
3
4
5
6
[
c]
A
B
C
[
d]
<2
<2
<2
>99
–
–
–
0
[
e]
[
f]
D
[9]
[
c]
effect that is perhaps closest to the type II aldolases, but
differing from proline and its relatives because enamine
A
[
10]
1
[
a] Based on crude H NMR data. [b] Yield of isolated products after
formation is not possible. In this case, boron enolate 9 is a
purification by column chromatography using silica gel. [c] Conditions A:
0 mol% aq 16m NaOH. [d] Conditions B: 20 mol% PhB(OH) . [e] Con-
[
11]
likely intermediate in the aldol addition of hydroxyacetone
4a), which is facilitated by transesterification via complex 8
2
2
(
ditions C: 20 mol% aq 16m NaOH and aq PhB(OH) . [f] Conditions D:
2
2
0 mol% aq 16m NaOH, aq PhB(OH) , and 7.
(Scheme 1). The intramolecular imidazole moiety activates
the boronate complextriggering deprotonation and forma-
tion of enolate 9. The resulting aldol addition step, that is
conversion of 9 into 10, is syn-selective because of hydrogen
2
raises the question of the origin of its reactivity, and whether it
acts as a source of hydroxide ions. Significantly, 2b can be
isolated as an analytically pure ate complex(see the
[
12]
bond stabilization of the acyclic-like transition state
in
which the R group of the aldehyde orientates away from the
bulk of the aryl boronate complex.
1
1
Supporting Information) showing a single B NMR chemical
shift at d = 0.3 ppm. Alternatively, 2b can be generated in situ
For the acetone-based aldol, direct deprotonation via 12 is
proposed (Scheme 2) to give enolate 13 which then follows a
similar mechanism to that of hydroxyacetone to give aldol 5
(X = H). Chalcone formation is proposed to occur via
transesterification of catalyst 2b, deprotonation (15), and
elimination via intermediate 16. Hence, the use of boronate
complex 2b potentially obviates the need for preactivation of
[7e]
in water from the corresponding boroxine (d = 19.7 ppm)
by the addition of three equivalents of sodium hydroxide,
1
1
which gives an identical B NMR spectrum with no signal
corresponding to uncomplexed boronic acid (d =
[
7e]
3
2.8 ppm).
The in situ generation of 2b can be directly
used to produce identical catalytic effects. Therefore, several
reactions were carried out (Table 1, entries 11–16) to address
the origin of the catalytic effect of complex 2b.
The discrete catalytic effect of 2b in
[3,4]
an enolate precursor
to generate a boron enolate. The
intramolecular benzimidazole activation in complex 2b is
the aldol reactions was supported by the
following observations 1) using 20%
NaOH alone (Table 1, entries 11 and
1
6) produced similar results to using
complex 2b; 2) both phenylboronic acid
(
(
entry 13) and its hydroxide ate complex
entry 14) were ineffective catalysts; 3) a
mixture of phenylboronic acid hydroxide
ate complexand phenyl benzimidazole 7
was also ineffective (entry 15). Indeed,
exactly the same results were obtained
when using acetone and benzaldehyde
(
entries 13–15). Hence, the reactivity of
catalyst 2b results from the intramolec-
ular interaction between the benzimida-
zole and boronate function, which acti-
vates the ate complex. To confirm if this
activity resulted from hydroxide release,
kinetic studies were carried out which
showed that the catalytically active spe-
Scheme 1. Proposed mechanism of action for catalyst 2b in the aldol addition of hydroxyace-
tone to an aldehyde.
Angew. Chem. Int. Ed. 2008, 47, 768 –770
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
769

Communications
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during transformation of 12 to 13 (Scheme 2).
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Received: September 17, 2007
Revised: October 10, 2007
Published online: December 4, 2007
Keywords: aldol reaction · bifunctional catalysts · boron ·
.
homogeneous catalysis · selectivity
770
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Angew. Chem. Int. Ed. 2008, 47, 768 –770