Synthesis of new enantiomerically pure C1- and C 2-symmetric N-alkyl-benzimidazolium and thiazolium salts

Article abstract of DOI:10.1016/j.tetasy.2003.09.050

Starting from the commercially available enantiopure (1S,2S)-2-amino-1- phenyl-1,3-propanediol novel enantiomerically pure benzimidazoles were prepared; N-alkylation gave chiral benzimidazolium salts, which were tested in asymmetric benzoin condensations.

Full text of DOI:10.1016/j.tetasy.2003.09.050

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 3827–3830
Synthesis of new enantiomerically pure C1- and C2-symmetric
N-alkyl-benzimidazolium and thiazolium salts
Simonetta Orlandi, Marinella Caporale, Maurizio Benaglia* and Rita Annunziata
Dipartimento di Chimica Organica e Industriale, Universita’ degli Studi di Milano, Via Golgi 19, I-20133 Milano, Italy
Received 12 September 2003; accepted 22 September 2003
Abstract—Starting from the commercially available enantiopure (1S,2S)-2-amino-1-phenyl-1,3-propanediol novel enantiomerically
pure benzimidazoles were prepared; N-alkylation gave chiral benzimidazolium salts, which were tested in asymmetric benzoin
condensations. The synthesis of conceptually new, enantiomerically pure, C2 symmetric bis-thiazolium and bis-benzimidazolium
salts was also developed. These new chiral heterocycles were employed as catalysts in the asymmetric dimerisation of benzaldehyde
to give benzoin with moderate enantioselectivity.
© 2003 Elsevier Ltd. All rights reserved.
Thiazolium-catalyzed additions of acyl anions to alde-
hydes or imines are reactions of great synthetic rele-
vance. The benzoin condensation1,2 (between two
aldehydes) and the Stetter reaction3 (between an alde-
hyde and a Michael acceptor) are two examples of this
type of transformation, which leads to highly function-
alized products, with the formation of a new stereocen-
ter. The generally accepted mechanism of the benzoin
condensation is shown in Figure 1. Since 1966, when
Sheehan et al. reported for the first time the use of an
enantiopure alkyl thiazolium salt in the self-condensa-
tion of benzaldehyde,4,5 several differently substituted
chiral thiazolium salts have been prepared and tested,
always showing moderate enantioselectivity (up to 57%
ee).6–11 A common feature of all these catalysts is the
presence of a chiral group attached to the nitrogen
atom of the thiazole; the conformational freedom of
such a group makes it difficult to predict which face of
intermediate C would be shielded, and is responsible for
the low stereoselection (Fig. 1).
Figure 1. Mechanism of thiazolium salt catalyzed benzoin condensation.
* Corresponding author. Tel.: ++39/02/50314171; fax: ++39/02/50314159; e-mail: maurizio.benaglia@unimi.it
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.09.050

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S. Orlandi et al. / Tetrahedron: Asymmetry 14 (2003) 3827–3830
A breakthrough in the field was obtained by Enders in
1995, via the use of the chiral 1,2,4-triazolium salt 1 as
a catalyst for the dimerisation of benzaldehyde, to
afford the corresponding benzoin in 66% yield and 75%
ee (Fig. 2).12,13 Comparable enantioselectivities were
later obtained by Knight and Leeper, by employing the
bicyclic triazolium salt 2.14 The comparison between the
enantiomeric excess obtained with 2 (80% ee) and a
similar, bicyclic thiazolium salt 3 (20.5% ee) seems a
clear indication of the importance of the N-aryl ring in
determining the stereochemical outcome of the reac-
tion. In 2 it is possible that the benzyl group at the
stereocenter preferably shields one side of the interme-
diate C in Figure 1, with the N-phenyl playing a
decisive role, in pre-orienting the approach and the
attack of the second molecule of aldehyde.
enantiomerically pure (1S,2S)-2-amino-1-phenyl-1,3-
propanediol 6 was reacted with ortho-fluoro nitroben-
zene, in the presence of potassium carbonate in
aqueous ethanol for 60 h to give 7 in 57% non opti-
mized yield; reduction of the nitro group followed by
the reaction with formic acid gave the benzimidazole 8
in 65% overall yield.17 Protection of the diol with
2,2-dimethoxypropane afforded 9. Alkylation with
iodomethane in acetonitrile gave the enantiomerically
pure N-methyl-benzimidazolium salt 10 in 95% yield.18
The ability of these chiral salts to act as a catalyst in
asymmetric benzoin reaction of benzaldehyde was then
investigated. Optimal reaction conditions were estab-
lished by preliminary experiments carried out with the
achiral salt 11 (Scheme 1). Selected data are shown in
Table 1. The N-methyl salt 11 promoted the reaction as
well in THF with DBU (entry 1), or NaH (entry 2), as
in methanol with DBU (entry 3) or NaOH 50% (entry
4). Having established that N-methyl benzimidazolium
salts were efficient catalysts, the activity of the chiral
salt 10 was investigated.19 Unfortunately 10 proved to
be less reactive than 11, as it did not catalyze the
reaction in the previously explored conditions (see for
example entry 5 versus 1). The best result obtained was
by using 5 mol% of the catalyst, in the presence of NaH
as base in THF; in these conditions the benzoin was
obtained in 31% yield after 2 h reaction at 60°C, as a
racemic mixture.
However catalyst 1 was unstable because of degrada-
tion due to competing deprotonation at the 3-position,
to irreversibly give an N-cyanobenzamidine, via triazole
ring opening.13 In order to solve the problem, we
decided to investigate the catalytic activity of chiral
N-alkyl benzimidazolium salts, structurally inspired by
catalyst 1 and in which degradation is not possible.
Recently Enders has developed the new chiral tri-
azolium salts 415 which are able to promote asymmetric
benzoin condensation with enantiomeric excesses up to
93%. A similar bicyclic triazolium salt 516 has also been
described as very efficient catalyst for intramolecular
Stetter reactions (ee up to 97%) (Fig. 2). Prompted by
these works, we report herein the synthesis of C1 and
C2 symmetric, conceptually new, chiral benzimida-
zolium and thiazolium salts and preliminary studies on
their catalytic activity.
Disappointed by the modest reactivity and enantiose-
lectivity shown by these catalysts, we decided to explore
the behavior of completely new chiral salts. Thus, the
synthesis of C2-symmetric enantiomerically pure salts
containing a stereogenic axis as stereochemical element
able to control the outcome of the reaction was
attempted (Scheme 2).
The synthesis of a chiral benzimidazolium salt is
described in Scheme 1. The commercially available
Figure 2. Chiral thiazolium and triazolium salts.

S. Orlandi et al. / Tetrahedron: Asymmetry 14 (2003) 3827–3830
3829
Scheme 1. Synthesis of new chiral salt 10.
Table 1. Benzoin reaction catalyzed by 5% mol of new N-alkyl benzimidazolium salts
Entry
Catalyst
Solvent
Base
T (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
11
11
11
11
10
10
10
THF
THF
DBU
NaH
DBU
NaOH 50%
DBU
65
65
65
25
65
65
65
2
2
2
20
20
20
2
41
93
42
48
–
MeOH
MeOH
THF
DCM
THF
BEMP
NaH
5
31
(R)-6,6%-Dimethylphenyl-2,2%-dicarboxylic acid 1220 was
reduced with LiAlH4 to give the corresponding diol 13
in 83% yield; the reaction with phosphorus tribromide
afforded dibromide 14 in 81% yield. Treatment of 14 with
N-benzyl-benzimidazole in acetonitrile at 60°C for 40 h
afforded the enantiopure bis-(N-benzylbenzimida-
zolium) salt 15. Analogously, treatment of 14 with
(4-methyl-5-thiazolyl)-2-ethanol 16 in acetonitrile gave
the corresponding chiral bis-(N-benzyl-thiazolium) salt
17 in its enantiomerically pure form.18
the reaction in methanol, in the presence of triethyl-
amine as base, to give after 4 h reaction at 60°C the
product in 40% yield, with modest enantioselectivity
(15% ee).21
In conclusion new enantiomerically pure catalysts for the
benzoin condensation have been prepared, including, for
the first time, C2-symmetric bis-(N-alkyl benzimida-
zolium) and bis-(N-benzyl-thiazolium) salts. These con-
ceptually new chiral heterocycles were tested as catalysts
in the asymmetric dimerisation of benzaldehyde to give
benzoin in moderate yield and enantioselectivity. Further
experiments are currently in progress to modify the
structure of the chiral salt in order to improve the
chemical and the stereochemical efficiency of the catalyst.
Preliminary experiments have demonstrated that while
15 is not an efficient catalyst for benzoin condensation,
the bis thiazolium salt is able to promote the dimerisation
of benzaldeyhde. For instance, 5% mol of 17 catalyzed

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S. Orlandi et al. / Tetrahedron: Asymmetry 14 (2003) 3827–3830
Scheme 2. Synthesis of new C2-symmetric salts 15 and 17.
Acknowledgements
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2925–2928.
Financial support by MIUR (Progetto Nazionale
Stereoselezione in Sintesi Organica. Metodologie ed
Applicazioni) is gratefully acknowledged.
12. Teles, J. H.; Melder, J.-P.; Ebel, K.; Schneider, R.; Gehrer,
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79, 1217–1221.
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