Chiral imidazoles and imidazole N-oxides as ligands for stereoselective cyclopropanation reactions

Article abstract of DOI:10.2174/157017812800221735

New, optically active ligands derived from imidazole were tested in the cyclopropanation reaction of styrene using ethyl diazoacetate and copper(I) triflate as a catalyst.

Full text of DOI:10.2174/157017812800221735

Letters in Organic Chemistry, 2012, 9, 89-91
89
Chiral Imidazoles and Imidazole N-Oxides as Ligands for Stereoselective
Cyclopropanation Reactions
Grzegorz Mlostoꢀ* , Paulina Mucha and Heinz Heimgartner*,b
,
a
a,[1]
aUniversity of ꢀódꢁ, Department of Organic and Applied Chemistry, Tamka 12, PL-91-403 ꢀódꢁ, Poland
bUniversity of Zurich, Institute of Organic Chemistry, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
Received May 28, 2011: Revised November 07, 2011: Accepted November 08, 2011
Abstract: New, optically active ligands derived from imidazole were tested in the cyclopropanation reaction of styrene
using ethyl diazoacetate and copper(I) triflate as a catalyst.
Keywords: Cyclopropanation, diazo compounds, imidazole N-oxides, styrene.
INTRODUCTION
The first cyclopropanation reaction, in which styrene and
EDA in a ratio of 4:1 were reacted in the presence of Cu(I)
triflate as a catalyst, was carried out at room temperature
without the addition of a ligand. The progress of the reaction
was monitored by IR spectroscopy and the disappearance of
Cyclopropanation reactions are well known and widely
applied in modern organic synthesis [2]. On the one hand,
diverse cylopropane derivatives are important building
blocks for the preparation of more complex molecules, e.g.
natural products [3], and on the other hand, cyclopropana-
tions are frequently used as test reactions in basic research.
Special attention is focused on stereoselective formation of
the cyclopropane ring, and both diastereoselectivity and
enantioselectivity are of interest [4]. A favorite procedure for
the examination of new chiral ligands is the metal complex
catalyzed cyclopropanation of prochiral olefins with ꢀ-diazo
compounds. The most popular substrates for these reactions
are styrene and its derivatives and ꢀ-diazo esters [4e].
-1
the strong diazo absorption at 2111cm evidenced the
completion of the reaction. The mixture of trans- and cis-2-
phenylcyclopropanecarboxylate 5 was isolated in 60% yield,
and the ratio of the trans- and cis-isomer was established by
1
H-NMR spectroscopy as 2:1 (Scheme 1) (see e.g. [8]).
An analogous experiment performed in the presence of
catalytic amounts (4 mol % relative to EDA used) of the bis-
imidazole 3,3ꢃ-dioxide (S,S)-1a led to a complex mixture of
products. The reaction to give the desired cyclopropane
derivatives occurred smoothly only in the presence of trace
amounts of hydrazine hydrate [9, 10]. After chromato-
graphic workup, the determination of the ee-values for trans-
and cis-5 was carried out by HPLC on a chiral solid phase
In recent times, chiral N-heterocycles and their N-oxides
have attracted attention as ligands for asymmetric synthesis
[
5]. However, there are only a few reports on the application
of imidazoles and imidazole N-oxides [6]. In a series of
recent papers, we reported on the synthesis of differently
substituted, optically active, 2-unsubstituted imidazole 3-
oxides and their conversion into other imidazole derivatives,
e.g. imidazole-2-thiones [7]. To the best of our knowledge,
neither imidazoles nor their N-oxides have been used in
asymmetric cyclopropanation.
(
Chiralcel OD). This method was applied for all studied
ligands (Table 1).
In general, the diastereoisomeric excess (de) observed in
the reactions performed in the presence of the chiral ligands
1-4 was slightly higher than in their absence.
The highest de value (81%) was obtained with (S,S)-1c.
The determined ee-values were rather low, but they were
higher in the case of cis-5 than in trans-5. The best induction
for cis-5 (94% ee) was achieved with the ligand (R,R)-2b.
On the other hand, the highest ee of trans-5 (20%) was
observed in the reaction with (S,S)-1d.
The goal of the present study was to test selected bis-
imidazoles and the corresponding N,Nꢂ-dioxides, derived
from enantiomerically pure trans-1,2-diaminocyclohexane,
as ligands in the Cu(I)-catalyzed reaction of styrene with
ethyl diazoacetate (EDA).
Mixtures of isomeric cyclopropanecarboxylates
5
obtained in the presence of catalytic amounts of catalysts
RESULTS AND DISCUSSION
(
S,S)-1d and (R,R)-2b, respectively, were separated and
The preparation of the chiral ligands 1-4 (Fig. (1)) has
been reported previously [7].
fractions containing analytically pure trans-5 were obtained.
In both cases, the optical rotatory power was measured.
Whereas in the first case the [ꢄ] value was +57 (c 0.2;
D
*
Address correspondence to these authors at the University of ꢁódꢂ,
CHCl
3
3
), in the second case it was –31 (c 0.2; CHCl ). Based
Department of Organic and Applied Chemistry, Tamka 12, PL-91-403
ꢁ
ódꢂ, Poland; Tel: +48 42 635 57 61; Fax: +48 42 665 51 62;
on the literature data for the optical rotation of (1S,2S)-trans-
E-mail: gmloston@uni.lodz.pl
5 ([ꢄ] = +269) and (1R,2R)-trans-5 ([ꢄ] = –279) [12], one
can conclude that in the experiments with (S,S)-1d the first
enantiomer predominated and, in the case of (R,R)-2b used
D
D
University of Zurich, Institute of Organic Chemistry, Winterthurerstrasse
1
6
90, CH-8057 Zurich, Switzerland; Tel: +41 44 635 42 82 , Fax: +41 44 635
8 12; E-mail: heimgart@oci.uzh.ch
1
875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

9
0
Letters in Organic Chemistry, 2012, Vol. 9, No. 2
Mlostoꢀ et al.
O
N
O
N
O
N
R1
R1
R1
N
R1
N
Ph
Me
N
N
N
N
N
N
N
R2
R2
R2
R2
Ph
Ph
Me
*
*
H
Me
Me
H
Ph
1
2
(
S,S)-1a R = R = Me
1
2
(
(
R,R)-2b R = Ph, R = Me
(R)-3
(S)-4
1
2
b R = Ph, R = Me
1
2
S,S)-2c R = Me, R = Ph
1
2
c R = Me, R = Ph
1
2
d R = R = Ph
Fig. (1). Imidazole derived ligands 1-4 used in the study.
CuOTf (4 mol%)
CH Cl , r.t.
Ph
CO Et
2
Ph
CO Et
2
+
N CHCO Et
2 2
Ph
+
2
2
trans-5
Scheme 1. Cyclopropanation of styrene with ethyl diazoacetate (EDA) in the presence of CuOTf.
cis-5
Table 1. Efficiency of Imidazole Ligands 1-4 in the Cyclopropanation Reaction of Styrene Using Ethyl Diazoacetate
Ligand
Yield [%]
trans-5:cis-5
ee trans-5 [%]
ee cis-5 [%]
(
S,S)-1a
52
34
60
50
48
29
41
54
3:1
2.3:1
4.4:1
2:1
-
4
-
(S,S)-1b
31
34
40
94
34
-
(
S,S)-1c
S,S)-1d
R,R)-2b
S,S)-2c
R)-3
S)-4
2
(
20
14
8
(
2.5:1
2.3:1
3:1
(
(
-
(
3:1
1
4
as a catalyst, the second enantiomer was the major
component.
metal
catalyzed
cyclopropanation
reactions
with
diazoacetates and styrene [4e]. To the best of our knowledge,
the presented ligands are the first imidazole derivatives
tested in the cyclopropanation reaction. In spite of the
relatively modest selectivities observed, the presented results
are encouraging for further modifications of the substitution
pattern in chiral imidazole derivatives.
CONCLUSIONS
The cyclopropanation reaction of styrene with EDA in
the presence of CuOTf and catalytic amounts of hydrazine
was studied in order to test the efficiency of chiral imidazole
derivatives as ligands with respect to the stereoselectivity of
the process. In comparison with the ‘ligand-free’ reaction,
the de-value in favour of trans-5 in general increased
slightly, and in the case of (S,S)-1c achieved the value of
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