Facile asymmetric synthesis of aziridine derivatives via the diastereoselective reaction of chiral imines with dimethylsulfonium methylide

Article abstract of DOI:10.3987/COM-02-S(M)32

A simple method for the synthesis of chiral 2-substituted aziridine derivatives is described. The reaction pathway consists of the diastereoselective addition of dimethylsulfonium methylide to chiral imines derived from (R)-phenylglycinol and various aldehydes.

Full text of DOI:10.3987/COM-02-S(M)32

HETEROCYCLES, Vol. 58, 2002, pp. 85-88, Received, 26th March, 2002
FACILE ASYMMETRIC SYNTHESIS OF AZIRIDINE DERIVATIVES
VIA THE DIASTEREOSELECTIVE REACTION OF CHIRAL IMINES
WITH DIMETHYLSULFONIUM METHYLIDE**
Kimio Higashiyama,* Masataka Matsumura, Ayako Shiogama,
Takayasu Yamauchi, and Sigeru Ohmiya
Institute of Medicinal Chemistry; Hoshi University, Ebara 2-4-41,
Shinagawa-ku, Tokyo 142-8501, Japan
E-mail: kimio@hoshi.ac.jp
Abstract- A simple method for the synthesis of chiral 2-substituted aziridine
derivatives is described. The reaction pathway consists of the diastereoselective
addition of dimethylsulfonium methylide to chiral imines derived from
(R)-phenylglycinol and various aldehydes.
Chiral aziridine derivatives are of interest not only for theoretical reasons but also because of their high
reactivity arising from the release of strain energy inherent in a small ring. Use of reactive aziridine
derivatives as intermediates in the asymmetric synthesis of several classes of compounds has been widely
explored,1 and many preparative methods have been developed for their synthesis.2 Among various
synthetic methods for chiral aziridine derivatives, one of most promising is aziridination through the
reaction of a chiral imine with a sulfur ylide3 which involves stereocontrolled nucleophilic addition as the
first step, followed by intramolecular nucleophilic substitution. However, the ylide methodologies can be
applied only to an activated imine, that is, to the C=N double bonds with an N-electron withdrawing group
such as p-tolylsulfonyl.4 This is a severe limitation of this methodology, especially because harsh
conditions are generally required to cleave the strong sulfonamide bond. Despite recent advances, the tosyl
group remains difficult to be removed from a sensitive substrate.
Ph
Ph
R
Ph
R
Ph
N
N
M–R'
S–ylide
HN
*
N
OCH3
S
OCH3
OCH3
*
H
OCH3
Aziridine
*
R
R'
R
H
Imine
Scheme 1
We recently showed that chiral imines prepared from (R)-O-methylphenylglycinol (1)5 and aldehydes react
** This paper is dedicated to the celebration of the 70th birthday of Professor A. I. Meyers.

with organometallic reagents in a stereoselective manner.6 These findings provided the possibility for a
reaction of chiral imines (non-activated imines) with dimethylsulfonium methylide in place of
organometallic reagents to produce chiral aziridine derivatives. Herein, we report a simple method for the
synthesis of chiral 2-substituted aziridine derivatives from various chiral imines and dimethylsulfonium
methylide.
First, the starting chiral imines (2a-n) were prepared as follows. Condensation of several aliphatic
aldehydes (ethanal, propanal, butanal, 2-methylpropanal, 2,2-dimethylpropanal, and 3-methyl-2-butenal)
with 1 in CH2Cl2 in the presence of anhydrous MgSO4 gave sensitive chiral imines (2a-f). Fluoral and
aromatic aldehydes (4-trifluoromethylbenzaldehyde, 4-chrolobenzaldehyde, benzaldehyde, 4-tolualdehyde,
3-anisaldeyhde, 4-anisaldeyhde, and veratraldeyhde) gave chiral imines (2g-n) in quantitative yields when
heated in toluene with azeotropic removal of water. Reaction of chiral imines (2a-n) with an excess
amount of dimethylsulfonium methylide prepared from trimethylsulfonium iodide in THF with 1 equiv. of
n-butyllithium at 0°C,7 gave the desired aziridine derivatives (3a-n) in moderate to good yields with high
diastereomeric excesses. The experimental results are presented in Table 1.
Ph
Ph
Ph
CH2S(CH3)2
THF, HMPA
RCHO
N
N
H2N
OCH3
3a-n
OCH3
OCH3
R
R
1
2a-n
Table 1. Synthesis of chiral aziridines (3a-n)8
R
product
ratio of S-3 : R-3a) yield of 3 (%)
[α]D of S-3b)
-63.1° (1.00)
-72.6° (1.17)
-50.3° (1.02)
-81.3° (1.00)
-54.4° (1.00)
-64.4° (1.11)
-70.1° (1.00)
CH3
CH2CH3
a
b
c
d
e
f
> 99 : < 1
> 99 : < 1
> 99 : < 1
> 99 : < 1
> 99 : < 1
91.3 : 8.7
91.6 : 8.4
95.6 : 4.4
93.3 : 6.7
95.4 : 4.6
91.9 : 8.1
91.9 : 8.1
94.1 : 5.9
90.4 : 9.6
79.1
81.0
91.7
81.4
90.1
78.4
71.1
84.0
64.0
89.0
67.0
69.0
67.0
61.0
CH2CH2CH3
CH(CH3)2
C(CH3)3
CH=C(CH3)2
CF3
g
h
i
p-C6H4CF3
p-C6H4Cl
+128.4° (1.05)
+164.8° (1.06)
+127.6° (1.15)
+143.7° (1.04)
+125.1° (1.09)
+138.5° (1.00)
+119.0° (1.02)
C6H5
j
p-C6H4CH3
m-C6H4OCH3
p-C6H4OCH3
m,p-C6H3(OCH3)2
k
l
m
n
a) Estimated by the 1H-NMR (270 MHz) spectral analysis.
b) Specific rotations (c 1.0-1.2, CHCl3).
It was found that with either reaction substrate, the reaction proceeded with a good yield. Generally, in the

reaction of sulfur ylide with imine, yield is high for activated imine, but is low for non-activated imine. In
our case, the reaction proceeded in a good yield even if a non-activated imine was used.
Following experiments were done to examine differences in this reactivity. When the imine (4) having no
oxygen functional group is used for the substrate, the reaction does not occur at all. Furthermore, raw
materials were collected by the reaction in which the imine (5) bearing a sterically bulky oxygen function
was employed as the substrate. These results indicate that an oxygen atom is obviously involved in this
reaction.
Ph
Ph
(CH3)2S-CH2
N
CH3
N
or
No Reaction
OTBDMS
CH3
CH3
4
5
Scheme 2
Moreover, since this reaction does not occur at all when the ylide is produced using NaH or sodium
bistrimethylsilylamide instead of n-butyllithium, the lithium ion appears to play an important role in the
reaction.
Stereoselectivity of these reactions is comparatively excellent. In particular, only one diastereomer was
produced when aliphatic aldehyde was used. We deduced the stereochemistries of newly formed
asymmetric carbons as follows. Reaction of 3a having a aliphatic substituent in the 2 position of aziridine
ring with dimethylcopperlithium in the presence of BF3-O(C2H5)2 gave known optically active 6a as a
single product. Also, reductive ring cleavage of 3b,d resulted in the high yields of known compounds
(6b,d). Thus, on the basis of the known signs of optical rotations and the absolute configurations of
6a,b,d,9 the configurations of 3a,b,d are unambiguously assigned as 2S,1’S. In the case of 3n which had a
aromatic substituent, the structure was verified by X-Ray crystal analysis.
Ph
OCH3
HN
(CH3)2CuLi
BF3O(C2H5)2
CH3
CH3
H
6a
Ph
N
THF
N
1'
OCH3
PtO2
H2
2
Ph
R
OCH3
HN
H
a
d
3
b
CH3
R
6b,d
CH3
i-C3H7
C2H5
R
Scheme 3
Figure. ORTEP drawing of 3n

Taking into account of structural similarity the configurations of the other aziridines are deduced based on
the signs of optical rotations.
An oxygen function of imine and lithium ion seems necessary to explain the mechanism of this reaction.
Thus, the high degree of stereocontrol in this reaction may be attributed to a highly ordered transitional
state resulting from significant chelation of the oxygen atom and imino nitrogen to the lithium atom and
subsequent delivery of the sulfur ylide from the least hindered face of carbon-nitrogen double bond.
Thus, the proposed method appears to be useful for the synthesis of chiral aziridines because, compared
with the results of similar reactions reported in the literatures,10 the chemical and stereoselective outcomes
of the reaction described here were superior. Further studies by our research team on the synthetic aspects
of this reaction are in progress.
REFERENCES AND NOTES
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dropwise over several minutes to a stirred solution of powdered trimethylsulfonium iodide (3.41 g,
16.7 mmol) and HMPA (3.0 g, 16.7 mmol) in 30 mL of dry THF under nitrogen at 0°. After stirring for
20 min, a solution of chiral imine (2c) in 5 mL of dry THF, which was prepared from 1 (1.0 g, 6.7
mmol) and butanal (0.48 g, 6.7 mmol), was added. After stirring for 30 min at 0°, the resulting mixture
was diluted with 30 mL of water and extracted with ether (2 x 30 mL). The combined organic layer
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