Enantioselective synthesis of aziridines from imines and alkyl halides using a camphor-derived chiral sulfide mediator via the imino Corey-Chaykovsky reaction

Article abstract of DOI:10.1016/S0040-4039(01)01016-4

Asymmetric one-pot aziridination of imines with alkyl bromides via the imino Corey-Chaykovsky reaction mediated by chiral sulfide is described. The desired aziridines are obtained in good yields with up to 98% ee of the trans isomer.

Full text of DOI:10.1016/S0040-4039(01)01016-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5451–5454
Enantioselective synthesis of aziridines from imines and alkyl
halides using a camphor-derived chiral sulfide mediator
via the imino Corey–Chaykovsky reaction
Takao Saito,* Masao Sakairi and Daisuke Akiba
Department of Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 27 April 2001; revised 4 June 2001; accepted 8 June 2001
Abstract—Asymmetric one-pot aziridination of imines with alkyl bromides via the imino Corey–Chaykovsky reaction mediated by
chiral sulfide is described. The desired aziridines are obtained in good yields with up to 98% ee of the trans isomer. © 2001
Elsevier Science Ltd. All rights reserved.
Aziridines, particularly optically active aziridines, are
useful and versatile intermediates for the synthesis of a
variety of nitrogen-containing compounds, and various
new synthetic methods for aziridines have been devel-
oped.1,2 The synthetic methods can conceptually be
represented by several approaches,1,2 e.g. the b-amine
ring closure starting from b-amino alcohol or its equiva-
lent (including the Gabriel–Cromwell method), the
replacement of an epoxy oxygen by a nitrogen, the
addition of a nitrogen source (including a nitrene spe-
cies) to an olefin, the addition of a carbenoid to an
imine, the aza Darzens type reaction, the imino Corey–
Chaykovsky type aziridination, and so on. In most of
these cases, metal complexes have been used not only to
promote (catalyze) the reaction but also to control the
regio- and stereo-selectivities as well as in the cases of
epoxides synthesis. Recently, the enantiomeric aziridi-
nation of imines with sulfonium ylides derived from
diazomethanes and sulfides and from sulfonium salts
has been independently reported by Aggarwal’s and
Dai’s groups, respectively.3 In these cases the stereo-
chemical outcome of the aziridination seems to be
significantly dependent upon the substrates sub-
stituents, reaction conditions and chiral sulfides, and
high enantioselectivity is obtained in very limited cases.
Moreover, chiral sulfonium ylide-mediated, enan-
tiomeric aziridination via a one-pot salt method has not
extensively been investigated.1–3
We have previously demonstrated asymmetric epoxida-
tion via the Corey–Chaykovsky reaction using a d-cam-
phor-derived chiral sulfide to show fairly good trans/cis
and enantioselectivities.4 In order to develop highly
enantioselective aziridination and to gain further insight
into the potentiality (applicability) of this chiral sulfide,
we carried out the related imino Corey–Chaykovsky
aziridination (Scheme 1). We report here our results in
this regard.
p-Tol
R1-CH2-Br
OH
R3
H
S
3
H
1
R2
N
H
+
R2CH=NR3
R1
H
base, solvent
4
2
Scheme 1. Enantioselective aziridination via imino Corey–Chaykovsky reaction.
Keywords: asymmetric synthesis; aziridines; aziridination; chiral sulfide.
* Corresponding author. Fax: +81 (0)3 3235 2214; e-mail: tsaito@ch.kagu.sut.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01016-4

5452
T. Saito et al. / Tetrahedron Letters 42 (2001) 5451–5454
The aziridination was performed in one-pot simply by
stirring a mixture of N-sulfonylimine 2, arylmethyl
bromide 3, chiral sulfide 1,4 and a base in an appropri-
ate solvent at room temperature (Table 1). A model
reaction (run 1) using powdered K2CO3 as a base in
MeCN as a solvent afforded the desired aziridine (4)
quantitatively in a trans:cis ratio of 75:25 with 92% ee
of the trans isomer. The use of Cs2CO3 as a base in the
reaction gave 4 with comparable high stereoselectivities
[trans:cis=76:24 and 94% ee (trans)] albeit in a lower
yield (53%) (run 2). The reactions employing other
bases such as KOH and NaH in MeCN failed. Screen-
ing of several solvents revealed that dry acetonitrile is
the solvent of choice (runs 1, 3 and 4).5 When the
amount of the chiral sulfide (1) added was reduced
(runs 5, 6 and 7 versus run 1), the reaction became
extremely slow (low yield) in each case though high
levels of both selectivities (trans:cis=75:25, 90–92% ee
of trans isomer) were still maintained. When the reac-
tion was carried out at a higher temperature of 82°C in
refluxing MeCN (run 8), the reaction was accelerated (2
h) as expected while the yield (94%) and the stereoselec-
tivities (72:28, 84% ee) were not so markedly decreased.
Table 1 suggests that an electron-withdrawing sub-
stituent R3 such as RSO2-groups (R=p-Tol, Ph, and
Me) on the imine nitrogen is necessary to activate the
CꢀN double bond for the nucleophilic attack by the
sulfonium ylide formed from 1+3 and the base.6 The
N-sulfonyl group-substituted aziridines can be depro-
tected to provide the corresponding N-unsubstituted
aziridines without concomitant ring opening.7 Both
electron-donating and electron-withdrawing sub-
stituents on aromatic groups in either R1 or R2 were
tolerated (runs 9–15).
Dai et al. reported aziridination of sulfonylimines with
some allylic sulfonium ylides (from salts) to give C-
vinylaziridines with moderate trans:cis selectivity, in
which only one example of the enantiomeric version
was included but its enantiomeric excess was not
shown.8 So, we investigated asymmetric aziridination
by applying our chiral sulfide to obtain optically active
styrylaziridine (Scheme 2). The results are summarized
in Table 2. Disappointingly, after efforts, we only
found moderate to low trans:cis ratios and ee’s of both
the trans and cis isomers of 7 albeit in good yield. It is
noteworthy that in MeCN/H2O (run 4), the cis isomer
of 7 is formed selectively (trans:cis=10:90) in contrast
to the other cases of varied solvents (runs 1–3).
In contrast to the above disappointing results, high
enantiomeric induction for both the trans and cis iso-
mers was attained to obtain the same styrylaziridine (7)
when the styrylimine 8 and benzyl bromide (9) were
used (Scheme 3, Table 3). In the presence of even a
catalytic amount of the sulfide 1 (run 5), the reaction in
MeCN still kept up the better high levels of stereoselec-
tivity. To our knowledge, this is the first example of the
catalytic, highly enantioselective one-pot synthesis of
C-vinylaziridine9 in the imino Corey–Chaykovsky
aziridination.
Table 1. Chiral sulfide-induced enantioselective aziridination from imines and arylmethyl bromidesa
Run
R1
Ph
R2
Ph
R3
Yield (%)b
trans:cisc
trans ee (%)c
1
2d
3e
4f
Ts (tosyl)
\99
53
\99
99
91
61
B10
94
87
\99
\99
94
75:25
76:24
70:30
75:25
75:25
75:25
75:25
72:28
74:26
65:35
79:21
63:37
78:22
76:24
67:33
92
94
89
85
92
90
91
84
89
98
89
86
92
92
92
5g
6h
7i
8j
9
p-Tol
p-NO2C6H4
Ph
Ph
Ts
Ts
Ts
Ts
Ts
PhSO2
MeSO2
10
11
12
13
14
15
Ph
Ph
Ph
Ph
Ph
p-Tol
p-MeOC6H4
p-ClC6H4
Ph
86
84
79
Ph
a Reactions were run using imine 2 (0.1 mmol), bromide 3 (0.3 mmol), sulfide 1 (0.1 mmol) and K2CO3 (0.3 mmol) in MeCN (5 cm3) at room
temperature for 1–2 days unless otherwise specified.
b Isolated yield.
c Determined by HPLC [Chiralcel OD, ethanol-hexane (1:20)]. The aziridines had a negative optical rotation (in CHCl3) and the absolute
configuration was assumed as [S,S] by correlation to epoxidation.
d Cs2CO3 was used as a base.
e CH2Cl2 was used as a solvent, time being for 4 days.
f t-BuOH was used as a solvent, time being for 3 days.
g 0.5 equiv. sulfide 1 was used.
h 0.2 equiv. sulfide 1 was used, time being for 4 days.
i 0.1 equiv. sulfide 1 was used, time being for 1 week.
j At 82°C for 2 h.

T. Saito et al. / Tetrahedron Letters 42 (2001) 5451–5454
5453
p-Tol
PhCH=N-Ts
OH
5
H
S
+
Ts
N
H
1 (1.0 equiv)
Ph
Br
Ph
Ph
6
K2CO3, r.t., 1-2 days
7
Scheme 2. Enantioselective aziridination of N-tosylimine with cinnamyl bromide.
Table 2. Aziridination of N-tosylimine with cinnamyl bromide to afford styrylaziridine
Run
Solvent
Yielda (%)
trans:cisa
ee (%)a
trans
cis
1
2
3
4
CH2Cl2
99
77
99
52
52:48
42:58
54:46
10:90
38
32
42
21
17
8
21
7
t-BuOH
MeCN
MeCN/H2Ob
a See corresponding footnotes in Table 1.
b Ratio v/v 9:1, time for 6 h.
p-Tol
OH
Ph
N-Ts
+
H
S
8
Ts
N
H
1 (n equiv.)
Ph-CH2-Br
Ph
Ph
9
K2CO3, r.t., 1-3 days
7
Scheme 3. Enantioselective aziridination of cinnamylidene-N-tosylimine with benzyl bromide.
Table 3. Aziridination of cinnamylidene-N-tosylamine with benzyl bromide to afford styrylaziridine
a
Run
Solvent
n (equiv.)
Yielda (%)
trans:cis
ee (%)a
trans
cis
1
2
3
CH2Cl2
t-BuOH
MeCN
1.0
1.0
1.0
0.5
0.1
69
50
99
73
52
63:37
48:52
75:25
80:20
74:26
85
78
94
93
93
91
75
84
88
87
4
5b
a See corresponding footnotes in Table 1.
b Time being for a week.
In conclusion, we have demonstrated stereoselective
imino Corey–Chaykovsky reaction by solid–liquid
phase transfer one-pot procedure to give optically
active aziridines with high enantiomeric excess. More-
over, the chiral sulfide was recovered optically pure
almost quantitatively after the reaction, and could be
reused repeatedly. Further studies on the scope and
limitation of this process are in progress.

5454
T. Saito et al. / Tetrahedron Letters 42 (2001) 5451–5454
Tardella, P. A.; Tofani, D. Tetrahedron 2000, 56, 4515; (i)
Acknowledgements
Ohno, H.; Toda, A.; Takemoto, Y.; Fujii, N.; Ibuka, T. J.
Chem. Soc., Perkin Trans. 1 1999, 2949; (j) Chemla, F.;
Hebbe, V.; Normant, J. F. Tetrahedron Lett. 1999, 40,
8093; (k) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy,
G. V.; Zhang, Y. J. Org. Chem. 1999, 64, 7559; (l) Antilla,
J. C.; Wulff, W. D. J. Am. Chem. Soc. 1999, 121, 5099; (m)
Wright, D. L.; McMills, M. C. Org. Lett. 1999, 1, 667; (n)
Aggarwal, V. K.; Stenson, R. A.; Jones, R. V. H.; Field-
house, R.; Blacker, J. Tetrahedron Lett. 2001, 42, 1587; (o)
Yang, K.-S.; Chen, K. J. Org. Chem. 2001, 66, 1676; (p)
Hanessian, S.; Cantin, L.-D. Tetrahedron Lett. 2000, 41,
787.
This work was supported by Grant-in-Aid for Scientific
Research from the Ministry of Education, Science,
Sports and Culture (Project No. 10640531).
References
1. For reviews on aziridines, see (a) Kemp, J. E. G. In
Comprehensive Organic Synthesis; Trost, B. M.; Fleming,
I., Eds.; Oxford: Pergamon, 1991; Vol. 7, pp. 467–513; (b)
Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599; (c)
Pearson, W. H.; Lian, B. N.; Bergmeier, S. C. In Compre-
hensive Heterocyclic Chemistry II, Katritzky, A. R.; Ree,
C. W.; Scriven, E. F.; Padwa, A. Eds.; Oxford: Pergamon,
1996; Vol. 1A, p. 1; (d) Rai, K. M. L.; Hassner, A. In
Comprehensive Heterocyclic Chemistry II, Katritzky, A.
R.; Ree, C. W.; Scriven, E. F.; Padwa, A. Eds.; Oxford:
Pergamon, 1996; Vol. 1A, p. 61; (e) Ibuka, T. Chem. Soc.
Rev. 1998, 27, 145; (f) Atkinson, R. S. Tetrahedron 1999,
55, 1519; (g) Osborn, H. M. I.; Sweeney, J. Tetrahedron:
Asymmetry 1997, 8, 1693; (h) Padwa, A.; Murphree, S. S.
In Progress in Heterocyclic Chemistry, Gribble, G. W.;
Gilchrist, T. L., Eds.; Oxford: Pergamon Elsevier Science,
2000; Vol. 12, Chapter 4.1, pp. 57–76; (i) Li, A.-H.; Dai,
L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97, 2341.
2. For recent papers on racemic and non-racemic aziridine
synthesis, see: (a) Juhl, K.; Harzell, R. G.; Jørgensen, K.
A. J. Chem. Soc., Perkin Trans. 1 1999, 2293; (b)
Minakata, S.; Ando, T.; Nishimura, M.; Ryu, I.;
Komatsu, M. Angew. Chem., Int. Ed. 1998, 37, 3392; (c)
Kubo, T.; Sakaguchi, S.; Ishii, Y. J. Chem. Soc., Chem.
Commun. 2000, 625; (d) Hori, R.; Aoyama, T.; Shioiri, T.
Tetrahedron Lett. 2000, 41, 9455; (e) Atkinson, R. S.;
Meades, C. K. Tetrahedron Lett. 2000, 41, 7769; (f) Sen-
gupta, S.; Mondal, S. Tetrahedron Lett. 2000, 41, 6245; (g)
Hori, K.; Sugihara, H.; Ito, Y. N.; Katsuki, T. Tetra-
hedron Lett. 1999, 40, 5207; (h) Fazio, A.; Loreto, M. A.;
3. (a) Aggarwal, V. K.; Thompson, A.; Jones, R. V. H.;
Standen, M. C. H. J. Org. Chem. 1996, 61, 8368; (b) Li,
A.-H.; Zhou, Y.-G.; Dai, L.-X.; Hou, X.-L.; Xia, L.-J.;
Lin, L. Angew. Chem., Int. Ed. 1997, 36, 1317; (c) Li,
A.-H.; Zhou, Y.-G.; Dai, X.-L.; Hou, X.-L.; Xia, L.-J.;
Lin, L. J. Org. Chem. 1998, 63, 4338.
4. Saito, T.; Akiba, D.; Sakairi, M.; Kanazawa, S. Tetra-
hedron Lett. 2001, 42, 57. The chiral sulfide was readily
prepared optically pure from a-methylenecamphorthione
via hetero Diels–Alder cycloaddition, followed by LiAlH4-
reduction and hydrogenation of the cycloadduct.
5. Reactions in solvents such as THF, DMF and acetone
failed, and wet solvents deteriorate the imine by hydrolysis
during prolonged reaction.
6. Almost no aziridination was observed with imines bearing
other substituents in R3 such as aromatic, alkyl and tosyl-
hydrazinyl groups under similar reaction conditions.
7. Bergmeier, S. C.; Seth, P. P. Tetrahedron Lett. 1999, 40,
6181 and references cited therein.
8. (a) Li, A.-H.; Dai, L.-X.; Hou, X.-L. J. Chem. Soc., Perkin
Trans. 1 1996, 867; (b) Li, A.-H.; Dai, L.-X.; Hou, X.-L.;
Chen, M.-B. J. Org. Chem. 1996, 61, 4641.
9. Recently, a new route to racemic and optically active
alkenylaziridines using a nitridomanganese complex and
conjugated dienes has been reported: Nishimura, M.;
Minakata, S.; Thongchant, S.; Ryu, I.; Komatsu, M.
Tetrahedron Lett. 2000, 41, 7089.
.