Highly stereoselective aziridination of imines with (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide

Article abstract of DOI:10.1016/j.tetlet.2007.03.117

Addition of (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide to N-tosyl imines afforded the corresponding sulfinyl aziridines with full enantio- and diastereoselectivity. The chiral sulfinyl substituent was removed without ring opening leading to enantiop

Full text of DOI:10.1016/j.tetlet.2007.03.117

Tetrahedron Letters 48 (2007) 3907–3910
Highly stereoselective aziridination of imines
with (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide
Wanda H. Midura*
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Department of Heteroorganic Chemistry,
90-363 Lodz, Sienkiewicza 112, Poland
Received 5 January 2007; revised 13 March 2007; accepted 21 March 2007
Available online 25 March 2007
Abstract—Addition of (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide to N-tosyl imines afforded the corresponding sulfinyl azir-
idines with full enantio- and diastereoselectivity. The chiral sulfinyl substituent was removed without ring opening leading to enan-
tiopure 2-substituted aziridines.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Chiral aziridines form an attractive class of compounds,
since they are versatile synthetic intermediates and easily
undergo ring opening reactions with different nucleo-
philes.1 While racemic aziridines are readily available,
procedures for their synthesis in enantiomerically pure
form are limited. An efficient strategy for their synthesis
is the reaction of sulfur ylides with imines. This was
accomplished using optically active sulfinimines in the
reaction with dimethyloxosulfonium methylide de-
scribed independently by Davis and Garcia-Ruano,2
and with dimethylsulfonium methylide as developed by
Stockman.3 In another approach, developed indepen-
dently by the groups of Aggarwal and Dai,4 an asym-
metric process for generating aziridines was mediated
by chiral sulfur ylides.
bon atom. Dimethylsulfonium p-tolylsulfinylmethylide
1 was prepared by methylation of readily available
(ꢀ)-(S)-p-tolyl methylthiomethyl sulfoxide and sub
sequent deprotonation (Scheme 1). Its reaction with
aldehydes gave a,b-epoxy sulfoxides with full enantio-
selectivity and moderate diastereoselectivity.5 A high
facial stereoselectivity was also observed in the reaction
of 1 with vinylic phosphonates leading to cyclopro-
panes.6 Encouraged by these results we decided to apply
ylide 1 to the aziridination of imines.
When ylide 1 was reacted with N-phenyl benzaldimine
no aziridine was produced (entry 1), only starting mate-
rials were recovered. The failure of this attempt was
probably caused by the low reactivity of the imine used
and may be overcome by its activation. It is known that
the presence of a tosyl group on an imine nitrogen en-
hances electrophilicity considerably7 facilitating nucleo-
philic attack by the sulfonium ylide. Indeed, the reaction
Continuing our work on the utilization of optically
active sulfinyl compounds in asymmetric synthesis, we
designed a new type of chiral sulfur ylide, containing
an enantiopure sulfinyl group bonded to the ylidic car-
of (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide
1
O
O
Me
O
S
Me
Me
S
S
MeI/AgBF4
-
S
NaH/MeCN
1 h, r.t.
S
BF4
Me
p-Tol
S
Me
overnight, r.t. p-Tol
p-Tol
α
[ ]D= +285.9 (c 1.2, acetone)
α
[ ]D= +193.3 (c 0.9, acetone)
(S)-1
Scheme 1.
Keywords: Asymmetric reaction; Chiral auxiliaries; Ylides; Aziridination; Sulfoxides.
*
Tel.: +48 42 6803202; fax: +48 42 6847126; e-mail: whmidura@bilbo.cbmm.lodz.pl
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.117

3908
W. H. Midura / Tetrahedron Letters 48 (2007) 3907–3910
Table 1. Aziridination of imines using ylide 1
R2
R2
O
S
Me
Me
N
N
S
+
MeCN
p-Tol
24 h / r.t.
R1
H
R1
3
SOTol-p
2
(S)-1
R2
Entry
Imine
R1
Product
Yield (%)
cis/transa
de (%)
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
Ph
Ph
Ph
Ts
Ts
Ts
Ts
Ts
TolS(O)
3a
3b
3c
3d
3e
3f
n.r.
88
92
93
72
—
—
100:0
100:0
100:0
100:0
100:0
90:10
100
100
100
100
100
100
p-BrC6H4
p-NO2C6H4
n-Bu
i-Pr
Ph
81
76a
2gb
3gc
a Determined by 1H NMR spectroscopy of the crude reaction mixture.
b Racemic sulfinimine.
c Obtained as a mixture of four diastereomers.
with N-tosyl aldimines 2 occurred smoothly affording
the corresponding aziridines in high yields (Table 1).
The aziridination8 was performed simply by the addition
of ylide 1 generated in acetonitrile solution to the appro-
priate imine and stirring the reaction mixture for 24 h at
room temperature. For all the N-tosyl imines (entries 2–
6) the reaction afforded the desired aziridines 3 as single
diastereomers (as seen from 1H NMR spectra of the
crude reaction mixtures).
Next, we performed desulfinylation reactions of N-phen-
yl 2-sulfinyl-3-arylaziridines 3 using different alkyl met-
als (Table 2) under the conditions described by Satoh13
for 2-sulfinyl-2,3-disubstituted aziridines. In contrast to
their results, we observed desulfinylation in each case
as indicated by the presence of signals for RS(O)Tol 6
1
in the H NMR spectra of the crude reaction mixture.
Although only a trace amount of the desired aziridine
3c was detected from the reaction with MeMgI, the
use of EtMgI considerably improved the yield. As
shown in Table 2, the reaction was most effective when
conducted with an excess of methyllithium.
According to the literature, the 3JH–H values of the cou-
pling constants of the aziridine CH signals for trans iso-
mers are smaller (4–5 Hz, dihedral angle 120ꢁ) than for
cis isomers (7–8 Hz, dihedral angle 0ꢁ).9 On this basis,
the cis geometry was assigned to the isomers obtained
of 3 having 3JH–H = 6.3 Hz. This value is consistent with
the 3JH–H = 6.5 Hz value observed for the cis-N-(p-tolu-
enesulfinyl)-2-carbomethoxyaziridines, reported by
Davis et al.10
Desulfinylation of (N-p-toluenesulfonyl-2-p-toluene-
sulfinyl)-3-phenylaziridine 3b was useful for the assign-
ment of absolute stereochemistry, since the absolute
configuration of the resulting (N-p-toluenesulfonyl)-2-
phenylaziridine 5b was firmly established.2,14 Hence,
the absolute configuration of enantiomer 5b obtained
22
(½aꢁD ꢀ65.4 (c 0.9, benzene)) was determined as R. Tak-
It is interesting to note that N-p-tolylsulfinyl imine
reacts with stabilized ylide 1 (entry 7). In this case a
complicated mixture of diastereomers was obtained
due to the presence of an additional stereogenic center
on the N-sulfinyl sulfur atom. Moreover, the reaction
was less stereoselective and 10% of trans-3g was found
in the crude reaction mixture.11 However, oxidation of
isolated cis-3g and N-tosyl analogue cis-3b gave the
same sulfone 4,12 which confirmed the same facial
selectivity in both cases (Scheme 2).
ing into account the cis configuration of 3 obtained in
the aziridination reaction, it is possible to assign the
2S,3R configuration for aziridines 3.
The high facial selectivity observed in the aziridination
reactions can be explained by the reasonable assumption
that ylide 1 adopts the conformation (A), which deter-
mines the stereochemical course of the process. The gen-
erally accepted mechanism for aziridine formation from
sulfur ylides and imines15 with the transoid approach can
be applied (Scheme 3).
Although low cis selectivity was predicted by computa-
tional calculations for stabilized ylides,16 exclusive for-
mation of cis isomers in our case is probably caused
by the difference in the ease of betaine formation. Tran-
sition state T2 leading to an anti betaine is disfavored
due to repulsive interactions between the sulfinyl moiety
of the ylide and the tosyl substituent on nitrogen. This
interaction in T2 must be much stronger than the inter-
action between the sulfinyl group and the R-group of the
Ts
3b
cis-
N
m-CPBA
SO2Tol-p
Ph
3g
cis-
Scheme 2.
-4
(2R,3S)

W. H. Midura / Tetrahedron Letters 48 (2007) 3907–3910
3909
Table 2. Desulfinylation of 2S,3R,SS-(N-p-toluenesulfonyl-2-p-toluenesulfinyl)-3-arylaziridines 3
Ts
N
Ts
N
O
S
RMet
+
Tol-p
R
R1
3
R1
5
SOTol-p
6
Entry
3
Conditions
Yield (%)
5
6
1
2
3
4
5
b
c
b
e
f
MeMgI/ꢀ35 ꢁC/0.5 h
EtMgI/ꢀ35 ꢁC/1.5 h
MeLi/ꢀ70 ꢁC/10 min
MeLi/ꢀ70 ꢁC/10 min
MeLi/ꢀ70 ꢁC/10 min
Trace
60b
75b
76
60a
95
80
83
80
72
a Determined by 1H NMR of the crude reaction mixtures.
b Isolated yield.
Ts
H
H
p-Tol
H
Ts
H
N
p-Tol
Ts
N
N
p-Tol
S
Me
S
Me
S
R
O
R
O
O
Me
R
H
Me
H
A
Ts
N
Tol-p
:
H
H
S
R
O
S
Me
Me
Scheme 3.
tosyl group can be cleaved with sodium naphthalenide,17
the present approach using (S)-dimethylsulfonium-(p-
tolylsulfinyl)methylide appears highly stereoselective
and efficient for the synthesis of 2-substituted aziridines.
T2
T1
Ts
Ts
Tol-p
Tol-p
N
N
:
:
H
R
S
H
H
H
S
R
O
O
Acknowledgements
S
S
Financial support by the Ministry of Education and Sci-
ence (Grant No. 3TO9A 18827) is gratefully acknowl-
edged. The author thanks Professor M. Mikolajczyk
for helpful discussions.
cis
trans
References and notes
Scheme 4.
1. For reviews, see: (a) Tanner, D. Angew. Chem., Int. Ed.
Engl. 1994, 33, 599–619; (b) McCoull, W.; Davis, F. A.
Synthesis 2000, 10, 1347–1365; (c) Sweeney, J. Chem. Soc.
Rev. 2002, 31, 247–258; (d) Cardillo, G.; Glentilucci, L.;
Tolomelli, A. Aldrichim. Acta 2003, 36, 39–50; (e) Lee, W.
K.; Ha, H. J. Aldrichim. Acta 2003, 36, 57–65; (f) Hu, X.
imine in the transition state T1 leading to a syn betaine
(Scheme 4).
In conclusion, the asymmetric synthesis described herein
provides enantiopure aziridines in high yields. Since the

3910
W. H. Midura / Tetrahedron Letters 48 (2007) 3907–3910
E. Tetrahedron 2004, 60, 2701–2743; (g) Yudin, A. K.
J = 6.3 Hz, CHC6H5); 4.32 (1H, d, J = 6.3 Hz, CHS);
7.13 and 7.40 (4H, A2B2 system, Ar); 7.22 and 7.55 (4H,
A2B2, system, Ar); 7.37 and 7.57 (4H, A2B2, system, Ar);
13C NMR (125 MHz, CDCl3) d: 21.5; 21.7; 44.8; 62.6;
123.2; 124.5; 128.2; 129.5; 129.6; 129.7; 129.8; 131.9; 133.1;
137.8; 142.2; 145.3. Anal. Calcd for C22H20BrNO3S2: C,
53.88; H, 4.11; N, 2.86. Found: C, 54.64; H, 4.12; N, 2.99.
9. Solladie-Cavallo, A.; Roje, M.; Welter, R.; Sunjiæ, V. J.
Org. Chem. 2004, 69, 1409–1412.
Aziridines and Epoxides in Synthesis; Wiley-VCH: Wein-
heim, 2006.
2. (a) Davis, F. A.; Zhou, P.; Liang, C.-H.; Reddy, R. E.
Tetrahedron: Asymmetry 1995, 6, 1511–1514; (b) Garcia
Ruano, J. L.; Fernandez, I.; Hamdouchi, C. Tetrahedron
Lett. 1995, 36, 295–298.
3. Morton, D.; Pearson, D.; Field, R. A.; Stockman, A.
Synlett 2003, 1985–1988.
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1997, 97, 2341–2372; (b) Dai, L.-X.; Hou, X.-L.; Zhou,
Y.-G. Pure Appl. Chem. 1999, 71, 369–376.
10. Davis, F. A.; Zhou, P.; Reddy, G. V. J. Org. Chem. 1994,
59, 3243–3245.
11. The JH–H value of the coupling constant of the aziridine
3
5. Midura, W. H. Synlett 2006, 733–736.
CH signals for trans-3g was 3.8 Hz.
6. Midura, W. H. In 22nd International Symposium on the
Organic chemistry of Sulfur; Saitama: Japan, 2006.
7. Li, A.-H.; Dai, L.-X.; Hou, X.-L.; Chen, M.-B. J. Org.
Chem. 1996, 61, 4641–4648.
12. 2S,3R-(N-p-Toluenesulfonyl-2-p-toluenesulfonyl)-3-pheny-
22
laziridine 4. ½aꢁD ꢀ67.7 (c 0.9, CHCl3); 1H NMR (500
MHz, CDCl3) d: 2.40 (3H, s, CH3C6H4S); 2.47 (3H, s,
CH3C6H4S) 4.08 (1H, d, J = 6.3 Hz, CHC6H5); 4.41 (1H,
d, J = 6.3 Hz, CHS); 7.13 and 7.50 (4H, A2B2 system, Ar);
7.21 and 7.58 (4H, A2B2, system, Ar); 7.28–7.43 (5H, m,
Ph). 13C NMR (125 MHz, CDCl3) d: 21.5; 21.7; 45.5; 62.9;
124.5; 127.9; 128.1; 128.4; 128.9; 129.7; 129.8; 130.4; 133.3;
138.1; 142.1; 145.1. Anal. Calcd for C22H21NO4S2: C,
61.80; H, 4.95; N, 3.28. Found: C, 61.73; H, 5.02; N, 3.30.
13. (a) Satoh, T.; Sato, T.; Oohara, T.; Yamakawa, K.
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Perkin Trans. 1 2001, 54, 3159–3166.
8. Typical procedure for aziridination: To a solution of
(S)-dimethylsulfonium-(p-tolylsulfinyl)methylide (1 mmol,
0.3 g) in 5 mL of dry MeCN, NaH (1.1 mmol, 0.03 g) was
added at rt under an argon atmosphere. The resulting
mixture was stirred for 30 min. The resulting precipitate
was filtered off and 1 mmol of N-tosyl p-bromobenzaldi-
mine (0.34 g) dissolved in 5 mL of dry MeCN was added.
After stirring at rt for 24 h, the reaction was quenched
with 20 mL of water, extracted with CH2Cl2 (4 · 5 mL)
and the combined organics dried over MgSO4. After
filtration, the solvent was evaporated under reduced
pressure affording 3 as a single isomer. A pure sample
was obtained by column chromatography on silica gel
(CHCl3–acetone, 30:1).
2S,3R,SS-(N-p-Toluenesulfonyl-2-p-toluenesulfinyl)-3-p-bro-
22
mophenylaziridine 3c. ½aꢁD ꢀ153.5 (c 0.9, CH2Cl2); mp
16. Robiette, R. J. Org. Chem. 2006, 71, 2726–2734.
17. Bergmeier, S. C.; Seth, P. P. Tetrahedron Lett. 1999, 40,
6181–6184.
1
161–162 ꢁC; H NMR (500 MHz, CDCl3) d: 2.41 (3H, s,
CH3C6H4S); 2.48 (3H, s, CH3C6H4S) 4.05 (1H, d,