Nucleophilic substitution of (sulfonyloxymethyl)aziridines: an asymmetric synthesis of both isomers of mexiletine

Article abstract of DOI:10.1016/j.tet.2008.09.068

The nucleophilic substitution reactions of 1-[1′(R)-α-methylbenzyl]-(2R)- and (2S)-(sulfonyloxymethyl)aziridines were carried out with various nucleophiles including N₃^-, MeO^-, CN^-, SCN^-, and diarylcuprates. The reaction pathway is influenced by the stereochemistry of the substrates, nucleophiles, and also the structure of the leaving groups. When the reaction site is less sterically hindered for the reactive nucleophiles to approach to the substrate 1-[1′(R)-α-methylbenzyl]-(2S)-(p-toluenesulfonyloxymethyl)aziridines, product is obtained as a single isomer while all the other starting materials afford a mixture of two isomers from two different reaction pathways. Application of this method enabled us to prepare both isomers of orally effective antiarrhythmic agent mexiletine.

Full text of DOI:10.1016/j.tet.2008.09.068

Tetrahedron 64 (2008) 11110–11114
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Nucleophilic substitution of (sulfonyloxymethyl)aziridines: an asymmetric
synthesis of both isomers of mexiletine
,
,
b
,
c,
*
Sang-Mi Han a, Sang-ho Ma a b, Hyun-Joon Ha a , Won Koo Lee
*
a Department of Chemistry, Hankuk University of Foreign Studies, Yongin, Kyunggi-Do 449-719, Republic of Korea
b Center for Bioactive Molecular Hybrids, Yonsei University, Seoul 120-749, Republic of Korea
c Department of Chemistry and Interdisciplinary Program of Integrated Biotechnology, Sogang University, Seoul 121-742, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
The nucleophilic substitution reactions of 1-[10(R)-
a-methylbenzyl]-(2R)- and (2S)-(sulfonyloxy-
Article history:
methyl)aziridines were carried out with various nucleophiles including Nꢀ3 , MeOꢀ, CNꢀ, SCNꢀ, and di-
arylcuprates. The reaction pathway is influenced by the stereochemistry of the substrates, nucleophiles,
and also the structure of the leaving groups. When the reaction site is less sterically hindered for the
Received 21 July 2008
Received in revised form
22 September 2008
Accepted 23 September 2008
Available online 1 October 2008
reactive nucleophiles to approach to the substrate 1-[10(R)-
a-methylbenzyl]-(2S)-(p-toluenesulfonyloxy-
methyl)aziridines, product is obtained as a single isomer while all the other starting materials afford
a mixture of two isomers from two different reaction pathways. Application of this method enabled us to
prepare both isomers of orally effective antiarrhythmic agent mexiletine.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
(Sulfonyloxymethyl)aziridines
Nucleophilic substitution
Stereochemistry
Chiral aziridine
Mexiletine
1. Introduction
a-methylbenzyl]-(2R)- and (2S)-(sulfonyloxymethyl)aziridines
with various nucleophiles including Nꢀ3 , MeOꢀ, CNꢀ, SCNꢀ, and
diarylcuprates and also the application of the methodology to
the efficient syntheses of both isomers of mexiletine.
A nitrogen containing three-membered ring compound azir-
idine can act as a molecular building block to provide various cyclic
and heterocyclic compounds including synthetically and bi-
ologically important molecules.1 Their representative synthetic
manipulations include the modification of the side chain attached
to the aziridine and regioselective ring openings.1 Since we
successfully prepared both enantiomers of aziridine-2-carboxyl-
ates, many nitrogen containing molecules were elaborated in op-
tically pure forms using regio- and stereoselective side-chain
modifications and ring openings.2 One of the most efficient side-
chain modification methods is the substitution reactions of 2-
(sulfonyloxymethyl)aziridines withvariousnucleophiles to introduce
diverse functional groups to the aziridine side chain.3 However,
the possible chemical pathway can be complicated by the
electron rich ring nitrogen of the aziridine, which also has good
nucleophilicity.4 Therefore, competition would be expected
between an external nucleophile and the ring nitrogen under
the reaction condition. Herein we would like to describe
the characteristics of nucleophilic substitution of 1-[10(R)-
2. Results and discussion
The possible competition between an external nucleophile and
the aziridine ring nitrogen during the substitution reaction of
2-(sulfonyloxymethyl)aziridines provides two different pathways, i
and ii, shown in Scheme 1. The pathway i is the direct displacement
of the leaving group by the nucleophile and the pathway ii involves
regioselective nucleophilic ring opening of the aziridine ring fol-
lowed by the ring closure by the nitrogen resulting in configura-
tional inversion at C2 of the aziridine. The results of substitution
reactions would be influenced by several factors including char-
acteristics of nucleophiles and the configuration at C-2 of the
substrate aziridines (Table 1).
We carried out the substitution reaction of 1-[10(R)-
a-methyl-
benzyl]-(2S)-toluenesulfonyloxymethylaziridine (2S)-1 with so-
dium azide to afford 2-azidomethylaziridne (2S)-4a in 72% yield
whose stereochemistry was identified by its derivatization of the
known compound (2S)-aminomethylaziridine5 with retention of
the configuration at C-2 of the aziridine (entry 1). This tells us that
the reaction gives the direct substitution product without ring
opening reaction. The same result was reported with NaOMe in
* Corresponding authors. Tel.: þ82 31 3304369 (H.-J.H.); Tel.: þ82 2 705 8449
(W.K.L.).
E-mail addresses: hjha@hufs.ac.kr (H.-J. Ha), wonkoo@sogang.ac.kr (W.K. Lee).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.068

S.-M. Han et al. / Tetrahedron 64 (2008) 11110–11114
11111
Me
Me
Me
Me
OSO2R
i
OSO2R
i
i
Ph
N
i
Ph
N
Ph
N
Ph
N
Nu
Nu
H
(2S)-4
H
H
H
(2R)-5
ii
ii
Nu-
Nu-
(2S)-1 (R=Tolyl)
(2S)-2 (R=Methyl)
(2R)-1 (R=Tolyl)
(2R)-2 (R=Methyl)
ii
ii
Me
Me
Me
Me
Ph
Nu
N
Ph
Nu
N
ii
Ph
N
Ph
N
ii
Nu
Nu
H
(2R)-5
OSO2R
H
(2S)-4
OSO2R
(2S)-3
(2R)-3
Scheme 1.
Table 1
The schematized results for the substitution reactions of the substrate (2S)-1, (2R)-1, (2S)-2 and (2R)-2 with various nucleophiles including Nꢀ3 , OMeꢀ, CNꢀ, SCNꢀ and
diphenylcuprate
Entry
Substrate
Nucleophile (reagents)a
Medium
Time (h)
Yieldb
Productsc
1
2
3
4
5
6
7
8
(2S)-1
(2S)-1
(2S)-1
(2S)-1
(2R)-1
(2R)-1
(2R)-1
(2R)-1
(2S)-2
(2S)-2
(2S)-2
(2S)-2
(2R)-2
(2R)-2
Nꢀ3 (NaN3)
DMF
MeOH
Et2O
Acetone/DMF (1:1)
DMF
MeOH
6
4
2
4
1
4
2
6
6
72
89
62
74
71
93
90
76
88
No rxn
83
91
No rxn
No rxn
(2S)-4a
(2S)-4b
(2S)-4c
(2S)-4d
(2R)-5a, (2S)-4a, (46:54)
(2R)-5b, (2S)-4b (52:48)
(2R)-5c, (2S)-4c (45:55)
(2R)-5d, (2S)-4d(84:16)
(2R)-5a, (2S)-4a, 6 (8:46:46)
MeOꢀ (NaOMe)
Phꢀ (LiCuPh2)
2,6-Me2PhOꢀ (2,6-Me2PhOꢀ)
Nꢀ3 (NaN3)
MeOꢀ (NaOMe)
Phꢀ (LiCuPh2)
2,6-Me2PhOꢀ (2,6-Me2PhOꢀ)
Nꢀ3 (NaN3)
Et2O
Acetone/DMF (1:1)
DMF
MeOH
CH3CN
CH3CN
9
10
11
12
13
14
MeOꢀ (NaOMe)
CNꢀ(NaCN)
6
6
(2R)-5e, (2S)-4e (50:50)
(2R)-5f, (2S)-4f (46:54)
SCN
Nꢀ3 (NaN3)
DMF
CH3CN
CNꢀ (NaCN)
a
Mole amount was used for the reactions.
Those were isolated yields and not to be optimized.
The ratios were determined by 1H NMR.
b
c
MeOH by De Kimpe and D’hooghe6 to obtain methoxymethylazir-
idine (2S)-4b with retention of configuration at C-2 of the aziridine7
(entry 2). Reaction with Ph2CuLi yielded the expected product (2S)-
4c in 62% yield with retention of configuration (entry 3). However,
difference between two stereoisomers by the density functional
model shown in Figures 1 and 2.8
The minimum energy conformation of 1-[10(R)-
a
-methyl-
benzyl]-(2S)-(sulfonyloxymethyl)aziridines is quite different from
that of 1-[10(R)-
-methylbenzyl]-(2R)-(sulfonyloxymethyl)azir-
idines. Especially the reaction site bearing toluenesulfonyloxy
leaving group in the isomer 1-[10(R)-
-methylbenzyl]-(2S)-(sulfo-
the same reaction of 1-[10(R)-
sulfonyloxymethyl)aziridine (2R)-1 with sodium azide yielded two
different isomers 1-[10(R)-
-methylbenzyl]-(2R)- and (2S)-azido-
a-methylbenzyl]-(2R)-(p-toluene-
a
a
a
methylaziridine (2R)-5a and (2S)-4a with the ratio of 46:54 in 71%
yield in 1 h in DMF (entry 5). The same reaction with NaOMe in
MeOH also yielded (2R)- and (2S)-methoxymethylaziridine (2R)-5b
and (2S)-4b with the ratio of 52:48 in 93% yield (entry 6). Reaction
with Ph2CuLi yielded both isomers of (2R)- and (2S)-benzylazir-
idine (2R)-5c and (2S)-4c with the ratio of 45:55 in 90% yield (entry
7). Therefore, the nucleophilic substitution reactions of 1-[10(R)-
nyloxymethyl)aziridines is relatively less hindered while that of the
other isomer is more sterically hindered and blocks the reaction
site shown in Figure 2. This indicates that two different reaction
pathways (i and ii) are available and the direct displacement
reaction (i) would be dominant only if the substrate is quite active
a
-methylbenzyl]-(2S)-(p-toluenesulfonyloxymethyl)aziridine
(2S)-1 proceeds by pathway i while 1-[10(R)-
a
-methylbenzyl]-(2R)-
(p-toluenesulfonyloxymethyl)aziridine (2R)-1 yields two products
coming from both pathways i and ii as in Scheme 1. Formation of
two products indicates that both electrophilic positions of the
substrate 1-[10(R)-
a-methylbenzyl]-(2R)-(sulfonyloxymethyl)azir-
idines are almost equally reactive toward the external nucleophile
while the electrophilic center in the side chain of the isomer 1-
[10(R)-
a-methylbenzyl]-(2S)-(sulfonyloxymethyl)aziridines is much
more reactive. We performed minimum energy calculations of both
Figure 1. The minimum energy conformer of 1-[10(R)-
a-methylbenzyl]-(2S)-p-tolue-
nesulfonyloxymethylaziridine (2S)-1 as its side view (A) and the view (B) in front of the
substrates (2S)-1 and (2R)-1 to figure out the configurational
carbon bearing toluenesulfonyloxy group with yellowish circle.

11112
S.-M. Han et al. / Tetrahedron 64 (2008) 11110–11114
NH2
H2
O
Me
(2S)-4d
84%
(S)-(-)-Mexiletine
NH2
O
H2
Me
(2R)-5d
Figure 2. The minimum energy conformer of 1-[10(R)-
a-methylbenzyl]-(2S)-p-tolue-
nesulfonyloxymethylaziridine (2R)-1 as its side view (A) and the view (B) in front of
87%
the carbon bearing toluenesulfonyloxy group with yellowish circle.
(R)-(+)-Mexiletine
Scheme 2.
with a good leaving group and also its conformation provides less
hindered electrophilic center for the coming nucleophile. Other-
wise, ring opening reaction followed by the concomitant ring
closure with the displacement of the leaving group by the ring
nitrogen as an internal nucleophile can compete with direct dis-
placement to give two reaction products. Examples were docu-
mented regarding the aziridine ring opening reaction followed by
ring closure with organocupper9 and alkyllithium10 reagents. If the
substrate has less reactive leaving group, the product by pathway ii
would be obtained even if the substrate has less hindered confor-
mation. When we carried out the substitution reaction of (2S)-2
with sodium azide three products were obtained including (2S)-
azidomethylaziridine (2S)-4a, (2R)-azidomethylaziridine (2S)-4b,
and 2-amino-1,3-diazidopropane (6) with the ratio of 8:46:46 in
88% yield (entry 9). Two isomers of aziridine were originated from
the reaction pathways i and ii shown in Scheme 1 while the diazido
compound (6) came from further azide ring opening reaction11 of
the azidomethylaziridine. The reaction of (2S)-2 with a cyanide
nucleophile in DMF yielded two isomeric 2-cyanomethylaziridines
(2R)-5e and (2S)-4e in 83% yield with the same ratio after 6 h of
reaction time while no change was observed with sodium
methoxide in MeOH (entries 10 and 11). The similar reaction of
(2S)-2 with SCNꢀ proceeded to afford two isomeric 2-thio-
cyanomethylaziridines (2R)-5f and (2S)-4f in 91% yield (entry 12).
In conclusion, the nucleophilic substitution reactions of 1-
[10(R)-
-methylbenzyl]-(2R)- and (2S)-(sulfonyloxymethyl)azir-
a
idines with various nucleophiles including Nꢀ3 , MeOꢀ, CNꢀ, SCNꢀ,
and diphenylcuperate yielded substitution products depending on
the stereochemistry of substrates, nucleophiles, and the charac-
teristics of the leaving groups. When the reaction site is less
sterically hindered for the reactive nucleophiles to approach to
the substrate 1-[10(R)-
a-methylbenzyl]-(2S)-(p-toluenesulfonyloxy-
methyl)aziridines, product is obtained as a single isomer while all
the other starting materials afford a mixture of two isomers from
two different reaction pathways.
3. Experimental
3.1. General methods
Chiral aziridines are available from Aldrich. All commercially
available compounds were used as received unless stated other-
wise. All reactions were carried out under an atmosphere of ni-
trogen in oven-dried glassware with magnetic stirring. Reactions
were monitored by thin layer chromatography (TLC) with 0.25 mm
E. Merck pre-coated silica gel plates (60 F254). Visualization was
accomplished with either UV light, or by immersion in solutions of
ninhydrin, p-anisaldehyde, or phosphomolybdic acid (PMA) fol-
lowed by heating on a hot plate for about 10 s. Purification of re-
action products was carried out by flash chromatography using
Kieselgel 60 Art 9385 (230–400 mesh). 1H NMR and 13C NMR
spectra were obtained using a Varian 200 (200 MHz for 1H and
50.3 MHz for 13C) spectrometer. Chemical shifts are reported rela-
However, the other isomer 1-[10(R)-
a-methylbenzyl]-(2R)-(methyl-
sulfonyloxymethyl)aziridine (2R)-2 was inert with all tested nu-
cleophiles including N3ꢀ, MeOꢀ, and CNꢀ (entry 13 and 14). The
conformation of the reaction site of this substrate is sterically
hindered as observed in (2R)-1 and also methanesulfonate is less
active toward nucleophiles compared with toluenesulfonate group.
This substitution reaction is valuable for introducing a new
group into the side chain of an aziridine and this method was ap-
plied for the preparation of both isomers of mexiletin (Scheme 2).
Mexiletine is an orally effective antiarrhythmic,12 antimyotonic,13
and analgesic14 agent in its racemic form and is available for
clinical use as the racemate. Mexiletine undergoes stereoselective
disposition in human associated with the selective binding of the
(R)-(ꢀ)-mexiletine to a cardiac sodium channel and the higher
antiarrhythmic activity of this enantiomer.15 This isomer was
tive to chloroform (
d
¼7.26) for 1H NMR and chloroform (
¼77.2) for
d
13C NMR. Data are reported as: br¼broad, s¼singlet, d¼doublet,
t¼triplet, q¼quartet, m¼multiplet. Coupling constants are given in
hertz. Ambiguous assignments were resolved on the basis of
standard one dimensional proton decoupling experiments. Optical
rotations were obtained using a Rudolph Autopol III digital polar-
25
imeter and optical rotation data were reported as follows: [a]
D
(concentration c¼g/100 mL, solvent). Elemental analyses were
performed by the Perkin–Elmer 240 DS elemental analyzer. High
resolution mass spectra were recorded on a 4.7 T IonSpec ESI-FTMS
or a Micromass LCT ESI-TOF mass spectrometer.
prepared from (2R)-1-[10(R)-
a-methylbenzyl]-(p-toluenesulfonyl-
oxymethyl)aziridine (2R)-1, which was transformed into 2-(2,6-
dimethyphenoxy)methylaziridine upon treatment with 2 equiv of
2,6-dimethylphenol in DMF/acetone (1:1) in the presence of K2CO3
under reflux for 4 h. Two diastereomers 2R- and 2S-(2,6-dimethy-
phenoxy)methylaziridines (2R)-5f and (2S)-4f were obtained with
the ratio of 84:16 in 76% yield (entry 8). The major isomer was
isolated and converted into (R)-(ꢀ)-mexiletine upon treatment with
H2 in MeOH in the presence of Pd(OH)2 in 87% yield.16 The other
isomer (S)-(ꢀ)-mexiletine was also obtained from the direct
3.2. General procedure for the preparation of (S)-1-[((R)-1-
phenylethyl)aziridin-2-yl]methyl 4-methylbenzenesulfonate
(2S)-1 or (R)-1-[((R)-1-phenylethyl)aziridin-2-yl]methyl 4-
methylbenzenesulfonate (2R)-1
Into the solution of (2S)- or (2R)-hydroxymethylaziridine
(450 mg, 2.54 mmol) in CH2Cl2 (5 mL) were added DMAP (30 mg,
0.254 mmol) and Et3N (290 mg, 0.4 mL, 2.80 mmol). The resulting
solution was cooled to 0 ꢁC and stirred for 10 min before adding
p-toluenesulfonylchloride (540 mg, 2.80 mmol). The reaction mix-
ture was stirred for 1 h until all the starting material was consumed.
substitution pathway of 1-[10(R)-
a-methylbenzyl]-(2S)-(p-toluene-
sulfonyloxymethyl)aziridine (2S)-1 by 2,6-dimethylphenol to yield
(2S)-(2,6-dimethyphenoxy)methylaziridine (2S)-4d as a single isomer
and followed by hydrogenolysis in 63% overall yield.

S.-M. Han et al. / Tetrahedron 64 (2008) 11110–11114
11113
The mixture was quenched with saturated aqueous NaHCO3 solu-
tion. The aqueous layer was extracted with CH2Cl2 and the com-
bined organic extracts were dried, filtered, and concentrated under
reduced pressure. Purification by silica gel column chromatography
(EtOAc/n-hexane, 1:1) provided products as oil.
dimethylcuperate at ꢀ78 ꢁC and then 0 ꢁC. The reaction was
quenched by adding water at room temperature and the mixture
was extracted with CH2Cl2 (50 mLꢂ3). The combined organic ex-
tracts were washed with brine, dried with anhydrous MgSO4, fil-
tered, and concentrated under reduced pressure. Purification by
silica gel chromatography provided analytically pure product.
3.2.1. (S)-1-[((R)-1-Phenylethyl)aziridin-2-yl]methyl 4-
methylbenzenesulfonate (2S)-16
3.4.1. (2S)-(Azidomethyl)-1-[(R)-1-phenylethyl]aziridine (2S)-4a
Yield 96%. Liquid. [
CDCl3)
a
]
þ1.0 (c 1.8, CHCl3). 1H NMR (200 MHz,
Liquid. [
a
]
D
þ16.5 (c 1.7, EtOAc). 1H NMR (200 MHz, CDCl3)
D
d
7.81 (2H, d, J¼8 Hz), 7.37–7.21 (7H, m), 3.96 (2H, t, 5.2 Hz),
d
7.34–7.21 (5H, m), 3.18–3.03 (2H, m), 2.87 (1H, q, J¼5.4 Hz), 1.87–
2.43 (3H, s), 2.50–2.41 (2H, m), 1.90–1.84 (1H, m), 1.54–1.53 (1H, m),
1.82 (1H, m), 1.67–1.46 (1H, m), 1.44–1.32 (4H, m). 13C NMR
1.41–1.37 (4H, m), 1.39 (3H, d, J¼6.6 Hz). 13C NMR (CDCl3, 50.3 MHz)
(50 MHz, CDCl3) d 144.2, 128.4, 127.2, 126.7, 69.8, 53.5, 37.1, 32.4,
d
144.9, 144.1, 133.1, 129.9, 128.4, 128.0, 127.2, 126.7, 73.0, 69.3, 37.3,
23.2. MS (ESþ) m/z (rel intensity): 225 [(MþNa), 100], 203 [(MþH),
31.4, 23.3, 21.8.
98]. HRMS (EI) calcd for C11H14N4: 202.1218, found 202.1216.
3.2.2. (R)-1-[((R)-1-Phenylethyl)aziridin-2-yl]methyl 4-
3.4.2. (2S)-(Methoxymethyl)-1-[(R)-1-phenylethyl]-
methylbenzenesulfonate (2R)-1
aziridine (2S)-4b
[
a]
D þ12.0 (c 1.0, EtOAc). 1H NMR (200 MHz, CDCl3)
d
7.82 (2H, d,
Liquid. [
a]
þ54.5 (c 1.0, EtOAc). 1H NMR (200 MHz, CDCl3)
D
J¼8.2 Hz), 7.36–7.28 (7H, m), 4.11 (1H, dd, J¼10.8, 4.8 Hz), 3.82 (1H,
dd, J¼10.6, 7.4 Hz), 2.43 (3H, s), 1.92–1.81 (1H, m), 1.53–1.52 (1H, d,
J¼3.2 Hz), 1.40–1.35 (1H, m), 1.36 (3H, d, J¼6.4 Hz). 13C NMR (CDCl3,
d
7.36–7.24 (5H, m), 3.46–3.38 (5H, m), 2.46 (1H, q, J¼6.2 Hz), 1.79–
1.77 (1H, m), 1.58–1.56 (1H, s), 1.49–1.31 (4H, m). 13C NMR (50 MHz,
CDCl3) 144.5, 128.3, 127.0, 126.8, 75.0, 69.8, 59.0, 39.1, 31.2, 23.3.
d
50.3 MHz)
d
144.6, 143.8, 133.0, 129.7, 128.1, 127.7, 126.9, 126.5, 72.7,
HRMS (EI) calcd for C12H17NO: 191.1310, found 191.1305.
68.9, 36.9, 31.1, 23.0, 21.4. Anal. Calcd for C18H21NO3S: C, 65.2; H,
6.39; N, 4.25. Found: C, 65.5; H, 6.69; N, 4.27.
3.4.3. (2S)-Benzyl-1-[(R)-1-phenylethyl]aziridine (2S)-4c
Liquid. [
a
]
þ23.8 (c 0.19, CHCl3). 1H NMR (200 MHz, CDCl3)
D
3.3. General procedure for preparation of (S)-1-[((R)-1-
phenylethyl)aziridin-2-yl]methyl methanesulfonate (2S)-2 or
(R)-1-[((R)-1-phenylethyl)aziridin-2-yl]methyl
methanesulfonate (2R)-2
d
7.75–7.06 (10H, m), 3.78 (1H, dd, J¼10.6, 5.2 Hz), 2.11–2.09 (1H, d,
J¼3 Hz), 1.67–1.43 (2H, m), 1.32–1.27 (3H, m), 1.04–0.96 (2H, m). 13C
NMR (50 MHz, CDCl3) d 145.1, 143.8, 128.4, 127.4, 127.1, 127.0, 125.9,
70.1, 49.4, 37.5, 34.0, 23.2. HRMS (EI) calcd for C17H19N: 237.1517,
found 237.1509.
The same procedure as for the preparation of (S)-1-[((R)-1-phe-
nylethyl)aziridin-2-yl]methyl 4-methylbenzenesulfonate (2S)-1 or
(R)-1-[((R)-1-phenylethyl)aziridin-2-yl]methyl 4-methylbenzene-
sulfonate (2R)-1 as described in Section 3.2 except that meth-
anesulfonyl chloride was used instead of p-toluenesulfonylchloride.
3.4.4. (2S)-[(2,6-Dimethylphenoxy)methyl]-1-[(R)-1-
phenylethyl]aziridine (2S)-4d
Liquid. [
a
]
ꢀ13.1 (c 0.49, CHCl3). 1H NMR (200 MHz, CDCl3)
D
d
7.47–7.28 (5H, m), 6.98–6.92 (3H, m), 3.87 (1H, dd, J¼5 and 10 Hz),
3.66 (1H, dd, J¼6 and 10 Hz), 2.67 (1H, q, J¼6.6 Hz), 2.23 (6H, s),
2.02–1.96 (1H, m), 1.64 (1H, d, J¼6.2 Hz), 1.55 (3H, d, J¼6.6 Hz),
3.3.1. (S)-1-[((R)-1-Phenylethyl)aziridin-2-yl]methyl
methanesulfonate (2S)-2
1.52–1.50 (1H, m). 13C NMR (50 MHz, CDCl3)
d 155.6, 144.4, 130.7,
Yield 87%. Liquid. [
a
]
þ15.5 (c 5.7, EtOAc). 1H NMR (200 MHz,
128.6, 128.2, 126.9, 126.5, 123.6, 73.7, 69.5, 37.8, 32.1, 23.3, 16.1. MS
(ESþ) m/z (rel intensity): 304 [(MþNa), 85]. HRMS (EI) calcd for
C19H23NO: 281.1780, found 281.1776.
D
CDCl3)
d
7.36–7.28 (5H, m), 4.21 (1H, dd, J¼11, 4.8 Hz), 3.89 (1H, dd,
J¼11, 7.0 Hz), 2.70 (3H, s), 2.57–2.47 (1H, m), 1.92–1.80 (2H, m), 1.60
(1H, d, J¼6.4 Hz), 1.42 (3H, d, J¼6.4 Hz). 13C NMR (CDCl3, 50.3 MHz)
d
143.8,128.2,127.2,126.7, 71.2, 69.3, 37.7, 36.1, 31.7, 22.7. Anal. Calcd
3.4.5. (2S)-(Thiocyanatomethyl)-1-[(R)-1-phenylethyl]-
for C12H17NO3S: C, 56.4; H, 6.71; N, 5.49. Found: C, 56.6; H, 6.90; N,
5.48.
aziridine (2S)-4f
Liquid. [
a
]
D
þ29.1 (c 0.61, EtOAc). 1H NMR (200 MHz, CDCl3)
d
7.31–7.29 (5H, m), 3.01–2.92 (1H, m), 2.79–2.70 (1H, m), 2.46 (1H,
3.3.2. (R)-1-[((R)-1-Phenylethyl)aziridin-2-yl]methyl
methanesulfonate (2R)-2
q, J¼6 Hz), 1.94–1.91 (1H, m), 1.78–1.74 (1H, m), 1.68–1.63 (1H, m),
1.38 (3H, d, J¼6.4 Hz). 13C NMR (50 MHz, CDCl3)
d 143.7,128.6,127.5,
Liquid. [
a
]
þ33.9 (c 3.6, CHCl3). 1H NMR (200 MHz, CDCl3)
126.9, 112.3, 69.8, 37.4, 36.9, 34.7, 22.7. MS (ESþ) m/z (rel intensity):
302 [(MþNa),100], 282[(MþH), 30]. HRMS (EI) calcd for C12H14N2S:
218.0878, found 218.0887.
D
d
7.34–7.26 (5H, m), 4.43–4.35 (1H, dd, J¼11, 4.4 Hz), 4.01 (1H, dd,
J¼11, 7.8 Hz), 3.06 (3H, s), 2.56–2.46 (1H, q, J¼6.6 Hz), 2.01–1.90
(1H, m), 1.67 (1H, d, J¼3.2 Hz), 1.46–1.43 (1H, m), 1.43 (3H, d,
J¼6.6 Hz). 13C NMR (CDCl3, 50.3 MHz)
d
143.7, 128.2, 127.0, 126.5,
3.4.6. (2R)-(Azidomethyl)-1-[(R)-1-phenylethyl]aziridine (2R)-5a
72.3, 68.9, 37.5, 37.2, 31.4, 23.0. Anal. Calcd for C12H17NO3S: C, 56.4;
H, 6.71; N, 5.49. Found: C, 56.3; H, 6.58; N, 5.61.
Liquid. [
a]
19.7 (c 4.3, EtOAc). 1H NMR (200 MHz, CDCl3)
D
d
7.47–7.32 (5H, m), 3.47–3.38 (1H, dd, J¼4.2 and 12.9 Hz), 3.20
(1H, dd, J¼7.6 and 12.9 Hz), 2.57 (1H, q, J¼6.2 Hz), 1.92–1.82 (1H,
sept), 1.68 (1H, d, J¼2.6 Hz), 1.58 (3H, d, J¼6.4 Hz), 1.42–1.38 (1H,
3.4. General procedure for the substitution reactions of 1-
[((R)-1-phenylethyl)aziridin-2-yl]methyl sulfonates (2S)-1,
(2R)-1, (2S)-2, and (2R)-2
m). 13C NMR (50 MHz, CDCl3)
d 144.4, 128.5, 127.2, 126.9, 69.7, 54.2,
38.7, 31.6, 23.3. MS (ESþ) m/z (rel intensity): 225 [(MþNa), 100],
203[(MþH), 10]. HRMS (EI) calcd for C11H14N4: 202.1218, found
202.1221.
To the solution of any one of the substrates among 1-[((R)-1-
phenylethyl)aziridin-2-yl]methyl sulfonates (2S)-1, (2R)-1, (2S)-2,
and (2R)-2 (0.5 mmol) in a specified solvent (15 mL) under nitrogen
at room temperature was added a nucleophile (1.5 mmol). The
mixture was stirred under reflux for the specified reaction time
until all the starting material was consumed, except for
3.4.7. (2R)-(Methoxymethyl)-1-[(R)-1-phenylethyl]-
aziridine (2R)-5b
Liquid. [
a
]D ꢀ24.6 (c 1.0, ethyl acetate).1H NMR (200 MHz, CDCl3)
d
7.32–7.19 (5H, m), 3.44–3.35 (1H, m), 3.28–3.20 (1H, m), 2.50–2.44

11114
S.-M. Han et al. / Tetrahedron 64 (2008) 11110–11114
(1H, m), 1.87–1.69 (3H, m), 1.59–1.50 (1H, m), 1.42–1.34 (5H, m). 13
NMR (50 MHz, CDCl3) 144.1, 128.4, 127.2, 126.8, 69.6, 46.5, 39.3,
C
3.5. (S)-(L)-Mexiletine
d
34.0, 23.1. HRMS (EI) calcd for C12H17NO: 191.1310, found 191.1311.
To the solution of (2S)-4d (158 mg, 0.56 mmol) in MeOH (3 mL)
was added 5 mg of Pd/C. The reaction mixture was stirred at room
temperature with atmospheric pressure of H2 for 12 h and then the
catalyst was filtered. The solution was concentrated in vacuo. The
residue was purified by silica gel chromatography (EtOAc/n-hexane,
3.4.8. 2-Benzyl-1-[(R)-1-phenylethyl]aziridine (2R)-5c, (2S)-5c
Liquid. 1H NMR (200 MHz, CDCl3)
d
7.75–7.06 (10H, m), 3.51–
3.43 (1H, m), 2.11–2.09 (1H, d, J¼3 Hz), 1.67–1.43 (2H, m), 1.32–1.27
(2H, m), 1.04–1.09 (3H, m). 13C NMR (50 MHz, CDCl3)
143.4, 141.2,
d
1:3) to provide analytically pure product in 84% yield. Liquid. [a]
D
128.9, 128.3, 128.1,127.5, 127.1,125.8, 70.7, 53.5, 32.0, 19.6,14.1. Anal.
Calcd for C17H19N: C, 86.3; H, 8.07; N, 5.90. Found: C, 86.1; H, 8.26;
N, 5.76.
þ2.9 (c 0.14, CHCl3), lit.:13
[
a
]
þ2.5 (c 4.9, CHCl3). Spectral data
D
were in agreement with those of the literature value.
3.4.9. (R)-2-[(2,6-Dimethylphenoxy)methyl]-1-[(R)-1-
phenylethyl]aziridine (2R)-5d
3.6. (R)-(D)-Mexiletine
Liquid. [
a
]
D þ54.4 (c 1.2, CHCl3). 1H NMR (200 MHz)
d 7.50–7.41
This was prepared in the same manner as (S)-(ꢀ)-mexiletine
starting from (2R)-5d. Liquid. [
a
]
ꢀ2.8 (c 0.34, CHCl3), lit.:13
[a]
D
(5H, m), 7.15–7.03 (3H, m), 3.96–3.89 (2H, m), 2.65 (1H, q, J¼2 Hz),
D
2.46 (6H, s), 2.13 (1H, q, J¼3 Hz), 1.77–1.74 (1H, m), 1.66–1.52 (4H,
ꢀ2.7 (c 4.7, CHCl3). Spectral data were in agreement with those of
m). 13C NMR (50.3 MHz)
d 155.7, 144.4, 130.8, 128.6, 128.2, 126.7,
the literature value.
123.6, 74.6, 69.5, 38.9, 31.0, 23.2, 16.3. MS (ESþ) m/z (rel intensity):
302 [(MþNa), 100], 282 [(MþH), 50]. MS (ESþ) m/z (rel intensity):
304 [(MþNa), 100]. HRMS (EI) calcd for C19H23NO: 281.1780, found
281.1785.
Acknowledgements
We acknowledge the financial supports from the Korea Science
and Engineering Foundation through the Center for Bioactive Mo-
lecular Hybrids and R01-2007-000-20037-0 to H.-J.H. Partial sup-
port of HUFS grant (2008) is also gratefully acknowledged.
3.4.10. 2-(R)-[1-((R)-1-Phenylethyl)aziridin-2-yl]acetonitrile (2R)-
5e and (2S)-4e as a mixture
Liquid. 1H NMR (200 MHz, CDCl3)
d
7.36–7.31 (5H, m), 3.78–3.73
(1H, m), 2.85–2.73 (2H, m), 2.57–2.27 (3H, m), 1.92 (1H, s), 1.73–
1.52 (2H, m), 1.43–1.33 (4H, m). 13C NMR (50 MHz, CDCl3)
144.5,
d
144.1, 128.8, 128.5, 127.5, 127.4, 126.7, 126.6, 118.7, 117.3, 69.6, 58.3,
58.1, 47.3, 33.4 33.2, 29.6, 29.4, 24.5, 24.3, 23.2, 21.4, 18.4, 18.3. Anal.
Calcd for C12H14N2: C, 77.4; H, 7.58; N, 15.4. Found: C, 77.3; H, 7.79;
N, 15.3.
References and notes
1. (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599; (b) Pearson, W. H.; Lian,
B. W.; Bergmeier, S. C. In Comprehensive Heterocyclic Chemistry II; Padwa, A., Ed.;
Pergamon: New York, NY, 1996; Vol. 1A; p 1; (c) Osborn, H. M. I.; Sweeney, J. B.
Tetrahedron: Asymmetry 1997, 8, 1693; (d) McCoull, W.; Davis, F. A. Synthesis
2000, 1347; (e) Zwanenburg, B.; ten Holte, P. In Stereoselective Heterocyclic
Chemistry III; Metz, P., Ed.; Springer: Berlin, 2001; pp 93–124; (f) Sweeney, J. B.
Chem. Soc. Rev. 2002, 31, 247; (g) Hu, X. E. Tetrahedron 2004, 60, 2701.
2. Lee, W.-K.; Ha, H.-J. Aldrichim. Acta 2003, 36, 57.
3. D’hooghe, M.; Van Speybroeck, V.; Waroquierb, M.; De Kimpe, N. Chem. Com-
mun. 2006, 1554.
4. (a) Kim, M. S.; Kim, Y.-W.; Hahm, H. S.; Jang, J. W.; Lee, W. K.; Ha, H.-J. Chem.
Commun. 2005, 3062; (b) Ma, S.-h.; Yoon, D.-H.; Ha, H.-J.; Lee, W. K. Tetrahedron
Lett. 2007, 48, 269 and references are cited therein.
3.4.11. 1-[(R)-1-Phenylethyl]-2(S)-(thiocyanatomethyl)aziridine
(2S)-4f
Liquid. [
a
]
þ29.1 (c 0.82, EtOAc). 1H NMR (200 MHz, CDCl3)
D
d
7.33–7.23 (5H, m), 3.04–2.96 (1H, m), 2.81–2.68 (1H, m), 2.48 (1H,
q, J¼6.2 Hz), 2.00–1.93 (1H, m), 1.75–1.72 (1H, m), 1.69–1.61(m, 1H),
13.9(d, J¼6.2 Hz). 13C NMR (CDCl3, 50 MHz)
d 143.8, 128.6, 128.3,
127.6, 126.9, 112.3, 69.9, 37.4, 36.9, 34.7, 22.8. HRMS (EI) calcd for
C12H14N2S: 218.0878, found 218.0882.
5. Reductions with LiAlH4 yielded the same (2S)-aminomethylaziridine from the
commercially available (S)-1-[(R)-a-methylbenzyl]-2-aziridinecarboxamide.
6. D’hooghe, M.; De kimpe, N. Synlett 2004, 271.
3.4.12. 1-[(R)-1-Phenylethyl]-2(R)-(thiocyanatomethyl)aziridine
7. Schwan, A. L.; Refvik, M. D. Tetrahedron Lett. 1993, 34, 4901.
(2R)-4f
8. The minimum energy conformers of 1-[10(R)-
a-methylbenzyl]-(2S)- and (2R)-
Liquid. [
a
]
D
þ40.8 (c 0.57, EtOAc). 1H NMR (200 MHz, CDCl3)
(p-toluenesulfonyloxymethyl)aziridine were generated from the calculation
with density functional model written in the commercial product SpartanÒ 04.
9. (a) Bergmeier, S. C.; Seth, P. P. J. Org. Chem. 1997, 62, 2671; (b) Sweeny, J. B.;
Cantrill, A. A. Tetrahedron 2003, 59, 3677.
10. Bergmeier, S. C.; Fundy, S. L.; Seth, P. P. Tetrahedron 1999, 55, 8025.
11. Kim, Y.; Ha, H.-J.; Han, K. S.; Ko, S. H.; Yun, H.; Chang, J. W.; Kim, M. S.; Lee, W. K.
Tetrahedron Lett. 2005, 46, 4407.
d
7.33–7.23 (5H, m), 3.33–3.22 (1H, m), 2.83–2.70 (1H, m), 2.51 (1H,
q, J¼6.2 Hz), 2.00–1.93 (1H, m), 1.71–1.70 (1H, m), 1.52–1.47 (4H,
m). 13C NMR (CDCl3, 50 MHz)
d
143.8, 128.5, 127.3, 126.8, 112.5, 69.4,
38.3, 38.1, 34.5, 23.5. HRMS (EI) calcd for C12H14N2S: 218.0878,
found 218.0874.
12. Fenster, P. E.; Comess, K. A. Pharmacotherapy 1986, 6, 1.
13. Rudel, R.; Lehmann-Horn, F. Physiol. Rev. 1985, 65, 310.
14. Kalso, E.; Tramer, M. R.; McQuay, H. J.; Moore, R. A. Eur. J. Pain 1998, 2, 3.
15. (a) Franchini, C.; Cellucci, C.; Corbo, F.; Lentini, G.; Scilimati, A.; Tortorella, V.;
Stasi, F. Chirality 1994, 6, 590; (b) Aav, R.; Parve, O.; Pehk, T.; Claesson, A.;
Martin, I. Tetrahedron: Asymmetry 1999, 10, 3033; (c) Carocci, A.; Catalano, A.;
Corbo, F.; Duranti, A.; Amoroso, R.; Franchini, C.; Lentinia, G.; Tortorella, V.
Tetrahedron: Asymmetry 2000, 11, 3619; (d) Carocci, A.; Franchini, C.; Lentini, G.;
Loiodice, F.; Tortorella, V. Chirality 2000, 12, 103.
3.4.13. (2S)-1,3-Diazido-N-[(R)-1-phenylethyl]propane-
2-amine (6)
Liquid. [
CDCl3)
a]
þ16.3 (c 1.4, ethyl acetate). 1H NMR (200 MHz,
D
d
7.34–7.21 (5H, m), 4.84–3.93 (1H, m), 3.47–3.18 (m, 4H),
2.64 (q, J¼6.2 Hz, 1H), 1.50–1.41 (m, 4H). 13C NMR (50 MHz, CDCl3)
d
145.0, 128.7, 127.3, 126.5, 55.6, 54.1, 53.1, 51.6, 24.9. HRMS (EI)
16. Yun, J. M.; Sin, T. B.; Hahm, H. S.; Lee, W. K.; Ha, H.-J. J. Org. Chem. 2003, 68,
7675.
calcd for C11H15N7: 245.1389, found 245.1383.