Optically pure trans-2,3-disubstituted N-sulfinyl aziridines. Regio- and stereoselective opening mediated by the sulfinyl group

Article abstract of DOI:10.1016/j.tet.2006.06.072

A new entry to optically pure trans-2,3-disubstituted N-sulfinyl aziridines starting from 1,2-aminosulfides, involving formation of a sulfonium salt intermediate followed by intramolecular nucleophilic attack by the sulfinamide nitrogen atom, is reported.

Full text of DOI:10.1016/j.tet.2006.06.072

Tetrahedron 62 (2006) 8525–8532
Optically pure trans-2,3-disubstituted N-sulfinyl aziridines.
Regio- and stereoselective opening mediated by
the sulfinyl group
a
a
a
Yolanda Arroyo,a, Angela Meana, J. Felix Rodrıguez, Mercedes Santos,
ꢀ
*
´
M. Ascension Sanz-Tejedor and Jose L. Garcıa-Ruano
ꢀ
a,
b,
*
*
´
ꢀ
ꢀ
a
´
ꢀ
Departamento de Quımica Organica (ETSII), Universidad de Valladolid, Po. Del Cauce s/n, 47011 Valladolid, Spain
b
´
Departamento de Quımica Orgaꢀnica (C-I), Universidad Autoꢀnoma, Cantoblanco, 2849 Madrid, Spain
Received 19 May 2006; accepted 21 June 2006
Available online 12 July 2006
Abstract—A new entry to optically pure trans-2,3-disubstituted N-sulfinyl aziridines starting from 1,2-aminosulfides, involving formation of
a sulfonium salt intermediate followed by intramolecular nucleophilic attack by the sulfinamide nitrogen atom, is reported. The regio- and
stereoselective opening of the aziridine ring can be achieved by anchimeric assistance of the sulfinyl group.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
method, aziridination of N-sulfonylimines with chiral ylides
derived from the camphor skeleton12 and Eliel’s oxathiane13
to afford cis-alkynylaziridines in moderate enantioselectiv-
ity and cis/trans mixtures in up to 99.9% ee has also been
reported. Aggarwal et al. have developed one of the best
catalytic imine aziridination procedure in which ylides
were generated in situ from diazocompounds or, more safely,
from the corresponding tosyl hydrazone salts and a chiral
sulfide.14 The procedure afforded aziridines in high ee
with diastereoselectivities depending on the activating group
on nitrogen (cis/trans ratio of ca. 1:3 and 1:6 using
N-SES14a,b and N-TcBoc aldimines,14c respectively). The
asymmetric aziridination of imines via aza-Darzens reaction
has also been reported. Thus, addition of a chiral bromoacyl-
sultam to imines afforded cis- or trans-aziridines with a high
levels of diastereoselectivity.15
Optically active aziridines are versatile building blocks that
have found widespread use in organic synthesis.1 Addition-
ally, the aziridine nucleus is also included in some natural
and biologically active products, such as mitomycins and
azinomycins,2 and has been used as ligands and auxiliaries
in asymmetric synthesis.1a,f,3
Asymmetric methods for aziridine synthesis are mainly
based on nitrene transfer or equivalents to olefins and car-
bene/carbenoids transfer to imines.4 Alkene aziridination
has allowed high enantioselectivities with cinnamate esters,
chromene derivatives, and styrene but simple alkenes re-
sulted in low enantioselectivity.4c,5 The addition of chiral
metallocarbenes to imines has been less successful.6 Best re-
sults have been achieved by addition of ethyl diazoacetate to
imines in the presence of chiral boron Lewis acid catalysts to
afford cis-aziridines (up to 99% ee).7 Recently, enantiopure
trans-2-ethenylaziridines have been synthesized from
allenyl zinc species and chiral N-sulfinylimines.8 The use
of S-chiral sulfinylimines with achiral bromoenolates9 and
a-halomethyl phosphonates10 has also been studied, but
only in the first case high levels of stereocontrol are observed.
As most of these methods are quite efficient to prepare cis-
aziridines whereas the trans selective aziridination remains
less settled, indirect routes involving preparation and cycli-
zation of enantiomerically enriched 1,2-amino alcohols16 or
1,2-aminosulfides17 stand as the most viable alternatives to
prepare these isomers.
Recently, we have reported a highly stereoselective one-step
asymmetric synthesis of anti-1,2-disubstituted 1,2-amino-
sulfide derivatives18 (Scheme 1). We now report an efficient
method to prepare trans-2,3-disubstituted aziridines starting
from these aminosulfides. Moreover, as the resulting aziri-
dines have a sulfinyl group at the appropriated position to
act as an anchimeric assistant in the opening reactions of
the aziridine rings, we have studied the ability of this group
The addition of achiral sulfonium and sulfoxonium ylides to
enantiopure sulfinylimines has been described but only mod-
erate diastereoselectivities were achieved.11 As alternative
* Corresponding authors. Tel.: +34 983184418; fax: +34 983423310
(M.A.S.-T.); tel.: +34 914974701; fax: +34 914973966 (J.L.G.-R.);
e-mail addresses: atejedor@dali.eis.uva.es; joseluis.garcia.ruano@uam.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.072

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Y. Arroyo et al. / Tetrahedron 62 (2006) 8525–8532
SOTol
SOTol
SMe
A range of 2,3-disubstituted aziridines bearing aromatic and
1) LDA, -78 °C
NHSOTol
heteroaromatic substituents of varying steric demand and
electronic effects were accessed as single stereoisomers
(de>98%; entries 1–6). No other isomer could be detected
by NMR (300 MHz) from the reaction crudes. In addition,
the synthesis of 2-alkyl-3-arylaziridine 2g was carried out
with analogous result (entry 7). The moderate yields
obtained for 2b and 2f (entries 2 and 6) were due to the
low solubility of the corresponding sulfonium salts in
CH2Cl2. The use of more efficient solvents did not allow
removing residual silver salts that partially inhibited the
further cyclization step.
SOTol
R
N
2)
SMe
>98% de
R
R = Aryl, Alkyl
NH2
R
SMe
>98% de
Scheme 1.
Hydrogenolysis of the Ar–SOTol bond can be made under
mild conditions with organolithium compounds21 and it
was possible to remove the chiral auxiliary before cycliza-
tion step. It has been illustrated by C-desulfinylation of 1a
and 1g with t-BuLi (1.8 equiv) followed by quenching
with saturated NH4Cl to afford the N-sulfinyl aminosulfides
1h and 1i, respectively, in nearly quantitative yield. Remark-
ably, the N-desulfinylation does not occur under these condi-
tions. Subsequent intramolecular cyclization of the 1h and 1i
takes place under the experimental conditions described
above, affording 2,3-diphenyl and 2-butyl-3-phenyl N-sulfi-
nyl aziridines, 2h and 2i, respectively, in good yields (entries
8 and 9). It suggests that the sulfinyl group at the aromatic
ring has no significant role in the cyclization process.
in controlling the regio- and stereoselectivity of these reac-
tions. This anchimeric assistance has been reported in
some reactions such as the hydrolysis of nitriles19 and the
addition of halogens to double bonds.20
2. Results and discussion
Aminosulfides 1a–e and 1g were synthesized as single
diastereoisomers18 by reaction of the lithium (S)-a-(methyl-
thio)-2-(p-tolylsulfinyl)benzyl carbanion with (S)-N-p-tolyl-
sulfinyl aldimines. For compound 1f, a 96:4 mixture of two
stereoisomers in 65% yield was achieved (see Section 4).
Although SN1 and SN2 processes are possible from benzyl-
sulfonium salts,22 the isolation of only one diastereoisomer
in all the substrates shown in Table 1 suggests that cycliza-
tion must occur with inversion of the configuration at C-2
according to an internal SN2 process (see scheme in Table 1).
The intramolecular attack of the sulfinamide anion to the
benzyl carbon must be much faster than heterolytic cleavage
of the C–S bond to generate the benzylic carbocation. This is
expected for aminosulfides 1a–g, bearing a sulfinyl group,
but it is also the case for 1h and 1i lacking of deactivating
group at the ring. Moreover, the complete stereoselectivity
observed in these reactions indicates that no base catalyzed
epimerization occurred and the intermediate did not revert
back to the corresponding ylide and imine.
Aminosulfides 1a–g were transformed into aziridines
through a one pot procedure. This method involves the
methylation at sulfenyl sulfur with MeI in the presence of
AgClO4. The resulting sulfonium salts were isolated simply
by filtration of the crude reaction mixture through a pad of
Celite followed by washing with CH2Cl2 and evaporate to
dryness. Sulfonium salts were then transformed to the corre-
sponding aziridines by cyclization with powered NaOH and
quenching the reaction mixture with water. The overall pro-
cess afforded analytically pure aziridines in moderate to high
yield after one chromatographic purification. The scope of
the aziridine synthesis is summarized in Table 1.
Table 1. Synthesis of N-sulfinyl aziridines 2a–i
SOTol
N
Y
Y
R
H
NHSOTol
R
NHSOTol
R
NaOH(s)
CH2Cl2
MeI
N
SOTol
H
Y
AgClO4
H
R
SMe
S(Me)2
Y
H
(Me)2S
ClO4
1a-i
2a-g (Y = SOTol)
2h, 2i (Y = H)
Entry
Substrate
Y
R
Aziridine
(% isolated yield)
de (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
SOTol
SOTol
SOTol
SOTol
SOTol
SOTol
SOTol
H
Ph
(2R,3R)-(ꢀ)-2a (78)
(2R,3R)-(+)-2b (43)
(2R,3R)-(ꢀ)-2c (65)
(2R,3R)-(ꢀ)-2d (65)
(2R,3R)-(ꢀ)-2e (76)
(2R,3R)-(ꢀ)-2f (45)
(2R,3R)-(+)-2g (75)
(2R,3R)-(+)-2h (77)
(2R,3R)-(+)-2i (76)
>98
>98
>98
>98
>98
>98
>98
>98
>98
o-BrC6H4
p-MeOC6H4
p-CNC6H4
2-Naphthyl
2-Pyridyl
n-Bu
Ph
n-Bu
H

Y. Arroyo et al. / Tetrahedron 62 (2006) 8525–8532
SOTol
8527
The trans-configuration for the aziridines 2a–i was based on
N
the reaction mechanism and clearly confirmed by the
coupling constants of the vicinal hydrogens H-2 and H-3
of 4.1–4.7 Hz.23 The absolute configuration was established
for (2R,3R)-2a and for (2R,3R)-2h by chemical correlation
with the known (+)-(R,R)-trans-2,3-diphenylaziridine 3.24
C-desulfinylation and N-desulfinylation of 2a, in one pot re-
action, take place in almost quantitative yield by reaction
with t-BuLi (2.2 equiv). For 2h the hydrolysis of the N–S
bond was carried out by reaction with TFA (1.5 equiv)/
MeOH without ring-opening (Scheme 2). The obtained
aziridine 3 exhibited the same specific optical rotation as
that reported in the literature,24 so that it was considered to
be enantiopure. These two reactions illustrate the way to ob-
tain NH-aziridines from the N-sulfinyl aziridines 2a–i shown
in Table 1. It is remarkable that the cleavage of the N–S bond
with t-BuLi is possible for 2a but not for 1a.18 The similar
behavior observed in all the cyclization reactions, all of
them evolving in a completely stereoselective manner, sug-
gests that the absolute configuration for compounds 2b–i is
identical to that determined for 2a.
Ph
H
O
NH2
H
S
i
Ph
R
R
S
S
OH
S
O
Tol
Tol
2a
4a
ii
NH2
S
R Ph
OH
NH2
S
S
S
Tol
Ph
R
O
OH
4b
5a
Scheme 3. Reagents and conditions: i. (1) TFA (1.5 equiv), MeOH, 0 ꢁC,
15 min, (2) HCl(aq) 1 M followed by neutralization; ii. Ni–Ra, THF.
In order to explain these results, the anchimeric assistance of
the sulfinyl group in the opening of the aziridine ring must
be assumed. After the hydrolysis of the N–S bond by TFA,
the protonation at aziridinic nitrogen must be followed by
the intramolecular attack of the sulfinyl oxygen to form an
oxysulfonium intermediate A (Scheme 4). The attack of
the nucleophile (H2O) to the sulfur of this intermediate,
maybe catalyzed by the protonation at oxygen with HCl,
would determine the formation of the sulfoxide 4a with
(R)-configuration at sulfur.
H
N
SOTol
N
Ph
H
Ph
H
H
tBuLi (2.2 equiv)
THF, -78 °C
H
SOTol
2a
3
TFA (1.5 equiv)/MeOH
85%
H
H
0 °C/10 min
N
NH2
Ph
H
SOTol
N
i
H
2a
S
Ph
R
Ph
H
H
H
H
O
O
S
H2O
S
S
S
Tol
Tol
A
2h
ii
Scheme 2.
4a
Scheme 4. Reagents and conditions: i. TFA (1.5 equiv), MeOH, 0 ꢁC,
15 min; ii. HCl(aq) 1 M.
In order to study the influence of the sulfinyl group on
the course of the opening ring we choose compound 2a.
According to the electronic effects of the aromatic rings,
the nucleophilic processes evolving through unimolecular
mechanisms (SN1) should mainly take place on the benzyl
carbon joined to the Ph group with epimerization. By
contrast, reactions involving SN2 mechanisms would be
completely stereoselective but moderately regioselective.
We first studied the reaction of 2a with TFA in MeOH
followed by reaction with aqueous HCl and neutralization.
Only one aminoalcohol, 4a, was formed under these condi-
tions, which indicates that the opening of the aziridine ring
of 2a has occurred with a complete control of the regio-
and stereoselectivity (Scheme 3).
Finally we have studied the reaction of 2c with TFA in meth-
anol. In this case, a 80:20 mixture of two b-aminoethers, 6c
and 60c, was obtained (Scheme 5). They were purified by
chromatography, but only the major one (6c) could be ob-
tained in diastereomerically pure form. Regiochemistry as
1
well as stereochemistry of 6c have been determined by H
NMR. The major isomer (6c) exhibits a coupling constant
in benzene (6.8 Hz), which increases in DMSO (8.0 Hz). It
suggests that population of the conformation with and anti
relationship between the coupled protons increases when in-
tramolecular associations of the OH and NH2 groups (hydro-
gen bonds) are minimized by the solvent. This behavior is
only expected for the erythro isomer with the opposite con-
figuration at the chiral carbons. Regiochemistry of 6c was
deduced from NOESY experiments performed in DMSO
(Fig. 1) and benzene. It is remarkable that the proton joined
to the oxygenated carbon exhibits a lower chemical shift
than the one joined to the nitrogenated carbon, which can
only be explained as a consequence of the anisotropic effect
of the S–O bond, which reinforces the regiochemistry postu-
lated for 6c.
The absolute configuration of the aliphatic chiral carbons at
4a was established by chemical correlation with the (1S,2R)-
2-amino-1,2-diphenylethane-1-ol 5a.25 This correlation was
performed by reaction of 4a with Ra–Ni.26 The configura-
tion at sulfur was established as R by comparison of the
NMR data of 4a with those of the 4b (Scheme 3), previously
obtained.27 As they are different, both compounds should
be diastereoisomers, which means that they differ in the
configuration at sulfur.

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Y. Arroyo et al. / Tetrahedron 62 (2006) 8525–8532
SOTol
N
OMe
diisopropylamine over KOH. n-BuLi (1.6 M solution in
ˆ
hexane) were purchased from Acros. All reaction vessels,
H
H
after being flame-dried, were kept under argon. Reactions
were monitored by TLC on commercially available
precoated plates (Merck silica gel 60 F254). Column chroma-
tography was performed by using Silica Gel Merck 60 (230–
400 mesh) and Varian SCX column. Melting points were
measured using a Gallemkamp apparatus in open capillary
tubes and are uncorrected. Optical rotations were measured
with a 141 Perkin–Elmer polarimeter. 1H NMR spectra
(300 MHz, CDCl3) and 13C NMR (75 MHz, CDCl3) spectra
were performed with a Bruker AC-300 spectrometer. Chemi-
cal shifts (d) are given in parts per million, relative to TMS,
coupling constants (J) in hertz. Mass spectra were measured
by electron impact (EI, 70 eV) or FAB with a VG AutoSpec
spectrometer.
R
H
i
S
O
S
NH2
S
Tol
OMe
O
Tol
B
2c
OMe
OMe
R
R
R
S
NH2
S
+
OMe
S
NH2
S
S
Tol
OMe
Tol
O
O
6c'
6c (72%)
Scheme 5. Reagents and conditions: i. (1) TFA (1.5 equiv), MeOH, 0 ꢁC,
15 min.
This is the typical result expected for SN1 processes involv-
ing stable benzyl carbocations stabilized by the p-OMe
group that can be attacked by the solvent, methanol, from
any of its diastereotopic faces, affording 6c and 60c. The
4.2. Synthesis of [1R,2S,(S)S]-N-{1-pyridyl-2-[(S)-2-(p-
toluenesulfinyl)phenyl]-2-(methylthio)ethyl}-p-toluene
sulfinamide,18 1f
A solution of n-BuLi (0.60 mmol, 1.6 M in hexane,
i
1.2 equiv) was added over Pr2NH (0.89 mmol, 1.8 equiv)
in THF (3 ml) at 0 ꢁC. After 45 min stirring, the mixture
was cooled at ꢀ78 ꢁC and then a solution of (S)-a-
methylthio-2-(p-tolylsulfinyl)toluene (138 mg, 0.50 mmol,
1.0 equiv) in THF (2 ml) was added. After 5 min
stirring, N-(2-pyridinemethylidene)-p-toluene sulfinamide28
(244 mg, 1.0 mmol, 2.0 equiv) dissolved in THF (4 ml) was
added at ꢀ78 ꢁC. When the reaction was completed (5 min),
the mixture was hydrolyzed at that temperature with satu-
rated aqueous NH4Cl (2 ml) and extracted with CH2Cl2
(3ꢂ10 ml). The combined organic extracts were dried with
MgSO4 and the solvent was removed under reduced pressure
to afford a mixture of epimers in C1, in 96:4 ratio. The
residue was purified by flash-column chromatography
(AcOEt/hexane 4:1) to give pure aminosulfide 1f (60%):
H
H
MeO
H
H
H
H N
S
2
OMe
O
Me
H
large NOE
small NOE
6c
Figure 1. Effects of NOEs observed for NOESY experiments from 6c.
low stability of the carbocations derived from 2a determines
that they cannot be spontaneously formed from the proton-
ated species shown in Scheme 4. It is also remarkable that
nucleophilic intramolecular attack of the sulfinyl oxygen
to the carbocation B (it would yield the alcohol instead of
the OMe derivative) is slower than the attack of the solvent.
It suggests that the formation of a five-membered ring like A
in Scheme 4 is much easier than the formation of a six-
membered ring that must be formed from B of Scheme 5.
1
[a]2D0 +18.4 (c 0.5, CHCl3); H NMR (300 MHz, CDCl3):
d 8.63 (dd, 1H, J 4.6, 1.5, H-arom.), 8.11 and 7.66 (2dd,
2H, J 7.2, 1.5, H-arom.), 7.69–7.57 (m, 3H, H-arom.), 7.33
(dd, 1H, J 7.7, 0.9, H-arom.), 7.26–7.22 (m, 1H, H-arom.),
7.60, 6.94, 6.87, and 6.50 (2 AA0BB0 systems, 8H,
H-arom.), 4.90 (d, 1H, J 10.5, H-C2), 4.68 (t, 1H, J 10.5,
H-C1), 4.39 (d, 1H, J 10.5, –NH), 2.34 and 2.11 (2s, 6H,
2CH3C6H4–), 1.63 (s, 3H, CH3S–); 13C NMR (75 MHz,
CDCl3): d 159.2, 144.5, 141.8, 141.4, 140.6 and 139.6
(C-arom.), 139.7, 136.5, 131.8, 129.6 (2C), 129.0 (2C),
128.9, 128.2, 126.1 (2C), 125.0 (2C), 124.5, 123.4 and
123.1 (CH-arom.), 65.1 and 49.7 (C-1 and C-2), 21.2
(2CH3C6H4–), 14.8 (CH3S–). HRMS calcd for
C28H28N2O2S3: 520.1313; found, 520.1307.
3. Conclusion
In summary a new entry to enantiopure trans-N-sulfinyl azir-
idines starting from enantiopure 1,2-aminosulfides is re-
ported. It involves their conversion into the corresponding
2-aminosulfonium salts followed by the completely stereo-
selective elimination of the sulfur moiety according to an
internal SN2 process. The anchimeric assistance of the sul-
finyl group allows the complete regio- and stereocontrolled
opening of some ortho-sulfinylphenyl aziridines in acidic
medium.
4.3. General procedure for the reactions of aziridination
summarized in Table 1
To a solution of 1,2-aminosulfides [(1a–i), 0.1 mmol]
in methyliodide (1 ml) was added silver perchlorate
(20.8 mg, 0.1 mmol). The mixture was stirred for 3 h at
room temperature and then filtered through a pad of Celite,
the filtrate was washed with CH2Cl2. The solvent was evapo-
rated to give the required salt, as a white solid, which was
used without further purification. To a solution of the appro-
priate salt (1 mmol) in CH2Cl2 (5 ml) was added powered
4. Experimental
4.1. General
Dry solvents and liquid reagents were distilled under
argon just prior to use. THF was distilled from sodium and
benzophenone ketyl, CH2Cl2 was dried over P2O5, and

Y. Arroyo et al. / Tetrahedron 62 (2006) 8525–8532
8529
KOH (4.1 mg, 0.062 mmol). The mixture was stirred for 1 h
at room temperature. The reaction was hydrolyzed with 4 ml
of water, and the mixture was extracted with CH2Cl2
(3ꢂ4 ml). The organic layer was dried over MgSO4, and
the solvent was removed under reduced pressure. The resi-
due was purified by flash-column chromatography.
CDCl3): d 143.2, 142.3, 142.1, 142.0, 140.6, 140.0, 133.8
and 133.2 (C-arom.), 132.3, 131.1, 130.1, 129.7, 129.6,
128.9, 128.6, 126.4, 124.7 and 124.5 (CH-arom.), 59.9 and
41.9(C-2andC-3), 21.4and21.2(2CH3C6H4–). HRMScalcd
for C22H17N2OS: (M+ꢀSOTol): 357.1062; found, 357.1054.
4.3.5. trans-(2R,3R)-2-(2-Naphthyl)-3-[(S)-2-( p-toluene-
sulfinyl)phenyl]-1-[(S)-(p-toluenesulfinyl)]aziridine, 2e.
Eluent for chromatography: hexane/AcOEt 1:1. Yield:
4.3.1. trans-(2R,3R)-2-Phenyl-3-[(S)-2-( p-toluenesulfinyl)-
phenyl]-1-[(S)-(p-toluenesulfinyl)]aziridine, 2a. Eluent
for chromatography: hexane/Et2O 1:4. Yield: 78%; white
1
76%; white syrup; [a]2D0 ꢀ91.5 (c 0.6, CHCl3); H NMR
syrup; [a]2D0 ꢀ23.6 (c 0.9, CHCl3); H NMR (300 MHz,
(300 MHz, CDCl3): d 8.04 (dd, 1H, J 7.8, 1.0, H-arom.),
7.85, 7.19, and 7.20 (part of AA0BB0 system, 4H, H-
arom.), 7.56–7.30 (m, 15H, H-arom.), 4.32 and 4.30 (2d,
2H, J 4.3, H-C2 and H-C3), 2.35 and 2.34 (2s, 6H,
2CH3C6H4–); 13C NMR (75 MHz, CDCl3): d 145.1, 142.7,
142.1, 141.6, 141.0, 133.2, 133.0, 132.7 and 131.4 (C-
arom.), 131.0, 130.1, 129.5, 129.4, 128.7, 128.3, 128.1,
128.0, 127.7, 126.5, 126.4, 125.3, 124.8 and 124.6 (CH-
arom.), (C-2 and C-3 are missing), 21.4 (2CH3C6H4–).
HRMS calcd for C25H20 NOS (M+ꢀSOTol): 382.1266;
found, 382.1252.
1
CDCl3): d 8.02 (dd, 1H, J 7.8, 0.9, H-arom.), 7.56–7.19
(m, 12H, H-arom.), 4.22 and 4.14 (2d, 2H, J 4.4, H-C2
and H-C3), 2.36 and 2.35 (2s, 6H, 2CH3C6H4–); 13C NMR
(75 MHz, CDCl3): d 145.1, 142.6, 142.0, 141.6, 141.0,
133.8 and 132.7 (C-arom.), 130.9, 130.1, 129.4, 129.3,
128.5, 128.4, 128.3, 126.4, 124.8 and 124.5 (CH-arom.),
(C-2 and C-3 are missing), 21.4 and 21.3 (2CH3C6H4–).
HRMS calcd for C21H18NOS (M+ꢀSOTol): 332.1109;
found, 332.1106.
4.3.2. trans-(2R,3R)-2-(o-Bromophenyl)-3-[(S)-2-( p-tol-
uenesulfinyl)phenyl]-1-[(S)-(p-toluenesulfinyl)]aziridine,
2b. Eluent for chromatography: hexane/Et2O 2:1. Yield:
4.3.6. trans-(2R,3R)-2-(Pyridyl)-3-[(S)-2-( p-toluenesulfi-
nyl)phenyl]-1-[(S)-(p-toluenesulfinyl)]aziridine, 2f. Elu-
ent for chromatography: hexane/Et2O 1:2. Yield: 45%;
white syrup; [a]D20 ꢀ46.3 (c 0.3, CHCl3); 1H NMR
(300 MHz, CDCl3): d 7.97 (d, 1H, J 7.9, H-arom.), 7.71
(dd, 1H, J 7.9, 1.7, H-arom.), 7.50–7.29 (m, 5H, H-arom.),
7.48, 7.45, 7.20, and 7.19 (2 AA0BB0 systems, 8H, H-
arom.), 4.48 and 4.19 (2d, 2H, J 4.1, H-C2 and H-C3),
2.35 (s, 6H, CH3C6H4–); 13C NMR (75 MHz, CDCl3):
d 154.9, 144.9, 142.5, 141.9, 141.6, 140.9 and 132.7 (C-
arom.), 139.5, 136.7, 131.0 (3C), 130.1, 129.4 (2C), 128.6,
126.2 (2C), 124.8 (2C), 124.3, 123.4 and 123.2 (CH-
arom.), (C2 and C3 are missing), 21.4 (2CH3C6H4–).
1
43%; white syrup; [a]2D0 +48.3 (c 0.2, CHCl3); H NMR
(300 MHz, CDCl3): d 7.96 (d, 1H, J 7.7, H-arom.), 7.59,
7.58, 7.45, and 7.44 (2 AA0BB0 systems, 8H, H-arom.),
7.56–7.50 (m, 1H, H-arom.), 7.34–7.17 (m, 6H, H-arom.),
4.33 and 4.29 (2d, 2H, J 4.7, H-C2 and H-C3), 2.38 (s,
6H, CH3C6H4–); 13C NMR (75 MHz, CDCl3): d 154.2,
151.8, 142.9, 142.2, 142.0, 141.6, 141.0 and 132.3 (C-
arom.), 132.4, 131.1, 130.1 (2C), 129.9, 129.6, 129.4 (2C),
128.7, 127.4, 126.4 (2C), 124.8 and 124.6 (3C, CH-arom.),
(C-2 and C-3 are missing), 21.4 (2CH3C6H4–). HRMS calcd
for C21H17BrNOS (M+ꢀSOTol): 410.0214; found,
410.0219.
4.3.7. trans-(2R,3R)-2-Butyl-3-[(S)-2-( p-toluenesulfinyl)-
phenyl]-1-[(S)-(p-toluenesulfinyl)]aziridine, 2g. Eluent
for chromatography: hexane/Et2O 1:3. Yield: 75%; colorless
oil; [a]2D0 +27.2 (c 0.3, CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.87 (dd, 1H, J 7.7, 1.1, H-arom.), 7.49, 7.45, 7.25, and
7.18 (2 AA0BB0 systems, 8H, H-arom.), 7.36 (dt, 1H, J
7.7, 1.1, H-arom.), 7.25 and 6.75 (2d, 2H, J 7.7, H-arom.),
3.81 (d, 1H, J 4.1, H-C3), 2.74 (dt, 1H, J 6.4, 4.1, H-C2),
2.38 and 2.35 (2s, 6H, 2CH3C6H4–), 2.07–1.38 (3m, 6H,
CH3(CH2)3–), 0.96 (t, 1H, J 7.2, CH3(CH2)3–); 13C NMR
(75 MHz, CDCl3): d 144.4, 142.8, 141.7, 141.4, 141.3 and
134.8 (C-arom.), 130.9, 130.1, 129.3, 128.5, 126.7, 125.8,
124.7 and 124.0 (CH-arom.), 49.8 and 33.9 (C-2 and C-3),
30.3, 28.2 and 22.4 (CH3(CH2)3–), 21.4 and 21.3
(2CH3C6H4–), 13.9 (CH3(CH2)3). HRMS calcd for
C19H22NOS (M+ꢀSOTol): 312.1422; found, 312.1420.
4.3.3. trans-(2R,3R)-2-(p-Methoxyphenyl)-3-[(S)-2-( p-tol-
uenesulfinyl)phenyl]-1-[(S)-(p-toluenesulfinyl)]aziridine,
2c. Eluent for chromatography: hexane/Et2O 1:2. Yield:
1
65%; yellow syrup; [a]2D0 ꢀ44.1 (c 0.5, CHCl3); H NMR
(300 MHz, CDCl3): d 7.98 (d, 1H, J 7.8, H-arom.), 7.45
(dd, 4H, J 8.0, 6.1, H-arom.), 7.34 (dd, 4H, J 6.4, 2.5, H-
arom.), 7.23–7.13 (m, 5H, H-arom.), 6.92 (d, part of AA0BB0
system, 2H, H-arom.), 4.27 and 4.00 (2d, 2H, J 4.1, H-C2
and H-C3), 3.83 (s, 3H, CH3O–C6H4–), 2.36 and 2.35 (2s,
6H, 2CH3C6H4–). 13C NMR (75 MHz, CDCl3): d 159.7,
144.8, 142.0, 141.6, 141.5, 141.2, 141.0 and 133.4 (C-
arom.), 132.0, 131.0, 130.8 (2C), 130.5, 130.2 (2C), 129.4
(2C), 128.0, 126.2 (2C), 124.8 (2C) and 114.3 (2C, CH-
arom.), 55.2 (CH3OC6H4–), (C2 and C3 are missing), 21.4
(2CH3C6H4–). HRMS calcd for C22H20NO2S (M+ꢀSOTol):
362.1215; found, 362.1225.
4.3.8. trans-[2R,3R,(S)S]-2,3-Diphenyl-1-( p-toluenesulfi-
nyl)aziridine, 2h. Eluent for chromatography: hexane/
Et2O 4:1. Yield: 77%; white syrup; [a]2D0 +117.9 (c 0.2,
CHCl3); 1H NMR (300 MHz, CDCl3): d 7.60 (d, 1H, J 8.2,
H-arom.), 7.45–7.32 (m, 8H, H-arom.), 7.23 (d, 1H, J 8.2,
H-arom.), 4.17 (s, 2H, H-C2 and H-C3), 2.36 (s, 3H,
CH3C6H4–); 13C NMR (75 MHz, CDCl3): d 143.0, 141.3
and 134.7 (C-arom.), 129.4 (2C), 128.4 (3C), 128.1 (3C)
and 124.9 (2C, CH-arom.), 43.7 (C2 and C3), 21.3
(CH3C6H4–).
4.3.4. trans-(2R,3R)-2-(p-Cyanophenyl)-3-[(S)-2-( p-tol-
uenesulfinyl)phenyl]-1-[(S)-(p-toluenesulfinyl)]aziridine,
2d. Eluent for chromatography: hexane/Et2O 1:2. Yield:
1
65%; white syrup; [a]2D0 ꢀ27.0 (c 0.6, CHCl3); H NMR
(300 MHz, CDCl3): d 7.97 (d, 1H, J 7.8, H-arom.), 7.65
(d, part of AA0BB0 system, 2H, H-arom.), 7.59–7.29 (m,
5H, H-arom.), 7.44, 7.43, 7.23, and 7.22 (2 AA0BB0 systems,
8H, H-arom.), 4.21 and 4.17 (2d, 2H, J 4.1, H-C2 and H-C3),
2.37 and 2.36 (2s, 6H, CH3C6H4–); 13C NMR (75 MHz,

8530
Y. Arroyo et al. / Tetrahedron 62 (2006) 8525–8532
4.3.9. trans-[2R,3R,(S)S]-2-Butyl-3-phenyl-1-(p-toluene-
sulfinyl)aziridine, 2i. Eluent for chromatography: hexane/
Et2O 4:1. Yield: 76%; colorless oil; [a]2D0 +16.0 (c 0.6,
CHCl3); 1H NMR (300 MHz, CDCl3): d 7.61 and 7.22
(AA0BB0 system, 4H, H-arom.), 7.26–7.16 (m, 3H, H-
arom.), 7.12 (dd, 2H, J 7.7, 2.2, H-arom.), 3.67 (d, 1H,
J 4.1, H-C3), 2.75–2.70 (m, 1H, H-C2), 2.10–1.21 (2m,
6H, –(CH2)3CH3), 0.95 (t, 3H, J 7.1, –(CH2)3CH3);
13C NMR (75 MHz, CDCl3): d 143.2, 141.2 and 137.1
(C-arom.), 129.4 (2C), 128.2 (2C), 127.3, 126.8 (2C) and
125.0 (2C, CH-arom.), 49.2 and 37.5 (C2 and C3),
30.4, 28.2 and 22.3 (–CH2)3CH3), 21.3 (CH3C6H4–), 14.0
(–(CH2)3CH3).
CDCl3): d 7.29–7.40 (m, 10H, H-arom.), 3.12 (s, 2H, H-
C2 and H-C3), 1.70 (br s, 1H, –NH).
4.5. Representative procedure N–S desulfinylation
Method A: To a stirred solution of aziridine 2a (0.05 mmol)
in methanol (1 ml) was added TFA (6.3 ml, 0.08 mmol,
1.5 equiv). After the mixture was stirred for 15 min at
0 ꢁC, the solvent was evaporated, and the residue was filtered
through SCX column chromatography. The reaction mixture
was diluted in methanol (1 ml) and then HCl (0.5 ml, 1 N)
was added. After 1 h, concentrated NH3 was added until
the solution was brought to pH 10. The solvent was evapo-
rated, and the residue was purified by SCX column chroma-
tography to afford the corresponding aminoalcohol.
4.4. Representative procedure for C–S desulfinylation
To a stirred solution of 1a and 1h (0.12 mmol) in THF
(2 ml) was added t-BuLi (0.15 ml, 0.22 mmol, 1.5 M in
hexane, 1.8 equiv). When the reaction was completed
(5 min), the mixture was hydrolyzed with saturated
aqueous NH4Cl (1 ml) and extracted with CH2Cl2
(3ꢂ3 ml). The combined organic layers were dried over
MgSO4, and the solvent was removed under reduced
pressure. The residue was purified by flash-column chroma-
tography.
4.5.1. (1R,2S)-2-Amine-2-phenyl-1-[(R)-(2-p-toluenesul-
finyl)phenyl]-ethanol, 4a. Eluent for chromatography:
NH3/methanol (7 M). Yield: 70%; colorless oil; [a]2D0 +40
(c 0.3, EtOH); 1H NMR (300 MHz, CDCl3): d 7.84 (d, 1H,
J 7.4, H-arom.), 7.77 (d, 1H, J 6.7, H-arom.), 7.60 (dd,
1H, J 7.4, 6.7, H-arom.), 7.48–7.32 (m, 6H, H-arom.),
7.26–7.17 (m, 4H, H-arom.), 4.93 (br s, 1H, HO-C1), 4.84
and 4.44 (2d, 2H, J 8.3, H-C1 and H-C2), 2.36 (s, 3H,
CH3C6H4–). HRMS calcd for C21H22NO2S (M++1):
352.1365; found, 352.1341.
4.4.1. [1R,2S,(S)S]-N-[1,2-(Diphenyl)-2-(methyl-
thio)ethyl]-p-toluene sulfinamide, 1h. This product was
obtained from 1a. Eluent for chromatography: hexane/
Et2O 1:1; quantitative yield; colorless syrup; spectroscopic
and optical rotation data of compound 1h are coincident
with those previously reported: [a]2D0 +155.0 (c 0.7,
CHCl3) [lit.18¼+155.8 (c 0.5, CHCl3)]; 1H NMR
(300 MHz, CDCl3): d 7.33–7.21 (m, 7H, H-arom.), 7.20–
7.15 (m, 3H, H-arom.), 7.00–6.98 (m, 2H, H-arom.), 4.76
(dd, 1H, J 6.1, 6.5, H-C1), 4.75 (br s, 1H, –NH), 4.21 (d,
1H, J 6.5, H-C2), 2.31 (s, 3H, CH3C6H4–), 1.84 (s, 3H,
CH3S–).
Method B: To a stirred solution of aziridine 2c (0.05 mmol)
in methanol (1 ml) was added TFA (6.3 ml, 0.08 mmol,
1.5 equiv). After the mixture was stirred for 15 min at
0 ꢁC, the solvent was evaporated, and the residue was puri-
fied by flash-column chromatography (CH2Cl2/MeOH
95:5) to give a mixture of amines 6c and 60c in a 80:20 ratio
(yield 90%). Only the major product could be isolated as
pure compound.
4.5.2. (1R,2S)-2-Methoxy-2-(p-methoxyphenyl)-1-[(S)-(2-
p-toluenesulfinyl)phenyl]-ethylamine, 6c. White syrup;
[a]2D0 ꢀ127.1 (c 0.7, CHCl3); 1H NMR (300 MHz, DMSO-
d6): d 7.56 (m, 2H, H-arom.), 7.43–7.32 (m, 2H, H-arom.),
7.48 and 7.28 (AA0BB0 system, 4H, CH3C6H4–), 7.01 and
6.75 (AA0BB0 system, 4H, H-arom.), 4.46 (d, 1H, J 7.98,
H-C1), 4.19 (d, 1H, J 7.98, H-C2), 3.67 (s, 3H, CH3O–
C6H4–), 3.12 (s, 3H, CH3O-C2), 2.29 (s, 3H, CH3C6H4–);
13C NMR (75 MHz, DMSO-d6): d 158.8, 144.0, 143.2,
141.0 and 140.3 (C-arom.), 130.7 (CH-arom.), 130.4 (C-
arom.), 130.1 and 128.8 (2C, CH-arom.), 128.4 and 128.3
(2C, CH-arom.), 125.1 (2C), 123.2 and 113.5 (2C, CH-
arom.), 87.6 (C-2), 56.5 and 56.4 (C-1 and CH3O-C-2),
55.1 (CH3OC6H4–), 21.0 (CH3C6H4–). 1H NMR
(300 MHz, C6D6): d 8.21 (m, 1H, H-arom.), 7.66 (m, 3H,
H-arom.), 7.24–7.09 (m, 4H, H-arom.), 6.85 (m, 4H, H-
arom.), 4.89 (br s, 1H, H-C1), 4.30 (d, 1H, J 6.80, H-C2),
3.35 (s, 3H, CH3O–C6H4–), 3.20 (s, 3H, CH3O-C2), 1.97
(s, 3H, CH3C6H4–). HRMS calcd for C23H26NO3S
(M++1): 396.1627; found, 396.1616.
4.4.2. [1R,2S,(S)S]-N-[1-Butyl-2-phenyl-2-(methyl-
thio)ethyl]-p-toluene sulfinamide, 1i. This product was ob-
tained from 1g. Eluent for chromatography: hexane/Et2O
4:1; quantitative yield; colorless oil; [a]2D0 +180.6 (c 0.7,
CHCl3); 1H NMR (300 MHz, CDCl3): d 7.53 and 7.40
(AA0BB0 system, 4H, H-arom.), 7.34–7.23 (m, 5H, H-
arom.), 4.26 (d, 1H, J 9.4, H-C2), 4.18 (d, 1H, J 5.0,
–NH), 3.65–3.56 (m, 1H, H-C1), 2.39 (s, 3H, CH3C6H4–),
1.96 (s, 3H, CH3S–), 1.51–0.92 (m, 6H, CH3(CH2)3–),
0.78 (t, 1H, J 7.0, CH3(CH2)3–); 13C NMR (75 MHz,
CDCl3): d 142.0, 141.0 and 139.2 (C-arom.), 129.2 (2C),
128.9 (2C), 128.3 (2C), 127.2 and 125.7 (2C, CH-arom.),
59.4 and 59.3 (C-1 and C-2), 32.1, 27.8 and 22.1
(CH3(CH2)3–), 21.4 and 21.2 (2CH3C6H4–), 15.0 and 13.8
(CH3S– and CH3(CH2)3). HRMS calcd for C19H22NOS:
312.1422; found, 312.1421.
4.4.3. (D)-(2R,3R)-2,3-Diphenylaziridine, 3. This product
was obtained from 2a following the procedure described
above but using 2.2 equiv of t-BuLi. The product was puri-
fied by SCX column chromatography. Yield: 75%; colorless
syrup; [a]2D0 +320 (c 0.5, CHCl3) [lit.24¼328.8 (c 1.25,
CHCl3)]; spectroscopic data of compound 3 are coincident
with those previously reported:24 1H NMR (300 MHz,
4.5.3. (1R,2R)-2-Methoxy-2-(p-methoxyphenyl)-1-[(S)-
(2-p-toluenesulfinyl)phenyl]-ethylamine, 60c. Whitesyrup;
1H NMR (300 MHz, CDCl3), described from a mixture of
compounds 6c and 60c: d 7.96 and 7.60 (2dd, 2H, J 7.5,
1.7, H-arom.), 7.55–7.37 (m, 2H, H-arom.), 7.48, 7.22,
7.11, and 6.86 (2 AA0BB0 systems, 8H, H-arom.), 4.58 and

Y. Arroyo et al. / Tetrahedron 62 (2006) 8525–8532
8531
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4.6. Representative procedure for C–S desulfinylation
with Ni–Ra
A solution of compound 4a (0.05 mmol) in THF (1 ml) was
added to a suspension of activated Raney nickel (350 mg) in
THF (1 ml). The mixture was stirred for 2 h, and the crude
was purified by SCX column to afford the aminoalcohol 5a.
4.6.1. (1S,2R)-2-Amino-1,2-diphenylethanol, 5a. Yield:
68%; [a]2D0 +6.9 (c 0.5, EtOH) [lit.25¼+7.0 (c 0.6, EtOH)];
spectroscopic data of compound 5a are coincident with those
previously reported:25 1H NMR (300 MHz, CD3OD): d
7.30–7.19 (m, 10H, H-arom.), 4.81 and 4.04 (2d, 2H, J 6.1,
H-C1 and H-C2).
´
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Acknowledgements
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We thank the DGYCT (BQU2003-04012) and JCYL
(VA07905) for financial support.
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