Activation of oxaziridines by Lewis acids: Application in enantioselective sulfoxidation

Article abstract of DOI:10.1021/jo048380k

(Chemical Equation Presented). The preparation of new and easily accessible chiral N-alkyloxaziridines for asymmetric sulfides oxidation was investigated. Most significantly, we report here that inert N-alkyloxaziridines can be activated by Lewis acids to

Full text of DOI:10.1021/jo048380k

Activation of Oxaziridines by Lewis Acids: Application in
Enantioselective Sulfoxidation
Se´bastien Schoumacker,† Olivier Hamelin,*,† Se´bastien Te´ti,† Jacques Pe´caut,‡ and
Marc Fontecave*,†
Laboratoire de Chimie et Biochimie des Centres Re´dox Biologiques, DRDC-CB, UMR 5047 Universite´
Joseph Fourier/CEA/CNRS, CEA Grenoble, 17 avenue des Martyrs, 38054 Grenoble Cedex, France, and
DRFMC, CEA Grenoble, 17 avenue des Martyrs, 38054 Grenoble Cedex, France
ohamelin@cea.fr; mfontecave@cea.fr
Received September 14, 2004
The preparation of new and easily accessible chiral N-alkyloxaziridines for asymmetric sulfides
oxidation was investigated. Most significantly, we report here that inert N-alkyloxaziridines can
be activated by Lewis acids to achieve a fast, selective, and efficient oxygen atom transfer to sulfides.
Asymmetric sulfoxidation by three new chiral oxaziridines (two of them were structurally
characterized by X-ray analysis) afforded enantioselectivities ranging from 22% to 63% ee with
the simplest aryl alkyl sulfides.
SCHEME 1. Activation of Oxaziridines by
Electron-Withdrawing Groups
Introduction
Oxaziridines, characterized by a reactive strained C,
N, O three-membered ring, have shown interesting
reactivities as nitrogen and oxygen atom transfer re-
agents since their first isolation in the mid-1950s by three
independent groups.1 It has been established that amino
group transfer is the normal reaction of N-H, N-alkyl,
N-aryl, N-acyl, N-carboxyamido, and N-alkoxycarbonyl
oxaziridines with various nucleophiles such as sulfides,
amines, phosphines, and carbanions.2 However, when the
oxaziridine is substituted by bulky3 or electron-with-
drawing4 substituents on the nitrogen atom or both the
nitrogen and the carbon atoms of the three-membered
ring (Scheme 1), the electrophilic reactivity is shifted
from the nitrogen to the oxygen atom and many oxida-
tions are allowed. For example, amines can be efficiently
converted to N-hydroxylamines, nitrones, or N-oxides and
alkenes, selenides, sulfides, and phosphines can be
converted to their corresponding oxides, whereas unac-
tivated alkanes can be oxidized to alcohols when the
highly reactive perfluorinated oxaziridines are used.4
Probably the most commonly used oxaziridines are
those developed by Davis and co-workers who reported
the use of N-sulfonyloxaziridines as the only oxaziridines
able to oxidize nucleophilic substrates at rates compa-
rable to peracids.5 Indeed, these reagents quantitatively
oxidize most sulfides to sulfoxides within a few minutes
and with high chemioselectivity, avoiding the formation
of sulfones as overoxidation products. A valuable exten-
sion of oxidations by oxaziridines has been the use of
* To whom correspondence should be addressed. Fax: (+33)438-
789-124.
† Universite´ Joseph Fourier.
‡ DRFMC.
(1) (a) Emmons, W. D. J. Am. Chem. Soc. 1957, 79, 5739. (b) Horner,
L.; Ju¨rgens, E. Chem. Ber. 1957, 90, 2184. (c) Krimm, H. Chem. Ber.
1958, 91, 1057.
(2) Page, P. C. B., Limousin, C.; Murrell, V. L. J. Org. Chem. 2002,
67, 7787 and references therein.
(5) (a) Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703.
(b) Davis, F. A., Lal, S. G. J. Org. Chem. 1988, 53, 5004. (c) Davis, F.
A.; Jenjins, R. H., Jr,; Awad, S. B.; Stringer, O. D.; Watson, N. H.;
Galloy, J. J. Am. Chem. Soc. 1982, 104, 5412.
(3) Hata, Y.; Watanabe, M. J. Org. Chem. 1981, 46, 610.
(4) Adam, W.; Saha-Mo¨ller, C. R.; Ganeshpure, P. A. Chem. Rev.
2001, 101, 3499-3548.
10.1021/jo048380k CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/09/2004
J. Org. Chem. 2005, 70, 301-308
301

Schoumacker et al.
SCHEME 2. Synthesis of the Imines 1-3 and of the Corresponding Oxaziridines 4-6
optically active N-sulfonyl5c,6 and sulfamyl7 oxaziridines
and related systems8 as well as chiral phosphinoylox-
aziridines.9 Although yields for asymmetric sulfoxidations
are excellent, enantioselectivities are highly substrate-
dependent and usually range from low to moderate ee’s
and reach a high level only with bulky sulfides. To the
exception of the system developed by Page and co-
workers using chiral sulfonylimine as a catalyst (10 and
20% mol) and potassium percarbonate as an oxidant,
which affords low enantiomeric excesses,10 all the other
reported catalytic asymmetric sulfoxidations are per-
formed with 1 equiv of imine with regard to sulfide.4 The
imine could be recovered nearly quantitatively at the end
of the reaction; thus, these reactions qualify as catalytic
sulfoxidations even though no catalytic turnovers were
reported using substoichiometric quantities of chiral
imine.
Oxaziridinium salts, first reported by Lusinchi in 1976,
have also been shown to be extremely reactive for oxygen
transfer to nucleophilic substrates.11 Several chiral imi-
nium salts, oxidized in situ by Oxone to the corresponding
oxaziridinium salt, have essentially been used as cata-
lysts in asymmetric epoxidations.12
The first report of an enantioselective sulfoxidation by
an oxaziridinium salt prepared from (+)-norephedrine
showed moderate enantioselectivity over the course of the
oxidation of methyl p-tolyl sulfide to sulfoxide.12a It was
also demonstrated that oxygen atom transfer from N-
alkyloxaziridine to sulfides could be promoted by acid.13
Activation of the oxaziridine was proposed to result from
protonation of the basic nitrogen leading to the corre-
sponding oxaziridinium, which was thought to be the
active oxidizing species. However, this reaction gives
moderate yields and enantiomeric excesses and requires
strong acids (trifluoroacetic acid or methanesulfonic acid)
generally incompatible with a number of functional
groups.
namely 2-isopropyl-3-phen-2-yloxaziridine (4),14 2-isopro-
pyl-3-pyridin-2-yloxaziridine (5), and 2-isopropyl-3-quino-
lin-8-yloxaziridine (6) bearing one or two nitrogens as
potential coordinating sites, were synthesized (Scheme
2). They were easily and efficiently prepared in two steps
via the formation of the Schiff bases benzylideneisopro-
pylamine (1),15 isopropylpyridin-2-ylmethyleneamine (2),16
and isopropylquinolin-8-ylmethyleneamine (3) by con-
densation of the corresponding aldehydes with isopropy-
lamine in methanolic solution. The oxidation of the
resulting imines was then performed using Oxone as
oxidant according to the convenient monophasic proce-
dure developed by Yang and co-workers.17 In all cases,
excellent stereoselectivity was achieved leading to only
(6) (a) Davis, F. A.; Chattopathyay, S.; Towson, J. C.; Lal, S.; Reddy,
T. J. Org. Chem. 1988, 53, 2087. (b) Davis, F. A.; Towson, M. C.;
Weismiller, M. C.; Lal, L.; Carroll, P. J. J. Am. Chem. Soc. 1988, 110,
8477. (c) Page, P. C. B.; Heer, J. P.; Bethell, D.; Collington, E. W.;
Andrews, D. Org. Synth. 1999, 76, 37.
(7) Davis, F. A.; McCauley, J. P., Jr; Chattopadhyay, S.; Harakal,
M. E.; Towson, J. C.; Watson, W. H.; Tavanaiepour, I. J. Am. Chem.
Soc. 1987, 109, 3370.
(8) (a) Page, P. C. B.; Heer, J. P.; Bethell, D.; Collington, E. W.;
Andrews, D. M. Tetrahedron: Asymmetry 1995, 6, 2911. (b) Page, P.
C. B.; Heer, J. P.; Bethell, D.; Collington, E. W.; Andrews, D. M. Synlett
1995, 773. (c) Rebeck, J. Jr; McCready, R.; J. Am. Chem. Soc. 1980,
102, 5602. (d) Nanjo, K.; Suzuki, K.; Sekiya, M. Chem. Lett. 1978, 1143.
(e) Rebeck, J., Jr.; Wolf. S.; Mossman, A. J. Org. Chem. 1978, 43, 180.
(f) Page, P. C. B.; Heer, J. P.; Bethell, D.; Collington, E. W.; Andrews,
D. M. Tetrahedron Lett. 1994, 35, 9629.
(9) Jennings, W. B.; Kochanewycz, M. J.; Lovely, C. J.; Boyd, D. R.
J. Chem. Soc., Chem. Commun. 1994, 2569.
(10) Bethell, D.; Page, P. C. B.; Vahedi, H. J. Org. Chem. 2000, 65,
6756.
(11) (a) Milliet, P.; Picot, A.; Lusinchi, X. Tetrahedron Lett. 1976,
1573. (b) Milliet, P.; Picot, A.; Lusinchi, X. Tetrahedron Lett. 1976,
1577.
(12) (a) Lacour, J.; Monchaud, D.; Marsol, C. Tetrahedron Lett. 2002,
43, 8257. (b) Page, P. C. B.; Rassias, G.; A.; Barros, D.; Ardakani, A.;
Buckley, B.; Bethell, D.; Smith, T. A. D.; Slawin, A. M. Z. J. Org. Chem.
2001, 66, 6926. (c) Page, P. C. Bulman, Rassias, G. A.; Barros, D.;
Bethell, D.; Schilling, M. B. J. Chem. Soc., Perkin Trans. 1 2000, 3325.
(d) Washington, I.; Houk, K., N. J. Am. Chem. Soc. 2000, 122, 2948.
Minakata, S.; Takemiya, A.; Nakamura, K.; Ryu, I.; Komatsu, M.
Synlett 2000, 1810.(e) Bohe´, L.; Lusinchi, M.; Lusinghi, X. Tetrahedron
1999, 55, 141. (f) Amstrong, A.; Ahmed, G.; Garnett, I.; Goacolou, K.
Synlett 1997, 1075. (g) Aggarwal, V. K.; Wang, M. F. Chem. Commun.
1996, 191. (h) Page, P. C. B.; Buckley, B. R.; Blacker, A. J. Org. Lett.
2004, 6, 1543. (i) Page, P. C. B.; Barros, D.; Buckley, B. R.; Ardakanis,
A.; Marples, B. J. Org. Chem. 2004, 36, 3595.
(13) (a) Bohe´, L.; Hanquet, G.; Lusinchi, M.; Lusinchi, X. Tetrahe-
dron Lett. 1993, 34, 5299, 7271. (b) Bohe´, L.; Lusinchi, M.; Lusinchi,
X. Tetrahedron 1999, 55, 155.
(14) Hata, Y.; Watanabe, M.J. Am. Chem. Soc. 1979, 101, 6671.
(15) (a) Larsen, J.; Jorgensen, K. A. J. Chem. Soc., Perkin Trans. 2
1992, 1213. (b) Surrey, A. R. J. Am. Chem. Soc. 1948, 70, 4262.
(16) Chan, L.; Lees, A. J. J. Chem. Soc., Dalton Trans. 1987, 513.
(b) Crabb, T. A., Newton, R. F. Tetrahedron 1968, 24, 6327.
(17) Yang, D.; Wong, M.-K.; Yip, Y.-C. J. Org. Chem. 1995, 60, 3887.
In this paper, we investigated new and easily accessible
chiral N-alkyloxaziridines for asymmetric sulfoxidation.
Most significantly, we show for the first time that inert
N-alkyloxaziridines can be activated not only by protons
but also by general Lewis acids, in particular ZnCl2.
Results
Synthesis of the Oxaziridines 4-6. To investigate
the potential of Lewis acids as activating agents of
oxaziridines for sulfide oxidation, three oxaziridines,
302 J. Org. Chem., Vol. 70, No. 1, 2005

Activation of Oxaziridines by Lewis Acids
TABLE 1. Effect of the Nature of the Lewis Acid and of
the Solvent on the Oxidation of Methyl Phenyl Sulfide
by 5a
5/Lewis acid/
sulfide
yield (%)
Lewis acid
ZnCl2
ratio (mM)
solvent
Et2O
acetone
CH3CN
CHCl3
CHCl3
CCl4
EtOH
CHCl3
CH3CN
(reaction timea) entry
10:10:100
10:10:100
10:10:100
10:10:100
10: 1:100
10:10:100
10:10:100
10:10:100
10:10:100
10:10:100
10:10:100
10:10:100
10:10:100
0b (60 min)
95 (5 min)
1
2
95 (5 min)
3
98 (5 min)
4
45 (1 h)
5
0b (60 min)
75 (5 min)
6
7
BF3
43 (5 min) (100)c
57 (5 min) (100)c
8
9
CH3COCH3 75 (30 h) (90)c
10
11
12
13
AlCl3
Ag(O2CCF3)
CHCl3
CHCl3
CH3CN
80 (3 h)
45 (5 min) (94)c
50 (5 min) (94)c
FIGURE 1. Evolution of the chemical shifts of the H4 of the
pyridinyl moiety and the H methine of the isopropyl substitu-
ent (inset) of 5 as a function of increasing addition of ZnCl2 to
compound 5.
a Time for maximal conversion. b Formation of a precipitate.
c Recalculated yield (%) based on the consumed oxaziridine.
one diastereoisomer which was then purified by distil-
lation for 4 and by column chromatography on deacti-
vated (Et3N) silica for 5 and 6. Due to the high stereo-
selectivity of the oxidation leading to the formation of
single diastereomers, we may assume that all the com-
pounds 4-6 have a trans configuration.
oxaziridine was not fully consumed at the end of the
reaction (entries 8-10, 12, 13).
Determination of the Active Species Involved in
the Oxidation. In the following section, we describe
experiments aimed at identifying the active species
formed during the reaction of ZnCl2 and oxaziridine 5.
1H NMR spectroscopy was used to analyze the reaction
of increasing amounts of ZnCl2 added to a solution of 5
in CDCl3. Significant shifts in the resonances of a
majority of protons could be observed (i.e., from 4.7 to
5.2 ppm for the proton located on the oxaziridine ring
and from 7.67 to 8.12 for the H4 proton of the pyridine
ring). It is worth noting that even under substoechio-
metric conditions a single species could be observed by
NMR spectroscopy suggesting a fast equilibrium between
5 and a ZnCl2/5 adduct. Moreover, the spectrum modi-
fication reached its maximum after addition of 1 equiv
of ZnCl2 as shown in Figure 1 for the chemical shifts
corresponding to H4 of the pyridinyl substituent and the
H methine of the isopropyl moiety. From this, one may
conclude the formation of a ZnCl2/5 adduct of 1:1 sto-
echiometry.
This hypothesis is also supported by UV spectroscopy
experiments. The light absorption spectrum of 5 in
chloroform displays a broad band in the 235-280 nm
region. Addition of ZnCl2 from 0 to 1.5 equiv by 0.25 equiv
portions with regard to 5 resulted in a significant red
shift and an increased intensity. The optical changes
occurred with an isobestic point (252 nm) indicating the
presence of only two species in the solution during the
conversion of 5 to the ZnCl2/5 adduct (Figure 2).
Catalytic Activity of ZnCl2. The catalytic activity of
ZnCl2 was then explored during oxidation of the test
substrate by 5 (10 mM) in chloroform. With a 1:0.1:10
5/ZnCl2/substrate ratio, we observed that ZnCl2 displayed
catalytic activity (Table 1, entry 5). However, the reaction
rate was greatly decreased (4.5 turnovers in 1 h), and
the reaction stopped after formation of 45% of the
sulfoxide with regard to the oxidant. We speculate that
the reason for this behavior resides in the stronger
affinity of the imine 2 (one of the reaction products) for
ZnCl2 as compared to 5. Thus, accumulation of 2 would
result in increased scavenging of ZnCl2, within a ZnCl2-
(2) complex, and consequently, inactivation of the cata-
Oxidation of Sulfides. Oxidation of methylphenyl-
sulfide by oxaziridines 4-6 (10 mM) was then investi-
gated as a probe reaction with 10 equiv of sulfide in
chloroform and under air atmosphere. Preliminary stud-
ies were carried out with a stoichiometric amount of
ZnCl2 with regard to the oxidant, and the results were
compared to those obtained from the reaction without
ZnCl2. The reaction products were identified and quanti-
fied by GC-MS during the course of the reaction. A fast
and efficient oxidation was observed with 5 and 6 in the
presence of ZnCl2 and resulted in the formation of the
sulfoxide (98% yield, 5 min) as the only oxidation product
and the release of the precursor imines 2 and 3, respec-
tively (NMR determination). No sulfone could be de-
tected. When the reaction was carried out with 4 or
without ZnCl2 no oxidation occurred, demonstrating the
crucial importance of both the heterocyclic aromatic ring
and the Lewis acid for the activation of the oxaziridine.
To optimize the oxidation of methylphenylsulfide by
5, several solvents and Lewis acids were tested under
the conditions described above (10:10:100 mM oxaziri-
dine/Lewis acid/substrate ratio; Table 1; entries 1-4,
6-13).
The reactivities of BF3, AlCl3, ZnCl2, and Ag(O2CCF3)
were then compared in several solvents (Table 1). Using
ZnCl2 as a Lewis acid, most of the solvents tested afforded
excellent yields (up to 95%) after only a few minutes
except Et2O and CCl4, for which a precipitate was
observed as soon as ZnCl2 was added to the mixture
(entries 1 and 6, respectively). All the Lewis acids allowed
the formation of the corresponding sulfoxide with moder-
ate to high yields. ZnCl2 in chloroform proved to be the
most efficient reagent, and the reaction was much faster
than with the hard AlCl3 Lewis acid (98% yield after 5
min for ZnCl2 (entry 4) as compared to 80% after 3 h for
AlCl3 (entry 11)). On the other hand, BF3 and Ag+ also
afforded high yields (based on measurement of the
consumed oxaziridine). However, in both cases, the
J. Org. Chem, Vol. 70, No. 1, 2005 303

Schoumacker et al.
could be detected. Expectedly, the oxidation of the more
nucleophilic sulfides was faster and was nearly quantita-
tive after a few minutes, whereas a few hours were
needed for full oxidation of sulfides bearing electron-
withdrawing substituents. As an example, 4-methox-
yphenyl methyl sulfide was oxidized in 5 min in 97% yield
whereas 5 h were needed for its nitro homologue, and in
this case, the reaction yield was lower (81%). Moreover,
oxidation of disulfides also proceeded with high selectivity
with the formation of the mono-oxide as the only product
even in the case of the highly reactive 2-phenyl-1,3-
dithiane.
Enantioselective Sulfoxidation. The asymmetric
version of the above system was investigated using the
optically pure (S)-1-phenylethylamine as a cheap chiral
auxiliary. Condensation of this amine with freshly dis-
tilled 2-pyridinecarbaldehyde in refluxing methanol af-
forded the imine 7 as a single isomer (assumed to be the
trans isomer) in excellent yield.18 Oxidation of 7 was then
performed with Oxone as for 4, 5, and 6 and resulted in
the formation of three diasteroisomers in a 7:28:65 ratio.
Column chromatography on deactivated (Et3N) silica
gave the two major isomers 8a and 8b in reasonable
yields (33% and 55%, respectively). Absolute configura-
tion of the minor isomer 8a (CS-NS)oxa-CS was deter-
mined by X-ray analysis of single crystals obtained by
slow evaporation of the solvent from a purified solution
of 8a (Scheme 3; Supporting Information). The absolute
configuration of 8b has not been determined.
Condensation of the chiral amine with 2,2′-dipyridinyl
ketone to prepare the imine 9 required more vigorous
conditions and was achieved in the presence of BF3‚OEt2,
as a catalyst, in refluxing toluene using the Dean-Stark
apparatus.19 Oxidation by slow addition of Oxone yielded
a unique isomer 10. After chromatographic purification,
the oxaziridine 10 was isolated in good yield (87%). X-ray
structural analysis of suitable single-crystal established
the absolute configuration of 10 to be (NR)oxa-CS, (Scheme
3; Supporting Information).
FIGURE 2. Electronic spectra of 5 (0.4 mM, CHCl3) in the
presence of (a) 0, (b) 0.25, (c) 0.50, (d) 0.75, (e) 1.00, (f) 1.25,
(g) 1.50, (h) 1.75 equiv of ZnCl2.
TABLE 2. Oxidation of a Variety of Sulfides by 5 in the
a
Presence of ZnCl2
R1-S-R2
yield (%)
R1
R2
(reaction timeb)
4-CH3O-C6H4-
C6H5-
4-Br-C6H4-
4-NO2-C6H4-
C6H5-
C6H5-
naphthyl-
-CH3
97 (5 min)
98 (1 h)
-CH3
-CH3
-CH3
-CH2CH3
-CH2C6H5
-CH3
98 (2 h)
81 (5 h)
98 (30 min)
95 (30 min)
87 (30 min)
14 (1 h)
4-methyldibenzothiophene
2-phenyl-1,3-dithiane
thianthrene
98 (5 min)
60 (30 min)
a 12:12:10 mM 5/ZnCl2/substrate ratio in chloroform. b Time for
maximal conversion.
lyst. The inhibition effect of 2 was confirmed in an
experiment using a 1:1:1 5/ZnCl2/substrate ratio in the
presence of 1 equiv of 2. Under such conditions, low yield
was achieved (34% instead of 85% when the reaction was
carried out without any additional imine) with consump-
tion of almost half of 5 (data not shown).
The ability of the chiral oxaziridines 8a, 8b, and 10 to
carry out enantioselective oxidations was then evaluated
during the oxidation of various alkyl aryl sulfides under
the conditions described in Table 3 (12:12:10 mM ox-
aziridine/ZnCl2/substrate ratio in chloroform). After the
reaction stopped, most of the solvent was evaporated and
the resulting solution was added to a large volume of
ether. The resulting precipitate was filtered, extracted
with dichloromethane and washed with saturated NaH-
CO3 aqueous solution to recover, after concentration, the
corresponding imines 5 or 7 in good yields (higher than
70%). The sulfoxides present in the etheral solution were
purified by column chromatography. The enantiomeric
excesses were measured either by chiral HPLC (Pirkle
Evidence for the formation of a 1:1 complex between 2
and ZnCl2 was confirmed by X-ray crystallography. Slow
evaporation of the solvent from a 1:1 mixture of the imine
2 and ZnCl2 in chloroform resulted in the formation of
crystals of a ZnCl2(2) complex suitable for X-ray analysis.
The structure of the complex, shown in the Supporting
Information section, indicates that the zinc binds the two
nitrogen atoms of 2 and keeps the two Cl- ligands. The
evidence for the presence of the same complex also in
solution was confirmed by positive ESI-MS. Indeed, mass
spectrometry analysis of a solution of these crystals in
methanol afforded m/z fragmentations at 247.1 and 394.8
corresponding to [ZnCl(2)]+and [ZnCl(2)2]+, respectively.
Oxidation of a Variety of Sulfides by 5. Finally,
an optimized procedure for oxidation of sulfides was
achieved with small excesses of both 5 and zinc chloride
with regard to the substrate (5/ZnCl2/sulfide ) 12:12:10
mM) in chloroform. Under these conditions, the oxidation
of a variety of sulfides was assayed and the results are
reported in Table 2. With the exception of the bulky
4-methyldibenzothiophene, the corresponding sulfoxides
were obtained in good to excellent yields and with
excellent selectivities, since no overoxidation products
1
Covalent (R,R) Whelk-O2) or by H NMR spectroscopy
in the presence of 2 equiv of (R)-(+)-2,2′-binaphthol as a
chiral shift reagent with regard to the isolated sulfoxide.20
The configurations of the sulfoxides were determined
from analogy with the spectroscopic behavior of the (R)-
(18) (a) Brunner, H.; Klankermayer, J.; Zabel, M. Organometallics
2002, 21, 5746. (b) Brunner, H.; Reiter, B.; Riepl, G. Chem. Ber. 1984,
117, 1330.
(19) Guilan, L.; Wenhao, H.; Yuzi, M.; Yaozhong, J.; Yang, T.-K.
Synth. Commun. 1994, 24, 3115.
(20) Toda, F.; Mori, K.; Okada, J. Chem. Lett. 1988, 131.
304 J. Org. Chem., Vol. 70, No. 1, 2005

Activation of Oxaziridines by Lewis Acids
SCHEME 3. Imines 7 and 9 and Related Oxaziridines 8a and 10
TABLE 3. Asymmetric Oxidation of Aryl Alkyl Sulfidesa
R1-S-R2
8a
8b
10
R1
R2
yield (%)
eeb (config)c
yield (%)
eeb (config)c
yield (%)
eeb (config)c
4-CH3O-C6H4-
C6H5-
-CH3
75
45
40
35
23
55
29
37 (S)
32 (S)
42 (S)
22 (S)e
33 (S)
42d
69
53
38
31
25
50
33
39 (R)
31 (R)
43 (R)
46 (R)e
32 (R)
56b
85
55
41
33
30
60
52
33 (R)
42 (R)
48 (R)
50 (R)e
55 (R)
63b
-CH3
4-Br-C6H4-
2-Br-C6H4-
4-NO2-C6H4-
C6H5-
-CH3
-CH3
-CH3
-CH2C6H5
-CH3
naphthyl-
53 (S)
60 (R)
58 (R)
a Oxaziridine/ZnCl2/substrate ratio ) 12:12:10 mM in chloroform. b ee’s were determined by NMR spectroscopy using (R)-(+)-2,2′-
binaphthol as chiral shift reagent. c See ref 21. d Absolute configuration not determined. e ee determination by chiral HPLC.
SCHEME 4. Activation of Oxaziridines by ZnCl2
methyl phenyl sulfoxide in the presence of the (R)-(+)-
2,2′-binaphthol.21 In most cases, absolute configuration
was confirmed by chiral HPLC by comparison with
optically pure commercially available samples.
The results are reported in Table 3. They show that
despite lower yields (ranging from 23 to 85%) and longer
reaction times (more than 3 h for completion) than those
observed for the less hindered oxaziridine 5, low to good
enantiomeric excesses were obtained. Interestingly, the
enantioselectivity does not depend on the absolute con-
figuration of the methylbenzyl moiety but on that of the
oxaziridine ring as shown with 8a and 8b which afforded
the S and R sulfoxide enantiomer as the major product,
respectively. As observed for 5, the rates of oxidation of
sulfides having electron-attracting groups were also
smaller in agreement with a SN2 mechanism (data not
shown).22 One may also note the positive effect of the
presence of an additional pyridinyl group (10 compared
to 8a,b) affording better yields and enantiomeric excesses
in most cases.
achieved with sulfonyl, sulfamyl, phosphinoyl, or triflu-
oromethyl substituents.4-9 Activation by formation of
oxaziridinium salts has also proven its efficiency for such
reactions.10,12 In this paper, we now demonstrate that
Lewis acids, different from H+, also have the potential
to activate the oxaziridine ring for sulfide oxidation.
However,when using the most efficient Lewis acid ZnCl2,
a heteroaromatic (i.e., pyridin-2-yl or quinolin-8-yl) sub-
stituent must be present since no reaction take place
when these groups are replaced by a phenyl one. This
suggests that, in the presence of a pyridinyl moiety acting
as an additional metal-complexing site, an active 1:1
oxaziridine/ZnCl2 adduct is formed. Formation of a
complex, such as that shown in Scheme 4, would explain
the activation of the oxaziridine. Indeed, coordination of
the Lewis acid by the nitrogen atom of the oxaziridine
ring increases the electron deficiency of the oxygen atom
and thus its electrophilic character. One may also note
that no difference in reactivity (yield and rate) was
observed when pyridin-2-yl or quinolin-8-yl, responsible
for the formation of a five- or a six-membered chelate
ring, respectively, in the activated state, was used as a
substituent.
The involvement of such a complex is supported by (i)
the changes of the UV-vis and NMR spectra of the
oxaziridine during addition of ZnCl2 (Figures 1 and 2)
and (ii) the crystal structure of the imine 2/ZnCl2 adduct
which demonstrates chelation by the two nitrogen atoms.
Except with low polarity solvents such as diethyl ether
and CCl4 in which the oxaziridine/ZnCl2 adduct is not
soluble, the sulfoxidation is weakly affected by the nature
of the solvent. Indeed, whatever the solvent used, high
yields were achieved within a few minutes. However, one
may note the lower yield (75%) obtained in ethanol which
Under the conditions described, no sulfone were
formed, which indicated that the enantioselectivities were
a direct result of the asymmetric sulfide oxidation and
not of a kinetic resolution by overoxidation of the result-
ing sulfoxide.
Discussion
It is now admitted that the oxygen atom transfer from
an oxaziridine to sulfides involves an SN2-type displace-
ment of the imine by the nucleophile.23 Consequently
introduction of electron-withdrawing groups on the ni-
trogen atom increases the electrophilic nature of the
oxygen atom and thus its reactivity. This is generally
(21) (a) Naruta, Y.; Tani, F.; Maruyama, K. Tetrahedron: Asym-
metry 1991, 2, 533. (b) Shinkai, S.;; Yamagushi, T.; Manabe, O.; Toda,
F. J. Chem. Soc., Chem. Commun. 1988, 1399.
(22) Bach, R. D.; Wolber, G. J. J. Am. Chem. Soc. 1984, 106, 1410.
(23) (a) Davis, F. A.; Reddy, R. T.; Han, W.; Carroll P. J. J. Am.
Chem. Soc. 1992, 114, 1428. (b) Davis, F. A.; Billmers, J. M.; Gosciniak,
D. J.; Towson, J. C.; Bach, R. D. J. Org. Chem. 1986, 51, 4240.
J. Org. Chem, Vol. 70, No. 1, 2005 305

Schoumacker et al.
SCHEME 5. Hypothetical Transition States Involved in the Enantioselective Oxidation of Alkyl Aryl
a
Sulfides by Oxaziridine 8a Activated by ZnCl2
a These are Newman-like representations in which the S and O atoms are superimposed.
could be attributed to a weaker oxaziridine-ZnCl2 as-
sociation in protic solvents.
In view of the efficiency of the ZnCl2/oxaziridine system
toward sulfide oxidation, the asymmetric induction of
various chiral oxaziridines and the catalytic activity of
ZnCl2 were investigated.
the aryl group varied from phenyl to naphthyl (32% to
53% ee for 8a, 31% to 60% ee for 8b, 42% to 58% ee for
10). This effect was defined by Davis and co-workers as
the group size difference (GSD) effect.7,12b,25 On the basis
of this effect transposed to the oxaziridine, one should
expect better stereoselectivities with 8a as compared to
10 which enjoys a greater topological symmetry. This,
in fact, was not the case except for 4-methoxyphenyl
methyl sulfide. A closer look at the interactions between
the substituents (π-π stacking, steric interactions, ap-
proach of the sulfide controlled by the Lewis acid, ...)
should allow a better understanding of the reaction
mechanism implying such oxaziridines.
As observed for asymmetric oxidations using enan-
tiopure N-sulfonyloxaziridines, the product stereochem-
istry in the reaction reported here is controlled by the
configuration of the oxaziridine three-membered ring
with steric factors being responsible for the chiral
recognition.6b,23a It was established that oxygen transfer
from oxaziridine to sulfide can proceed through two
possible transition states, planar and spiro.24 In the
planar state, both electron pairs on the sulfur atom are
in the plane containing the oxaziridine ring. In contrast,
in the spiro one, the plane containing the two electron
pairs is perpendicular to this plane. With the constraint
of its (CS-NS)oxa configuration of the oxaziridine ring, the
eight possible transition states in the case of the oxaziri-
dine 8a are depicted in Scheme 5. The pro-S (P1) and
the pro-R (S3) arrangements are clearly the most steri-
cally favorable ones since the aryl group of the sulfide is
on the less hindered quadrant D, away from the three
large groups of the oxaziridine. However, P1 and S3 differ
from each other regarding the relative position of the
sulfide methyl group and the oxaziridine pyridinyl group,
with less steric hindrance in the case of S3. From this
analysis, the (S) sulfoxide should be formed predomin-
antely which is in agreement with the experimental
results.
The sulfoxidation by the reported oxaziridines goes
with the parallel formation of the corresponding imine
which undoubtedly is a stronger Lewis base than the
oxaziridine. Consequently, both bases compete for ZnCl2,
and the equilibria are shifted toward the formation of
the more stable imine-ZnCl2 adduct as the reaction
progresses since the concentration of the imine formed
increases and that of the unreacted oxaziridine decreases.
The strong affinity of the imine 2 for ZnCl2 has been
demonstrated and the crystal structure of the complex
obtained. Furthermore, inhibition of sulfoxidation by the
imine has been shown when the reaction was carried out
in the presence of the imine. On the other hand, it is
noticeable that, under standard conditions, the reaction
is nearly quantitative within a few minutes, suggesting
that the oxygen atom transfer from the oxaziridine-
ZnCl2 adduct is a very efficient reaction and proceeds
likely with a high rate constant. Finally, this inhibitory
effect is probably at the origin of the limitation we
encountered to make the system catalytic in ZnCl2. Even
though we clearly demonstrated the possibility of using
Consequently, increasing the difference in size of the
two substituents of the sulfide should result in a better
asymmetric induction. This was indeed observed when
(24) Bach, R. D.; Coddens, B. A.; McDoall, J. J. W.; Schelegel, H.
B.; Davis, F. A. J. Org. Chem. 1990, 55, 3325.
(25) Davis, F. A.; McCauley, J. P., Jr; Harakal, M. E. J. Org. Chem.
1984, 49, 1465.
306 J. Org. Chem., Vol. 70, No. 1, 2005

Activation of Oxaziridines by Lewis Acids
of freshly distilled 8-quinolinecarboxaldehyde26 (576 mg; 3,67
mmol) in methanol (100 mL) cooled to 0 °C. The resulting
yellow solution was stirred for 1 h at room temperature. After
concentration in vacuo, the crude yellow oil residue was
purified by silica gel column chromatography (ethyl acetate/
hexane ) 3/7) and 3 was obtained as a colorless oil (574 mg;
ZnCl2 as a catalyst with regard to the oxaziridine, the
reaction stopped after a few turnovers. In designing a
catalytic system, we will need to solve this competition
problem.
Conclusion
1
3.34 mmol; 91%). H NMR (300 MHz, CDCl3) δ: 9.64 (s, 1H);
It is well-known that oxaziridines can be activated by
an electron-withdrawing group covalently bound to the
nitrogen atom and used as reagents for sulfides oxidation.
In this paper, we describe a novel, simple, and general
mechanism for activation of oxaziridines. We demon-
strate that oxaziridines, easily accessible in two steps
from inexpensive starting material, are able to transfer
their oxygen atom to sulfides efficiently, simply upon
addition of a Lewis acid such as ZnCl2. Asymmetric
sulfoxidation by three new chiral oxaziridines (two of
them were structurally characterized by X-ray analysis)
afforded enantioselectivities ranging from 22% to 63% ee
with the simplest alkyl aryl sulfides in moderate to good
yields. We are fully aware that the enantioselectivities
obtained by the described system are not yet optimized.
However, we draw attention to the fact that (i) this is
the first example of Lewis acid-promoted oxidation of
sulfides by oxaziridines, (ii) the level of asymmetric
induction is in the upper range of that reported with
other oxaziridines, and (iii) it is likely that new oxaziri-
dines, with stronger asymmetric induction groups, will
provide larger ees, thus improving the system. This
aspect is currently being investigated in our laboratory.
8.93 (dd, 1H, J ) 3.9, 1.8 Hz); 8.40 (dd, 1H, J ) 7.5, 1.5 Hz);
8.16 (dd, 1H, J ) 8.4, 1.8 Hz); 7.86 (dd, 1H, J ) 8.1, 1.5 Hz);
7.59 (dd, 1H, J ) 8.1, 7.5 Hz); 7.42 (dd, 1H, J ) 8.4, 3.9 Hz);
3.76 (hept, 1H, J ) 6.3 Hz); 1.31 (d, 6H, J ) 6.3 Hz). 13C NMR
(76 MHz, CDCl3) δ: 156.3 (CH); 149.9 (CH); 146.6 (C); 136.4
(CH); 133.3 (C); 130.1 (CH); 128.2 (C); 127.7 (CH); 126.5 (CH);
121.2 (CH); 61.9 (CH); 24.2 (2 CH3). IR: 1635 cm-1. ESI-MS,
m/z: 261.1 (100) [3+H]+; 284.1 [3 + Na]+. Anal. Calcd for
C13H14N2: C, 78.75; H, 7.12; N, 14.13. Found: C, 79.08; H,
7.15; N, 14.21.
2-Isopropyl-3-phenyloxaziridine (4).14 To a solution of
1 (850 mg; 5.8 mmol) in acetonitrile (50 mL), cooled at 0 °C,
were successively added a solution of NaHCO3 (1.94 g; 23.1
mmol) in water (50 mL) at 0 °C and for 15 min a solution of
KHSO5 (5.33 g; 8.7 mmol) in water (50 mL). The colorless
solution was vigorously stirred. After 45 min, the product was
extracted with CHCl3 (4 × 20 mL). The organic layer was dried
over Na2SO4, and the solvent was removed under vacuo to
afford 4 as a colorless oil. The oxaziridine was distillated under
reduced pressure (bp ) 80 °C; 25 mbar) to yield a colorless oil
(792 mg; 4.9 mmol; 84%). 1H NMR (300 MHz, CDCl3) δ: 7.44-
7.34 (m, 5H); 4.48 (s, 1H); 2.34 (hept, 1H, J ) 6.3 Hz); 1.31 (d,
3H, J ) 6.3 Hz); 1.16 (d, 3H, J ) 6.3 Hz). 13C NMR (76 MHz,
CDCl3) δ: 135.1 (C); 129.9 (CH); 128.4 (CH); 127.4 (CH); 80.0
(CH); 62.6 (CH); 21.2 (CH3); 18.9 (CH3). IR: 3068, 3036, 2972,
2931, 2876, 1461, 1312, 1161, 879, 856, 756, cm-1. ESI-MS,
m/z: 185.9 (100) [4 + Na]+.
Experimental Section
2-Isopropyl-3-pyridin-2-yloxaziridine (5). A solution of
2 (850 mg; 5,74 mmol) in acetonitrile (50 mL) was cooled to 0
°C. To this vigorously stirred colorless solution were succes-
sively added a solution of NaHCO3 (1.93 g; 23.00 mmol) in
water (50 mL) cooled to 0 °C and, over 10 min, a solution of
KHSO5 (5.30 g; 8.61 mmol) in water (50 mL) at 0 °C. After
extraction with CHCl3, the solution was dried over Na2SO4 and
concentrated under vacuo to give a colorless oil. Purification
by silica gel column chromatography (ethyl acetate/hexane )
2/8) previously treated with Et3N afforded 5 as a colorless oil
(800 mg; 4.88 mmol; 85%). 1H NMR (300 MHz, CDCl3) δ: 8.49
(ddd, 1H, J ) 4.8, 1.8, 1.2 Hz); 7.61 (ddd, 1H, J ) 7.8, 7.8, 1.8
Hz); 7.27 (ddd, 1H, J ) 7.8, 1.2, 1.2 Hz); 7.21 (ddd, 1H, J )
7.8, 4.8, 1.2 Hz); 4.62 (s, 1H); 2.32 (q, 1H, J ) 6.3 Hz); 1.24 (d,
3H, J ) 6.3 Hz); 1.11 (d, 3H, J ) 6.3 Hz). 13C NMR (76 MHz,
CDCl3) δ: 154.9 (C); 148.9 (CH); 136.7 (CH); 124.4 (CH); 121.2
(CH); 80.0 (CH); 62.5 (CH); 21.1 (CH3); 18.7 (CH3). IR: 3061,
3013, 2974, 2933, 2881, 1593, 1573, 1465, 1439, 1383, 1368,
1163, 862, 772 cm-1. ESI-MS, m/z: 186.9 (100) [5 + Na]+. Anal.
Calcd for C9H12N2O: C, 65.83; H, 7.37; N, 17.06. Found: C,
65.90; H, 7.41; N, 17.02.
Benzylideneisopropylamine (1).15 Under a nitrogen at-
mosphere, a solution of isopropylamine (700 mg; 11.9 mmol)
in methanol (50 mL) was added for 15 min to a solution of
freshly distilled benzaldehyde (1.08 g; 10.2 mmol) in methanol
(100 mL) cooled to 0 °C. The resulting clear solution was
stirred for another 1 h at room temperature. Concentration
in vacuo afforded the crude product as a yellow oil. Distillation
under reduce pressure (bp ) 75 °C; 25 mbar) afforded 1 as a
colorless oil (1.32 g; 8.98 mmol; 88%). 1H NMR (300 MHz,
CDCl3) δ: 8.29 (s, 1H); 7.73-7.68 (m, 2H); 7.40-7.34 (m, 3H);
3.52 (hept, 1H, J ) 6.3 Hz); 1.25 (d, 6H, J ) 6.3 Hz). 13C NMR
(76 MHz, CDCl3) δ: 158,0.0 (CH); 136.3 (C); 130.2 (CH); 128.3
(CH); 127.9 (CH); 61.5 (CH); 24.0 (CH3). IR: 3062, 3027, 2968,
2930, 2850, 1648, 1451, 1383, 1397, 1142, 968, 756, 694 cm-1
.
ESI-MS: m/z 148.1 (100) [1 + H]+.
Isopropylpyridin-2-ylmethyleneamine (2).16 Under a
nitrogen atmosphere, a solution of isopropylamine (650 mg;
10.5 mmol) in methanol (50 mL) was added over 1 h to a
solution of freshly distilled 2-pyridincarboxaldehyde (1.07 g;
10.0 mmol) in methanol (100 mL) cooled to 0 °C. The resulting
yellow solution was stirred for 1 h at room temperature. After
concentration in vacuo, the crude yellow oil residue was
distilled under reduce pressure (bp ) 90 °C; 33 mbar) yielding
the imine as a pale yellow oil (1.41 g; 9.52 mmol; 95%). 1H
NMR (300 MHz, CDCl3) δ: 8.59 (ddd, 1H, J ) 4.8, 1.5, 1.1
Hz); 8.36 (s, 1H); 7.94 (ddd, 1H, J ) 7.8, 1.2, 1.1 Hz); 7.67
(ddd, 1H, J ) 7.8, 7.8, 1.5 Hz); 7.24 (ddd, 1H, J ) 7.8, 4.8, 1.2
Hz); 3.59 (q, 1H, J ) 6.3 Hz); 1.23 (d, 6H, J ) 6.3 Hz). 13C
NMR (76 MHz, CDCl3) δ: 159.2 (CH); 154.8 (C); 149.3 (CH);
136.4 (CH); 124.4 (CH); 121.3 (CH); 61.3 (CH); 23.9 (CH3). IR:
3055, 3009, 2969, 2926, 2863, 1647, 1588, 1567, 1467, 1140,
974, 775 cm-1. ESI-MS, m/z: 149.1 (100) [2 + H]+; 171.0 (45)
[2 + Na]+; 203.0 (15) [2 + Na + MeOH]+.
2-Isopropyl-3-(quinolin-8-yl)oxaziridine (6). A solution
of the imine 3 (396 mg, 1.0 mmol) in acetonitrile (25 mL) was
to cooled to 0 °C, and then a solution of NaHCO3 (336 mg, 4
mmol) in water (25 mL) was successively added at 0 °C
followed by a solution of KHSO5 (862 mg, 1.4 mmol) in water
(25 mL) over 15 min. The colorless solution was vigorously
stirred for 45 min. The product was extracted with CHCl3 (4
× 20 mL), and the organic layer was dried over Na2SO4. The
solvent was removed under vacuo to afford 6 as colorless oil.
The crude residue was purified by silica gel column chroma-
tography (ethyl acetate/hexane ) 3/7), and 6 was obtained as
1
a colorless oil (182 mg, 0.85 mmol, 85%). H NMR (300 MHz,
CDCl3) δ: 8.92 (dd, 1H, J ) 4.2, 1.5 Hz); 8.15 (dd, 1H, J )
8.4, 1.5 Hz); 7.81 (dd, 1H J ) 8.1, 1.2 Hz); 7.73 (dd, 1H, J )
7.5, 1.2 Hz); 7.53 (dd, 1H, J ) 8.1, 7.5 Hz); 7.42 (dd, 1H, J )
Crystallographic data for the ZnCl2(2) complex: orthorhom-
bic, P2(1)2(1)2(1), a ) 7.1662(14) Å, b ) 7.6325(15) Å, c )
23.207(5) Å, V ) 1269.3(4) Å3, Z ) 4, R ) 0.0956, Rw ) 0.1703.
Isopropylquinolin-8-ylmethylenamine (3). Under a ni-
trogen atmosphere, a solution of isopropylamine (250 mg; 4.04
mmol) in methanol (50 mL) was added over 1 h to a solution
(26) (a) Meyer, A. E. Chem. Abstr. 1951, 45, 9117. (b) Seyhan, M.;
Fernelius, W. C. J. Org. Chem. 1957, 22, 217.
J. Org. Chem, Vol. 70, No. 1, 2005 307

Schoumacker et al.
8.4, 4.2 Hz); 2.57 (hept, 1H, J ) 6.3 Hz); 1.35 (d, 3H, J ) 6.3
Hz, 3H); 1.30 (d, 3H, J ) 6.3 Hz). 13C NMR (76 MHz, CDCl3)
δ: 150.0 (CH); 147.3 (C); 136.1 (CH); 133.1 (C); 128.9 (CH);
127.8 (C); 127.2 (CH); 126.4 (CH); 121.3 (CH); 76.9 (CH); 62.7
(CH); 21.4 (CH3); 18.9 (CH3). IR: 3037, 2972, 2932, 2877, 1596,
1583, 1503, 1468, 1361, 1261, 1232, 1159, 884, 822, 792, 765,
627. ESI-MS, m/z: 277.1 (45) [6 + H]+; 260.1 (100) [6 - OH]+.
Anal. Calcd for C13H14N2: C, 72.87; H, 6.59; N, 13.07; O, 7.47.
Found: C, 72.95; H, 6.61; N, 12.98.
(1-Phenylethyl)[2]pyridinylmethyleneamine (7). Under
a nitrogen atmosphere, a solution of 1(S)-phenylethylamine
(1.14 g; 9.43 mmol) in methanol (20 mL) was added over 30
min to a cooled (0 °C) solution of freshly distilled 2-pyridin-
ecarboxaldehyde (1.11 g; 10.4 mmol) in methanol (75 mL). The
resulting yellow solution was stirred for an additional 1 h at
room temperature. Concentration in vacuo afforded the crude
product as a yellow oil. The oxaziridine was purified by silica
gel column chromatography (ethyl acetate/hexane ) 2/8)
previously treated with Et3N, and 7was obtained as a yellow
oil (1.72 g; 8.19 mmol; 87%). [R]25D: +85 (c 0.6, CHCl3). 1H
NMR (300 MHz, CDCl3) δ: 8.29 (s, 1H); 8.60 (ddd, 1H, J )
4.8, 1.5, 0.9 Hz); 8.45 (s, 1H); 8.08 (dd, 1H, J ) 7.8, 0.9 Hz);
7.74 (ddd, 1H, J ) 7.8, 7.5, 1.5 Hz); 7.42 (d, 2H, J ) 7.2 Hz);
7.33 (dd, 2H, J ) 7.2, 7.2 Hz); 7.27 (ddd, 1H, J ) 7.5, 1.2, 1.2
Hz); 7.25 (t, 1H, J ) 7.2 Hz); 4.63 (q, 1H, J ) 6.6 Hz); 1.60 (d,
3H, J ) 6.6 Hz). 13C NMR (76 MHz, CDCl3) δ: 160.4 (CH);
154.7 (C); 149.2 (CH); 144.5 (C); 136.5 (CH); 128.4 (CH); 127.0
(CH); 126.6 (CH); 124.7 (CH); 121.4 (CH); 69.5 (CH); 24.4
(CH3). IR: 3060, 3028, 2972, 2927, 2862, 1647, 1568, 1468,
1371, 968, 763, 700 cm-1. ESI-MS, m/z: 233.1 (40) [7 + Na]+;
224.1 (100) [(7)2 + Na]+.
9 was obtained as pale yellow crystals (471 mg; 1.64 mmol;
1
82%). [R]25
D: -5 (c 0.19, CHCl3). H NMR (300 MHz, CDCl3)
δ: 8.74 (d, 1H, J ) 4.8 Hz); 8.48 (d, 1H, J ) 4.8 Hz); 8.29 (d,
1H, J ) 8.1 Hz); 7.75 (ddd, 1H, J ) 15.6, 7.5, 1.8 Hz); 7.40-
7.10 (m, 9H); 4.58 (q, 1H, J ) 6.3 Hz); 1.53 (d, 3H, J ) 6.3
Hz). 13C NMR (76 MHz, CDCl3) δ: 164.9 (C); 157.2 (C); 155.6
(C); 149.7 (CH); 148.7 (CH); 145.2 (CH); 136.3 (CH); 135.9
(CH); 126.7 (CH); 126.6 (CH); 124.0 (CH); 124.0 (CH); 123.4
(CH); 123.0 (CH); 122.5 (CH); 61.4 (CH); 24.5 (CH3). IR: 3061,
3029, 2979, 2932, 1590, 1571, 1437, 1387, 991, 772, 698 cm-1
.
ESI-MS m/z: 288.0 (100) [9 + H]+; 310.1 (45) [9 + Na]+; 596.8
(45) [(9)2 + Na]+. Anal. Calcd for C19H17N3: C, 79.41; H, 5.96;
N, 14.62. Found: C, 79.36; H, 6.01; N, 14.63.
3,3-Bispyridinyl-2-(1-methylbenzyl)oxaziridine (10).
To a solution of 9 (240 mg; 836 µmol) in acetonitrile (20 mL),
cooled to 0 °C, were successively added a solution of NaHCO3
(281 mg; 3.35 mmol) in water (10 mL) and, over a 1 h period,
a solution of KHSO5 (770 mg; 1.25 mmol) in water (20 mL).
The resulting solution was vigorously stirred for completion
for an additional 1 h at room temperature. After extraction
with CHCl3, the organic layer was dried over Na2SO4 and the
solvent was evaporated to afford a pale yellow oil. The crude
product was obtained as a yellow oil. Purification by silica gel
(previously treated with Et3N) chromatography using chro-
matotron apparatus (ethyl acetate/hexane ) 3/7) yielded 10
as a colorless oil (200 mg, 660 µmol, 79%). [R]25D: +10 (c 0.10,
CHCl3). 1H NMR (300 MHz, CDCl3) δ: 8.50-8.44 (m, 2H); 7.73
(ddd, 1H, J ) 7.8, 7.8, 1.8 Hz); 7.70-7.68 (m, 1H); 7.67 (ddd,
1H, J ) 7.8, 7.8, 1.8 Hz); 7.58 (ddd, 1H, J ) 7.8, 1.2, 0.9 Hz);
7.28 (ddd, 1H, J ) 7.5, 4.8, 1.2 Hz); 7.23-7.18 (m, 3H); 7.17
(ddd, 1H, J ) 6.3, 4.8, 2.7 Hz); 6.97-6.91 (m, 2H); 3.27 (q, 1H,
J ) 6.3 Hz); 1.62 (d, 3H, J ) 6.3 Hz). 13C NMR (76 MHz,
CDCl3) δ: 157.4 (C); 153.8 (C); 149.0 (CH); 148.9 (CH); 139.9
(C); 136.7 (CH); 135.7 (CH); 128.3 (CH); 127.7 (CH); 127.2
(CH); 124.4 (CH); 123.7 (CH); 123.6 (CH); 122.6 (CH); 86.6 (C);
63.2 (CH); 22.9 (CH3). IR: 3061, 3029, 2973, 2931, 1641, 1570,
1442, 1390, 975, 765, 697 cm-1. ESI-MS m/z: 286.2 (100) [10
- H]+; 325.9 (10) [10 + Na]+. Anal. Calcd for C19H17N3O: C,
75.23; H, 5.65; N, 13.85. Found: C, 75.27; H, 5.61; N, 13.90.
Crystallographic data: orthorombic, P2(1)2(1)2(1) a ) 8.0723-
(16) Å, b ) 12.111(2) Å, c ) 34.684(7) Å, V ) 3391.0(12) Å3, Z
) 8, R ) 0.0462, Rw ) 0.0825.
Standard Conditions for Sulfoxidation Were As Fol-
lows: To a solution of the oxaziridine (100 µmol) in 8.3 mL of
solvent were successively added sulfide (83 µmol) and Lewis
acid (100 µmol) (1.2:1.2:1 oxaziridine/Lewis acid/sulfide ratio).
An internal standard (30 µL of a 1 M solution of benzophenone
or fluorenone in toluene) was added to the reaction mixture.
The characterization of the sulfoxides was done by GC-MS.
Unambiguous identification of the products was made by
comparison with pure compounds, which were either prepared
independently or commercially available. All the sulfoxides
were isolated by column chromatography on silica gel (ethyl
acetate/hexane ) 20/80 then 80/20). The enantiomeric excesses
were determined by 1H NMR in CDCl3 for the purified products
as follows: 1-2 equiv of (R)-(+)-2,2′-binaphthol were added
by small portions until a good splitting of the CH3 singlet
(between 2.7 and 3.0 ppm) was obtained.21 The ee was
calculated from the deconvolution of these two peaks.
3-Pyridinyl-2-(1-me´thylbenzyl)oxaziridine (8). To a
vigorously stirred solution of 7 (336 mg; 1.6 mmol) in aceto-
nitrile (20 mL) cooled to 0 °C were successively added a
solution of NaHCO3 (538 mg; 6.4 mmol) in water (20 mL) and,
over 30 min, a solution of KHSO5 (1.47 g; 2.39 mmol) in water
(20 mL). After extraction with CHCl3 the solution was dried
over Na2SO4 and concentrated in vacuo. The crude product
was obtained as a yellow oil containing three stereoisomers
(1:4:9.3 ratio). Silica gel chromatographic purification using
chromatotron apparatus (ethyl acetate/hexane ) 15/85) previ-
ously treated with Et3N afforded 8a as a colorless solid (128
mg, 35%) and 8b as a colorless oil (160 mg, 50%). 8a. [R]25
:
D
1
+59 (c 0.5, CHCl3). H NMR (300 MHz, CDCl3) δ: 8.59 (ddd,
1H, J ) 4.8, 1.5, 0.9 Hz); 7,70 (ddd, 1H, J ) 7.5, 7.5, 1.8 Hz);
7.60 (m, 2H); 7.37 (m, 3H); 7.28-7.34 (m, 2H); 4.85 (s, 1H);
3.42 (q, 1H, J ) 6.9 Hz); 1.53 (d, 3H, J ) 6.9 Hz). 13C NMR
(76 MHz, CDCl3) δ: 154.8 (C); 149.0 (CH); 141.6 (C); 136.9
(CH); 128.5 (CH); 127.6 (CH); 127.0 (CH); 124.6 (CH); 121.5
(CH); 80.5 (CH); 70.3 (CH); 19.5 (CH3). IR: 3062, 3029, 2979,
2932, 1593, 1572, 1439, 1390, 1083, 995, 776, 698 cm-1
.
Crystallographic data: orthorombic, P2(1)2(1)2(1), a ) 15.139-
(3) Å, b ) 7.9773(16) Å, c ) 10.163(2) Å, V ) 1227.4(4) Å3, Z
) 4, R ) 0.0492, Rw ) 0.0887. 8b. [R]25D: -38 (c 0.5, CHCl3).
1H NMR (300 MHz, CDCl3) δ: 8.48 (ddd, 1H, J ) 4.8, 1.5, 0.9
Hz); 7.65 (ddd, 1H, J ) 7.5, 1.8, 1.8 Hz); 7.5-7.2 (m, 7H); 4.81
(s, 1H); 3.34 (q, 1H, J ) 6.3 Hz); 1.66 (d, 3H, J ) 6.3 Hz). 13
C
NMR (76 MHz, CDCl3) δ: 154.6 (C); 149.0 (CH); 139.5 (C);
136.8 (CH); 128.7 (CH); 128.0 (CH); 127.3 (CH); 124.5 (CH);
121.5 (CH); 80.4 (CH); 71.2 (CH); 21.5 (CH3). IR: 3062, 3029,
2979, 2932, 1593, 1572, 1439, 1390, 1083, 995, 776, 698 cm-1
.
ESI-MS m/z: 209.2 (100) [8b - H]+; 227.0 (15) [8b + H]+; 248.9
(22) [8b + Na]+; 444.1 (55) [(8b)2 + Na]+. Anal. Calcd for
C14H14N2O: C, 74.31; H, 6.24; N, 12.38. Found: C, 74.28; H,
6.30; N, 12.39.
Acknowledgment. We are grateful to the “Minis-
te`re Franc¸ais de la Recherche et de la Technologie” for
an “ACI Jeunes Chercheurs 2000” grant. We also thank
C. Lebrun (DRFMC, CEA-Grenoble) for the ES-MS
analysis.
(1-Phenylethyl)[2]bispyridinylmethyleneamine (9). Un-
der a nitrogen atmosphere, a solution of 2,2-dipyridinyl ketone
(368.4 mg; 2.0 mmol), 1(S)-phenylethylamine (262 mg; 2.0
mmol), and boron trifluoride diethyl etherate (30 µL; 0.24
mmol) in toluene (25 mL) was refluxed for 24 h using Dean-
Stark apparatus. The resulting orange solution was concen-
trated in vacuo yielding the crude product as an orange oil.
The residue was purified by silica gel column chromatography
(ethyl acetate/hexane ) 3/7) previously treated with Et3N and
Supporting Information Available: 1H and 13C NMR
spectra of all the compounds excepted 1 and 4 and X-ray
crystallographic data for the ZnCl2(2) complex, 8a, and 10. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO048380K
308 J. Org. Chem., Vol. 70, No. 1, 2005