On the enantioselectivity of aziridination of styrene catalysed by copper triflate and copper-exchanged zeolite Y: Consequences of the phase behaviour of enantiomeric mixtures of N-arene-sulfonyl-2-phenylaziridines

Article abstract of DOI:10.1039/c0ob00724b

By synthesising S-2-phenyl-N-(4-nitrophenyl)aziridine from S-phenylglycinol, it has been demonstrated that the aziridination of styrene by [N-(4-nitrobenzenesulfonyl)imino]phenyliodinane (nosyliminophenyliodinane, PhINNs) in the presence of S,S-2,2′-isopr

Full text of DOI:10.1039/c0ob00724b

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 1079
www.rsc.org/obc
PAPER
On the enantioselectivity of aziridination of styrene catalysed by copper
triflate and copper-exchanged zeolite Y: consequences of the phase behaviour
of enantiomeric mixtures of N-arene-sulfonyl-2-phenylaziridines†
Laura Jeffs,a Damien Arquier,a Benson Kariuki,a Donald Bethell,a Philip C. Bulman Pageb and
Graham J. Hutchingsa
Received 15th September 2010, Accepted 9th November 2010
DOI: 10.1039/c0ob00724b
By synthesising S-2-phenyl-N-(4-nitrophenyl)aziridine from S-phenylglycinol, it has been
demonstrated that the aziridination of styrene by [N-(4-nitrobenzenesulfonyl)imino]phenyliodinane
(nosyliminophenyliodinane, PhINNs) in the presence of S,S-2,2¢-isopropylidene-bis(4-phenyl-
2-oxazoline), catalysed by copper(II) triflate in CH3CN solution or heterogeneously by CuHY, has
predominantly an R-configuration. The enantioselectivity of the aziridination of styrene by
[N-arenesulfonylimino]-phenyliodinanes catalysed by copper-exchanged zeolite Y (CuHY), in
conjunction with a chiral bis-oxazoline ligand, has been re-examined. In the case of PhINNs, it is
shown that the product mixture of enantiomeric aziridines, on treatment with hexane, gives rise to a
solid phase of low enantiomeric excess (ee) and a solution phase of high ee. Separation of the solid
phase and recrystallisation afforded a true racemate (racemic compound), which has been confirmed by
X-ray crystallography. The aziridine obtained from the solution phase could be recrystallised to
produce the pure enantiomer originally in excess. A consequence of the new findings is that previous
reports on the enantioselectivity of copper-catalysed aziridination, both in heterogeneous and
homogeneous conditions, should be regarded with caution if the analytical procedure involved HPLC
with injection of the enantiomeric mixture in a hexane-rich solvent. Such a method has been used in
previous work from this laboratory, but has also been used elsewhere, following the procedure
developed by Evans and co-workers when the (homogeneous) copper-catalysed aziridination by
PhINTs was first discovered. Evidently, the change of substituent in the benzenesulfonyl group reduces
the solubility in hexane, affording a solution phase of enhanced ee.
alkene, as had been necessary in homogeneous solution, because
of an apparent affinity of the alkene for the pore interior of
the zeolite. About the same time, Sodergren et al. reported
Introduction
The development of enantioselective organic reactions continues
apace, and adaptation of such procedures for commercial appli-
that alteration of the 4-substituent in PhINTs (e.g. to NO2 or
cations in the pharmaceutical field, for example, is an important
OMe) afforded an aziridinating agent that gave higher yields of
aziridine in homogeneous reactions without an excess of alkene,4
and gave greater enantioselectivities in reactions in the presence
of S,S-2,2¢-isopropylidene-bis(4-phenyl-2-oxazoline).5 Under our
heterogeneous conditions, the use of the nitro-substituted azirid-
inating agent [N-(4-nitrobenzenesulfonyl)imino]phenyliodinane
(nosyliminophenyliodinane, PhINNs) and the same bis(oxazoline)
ligand in the reaction with styrene also showed improved yields of
N-nosyl-2-phenyaziridine and apparent enantioselectivities that
were even higher (82%) than had been reported for the homoge-
neous reaction under otherwise similar conditions (66%).6–8
We now report a further examination of the reaction of styrene
with PhINNs catalysed by copper(II) triflate and CuHY in the
presence of S,S-2,2¢-isopropylidene-bis(4-phenyl-2-oxazoline) in
acetonitrile. Focusing particularly on the homogeneous reaction,
we show, by the use of an improved analytical procedure, that the
part of the worldwide effort. Following our earlier work on the gas-
phase dehydration of 2-butanol in the chirally modified pores of
zeolite Y,1 we developed a heterogeneous version of the Evans
copper salt-catalysed aziridination of alkenes by [N-(toluene-
4-sulfonyl)imino]phenyliodinane (PhINTs) in the presence of
non-racemic bis(oxazoline) ligands2 using copper(II)-exchanged
zeolite Y (CuHY). Using PhINTs, the heterogeneous process
yielded enantiomeric mixtures of aziridines of comparable ee to
Evans’ homogeneous procedure.3 High yields of aziridine could
be achieved with CuHY without the use of large excesses of
aSchool of Chemistry, Cardiff University, Cardiff, CF10 3AT, UK
bSchool of Chemistry, University of East Anglia, Norwich, NR4 7TJ, UK
† CCDC reference numbers 791821 and 791965. For crystallographic data
in CIF or other electronic format see DOI: 10.1039/c0ob00724b
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 1079–1084 | 1079
©

View Article Online
true enantioselectivity of the reaction is much less than previously
reported (35% ee). The discrepancy is attributable to the earlier use
of chiral HPLC protocols that involved the injection of solutions
of enantiomeric mixtures of aziridines in hexane, in which the
racemates of the aziridine products are of low solubility. The phase
behaviour of the ternary system hexane–R- and S-2-phenyl-N-(4-
nitrobenzene-sulfonyl)aziridine has also been investigated in more
detail.
desiccator in the dark until use. The 1H NMR spectroscopic data
agreed with literature values.6
Synthesis of (S)-(N-p-nosyl)-2-phenylaziridine. A method sim-
ilar to that first described by Farra´s et al.10 was used. 4-
Nitrobenzenesulfonyl chloride (13.3 g; 60 mmol) was added in
one portion to a suspension of (S)-(+)-2-phenylglycinol in dry
DCM–pyridine (2 : 1 v/v; 20 mL) at 0 ◦C, and the resulting
mixture was stirred at room temperature for 4 h. It was then
diluted with further DCM (300 mL) and washed with aqueous
HCl (2 M; 3 ¥ 100 mL); the aqueous washings were extracted
with DCM (50 mL). The combined organic layers were carefully
shaken with aqueous KOH (2 M; 6 ¥ 200 mL), and the aque-
ous extracts subsequently extracted with DCM (150 mL). The
organic portions were combined, washed with water (300 mL),
dried (Na2SO4) and the solvent removed to yield (S)-(N-(p-
nosylsulfonyl)imino)phenyliodinane, which was purified by flash
chromatography twice using DCM. Recrystallisation was from
DCM–hexane. NMR spectral data and [a]D = +77.80 were in
agreement with literature values.10
Experimental
Catalyst preparation
Two catalysts were used in this study. Copper(II) triflate (Aldrich)
was used as supplied. CuHY was prepared as follows: NH4Y
zeolite was calcined in air at 550 ◦C overnight to obtain HY zeolite.
HY zeolite (4.0 g) was stirred in aqueous copper(II) sulfate (0.1 M,
100 mL) overnight at room temperature. The solution was then
filtered and washed with distilled water. The catalyst was dried in
an oven at 100 ◦C. The copper-zeolite was recalcined at 550 ◦C for
4 h prior to use. The Cu content was 1.7% by weight, which was
determined by atomic absorption spectroscopy.
Catalytic reactions
Prior to the catalytic reactions, CuHY (0.326 g, 1.7% weight
Cu, 8.73 ¥ 10-5 mol of Cu) and Cu(OTf)2 (0.0316 g, 17.6% weight
Cu, 8.73 ¥ 10-5 mol) were stirred with the chiral modifier (S,S)-
2,2¢-isopropylidenebis(4-phenyl-2-oxazoline) (0.0584 g, 1.75 ¥
10-4 mol) in MeCN (5 mL) for 15 min at room temperature.
Catalytic reactions were carried out using both homogeneous and
heterogeneous catalysts.
Standard homogenous reaction. Copper triflate (0.0316 g,
8.73 ¥ 10-5 mol) was stirred with the bis(oxazoline) chiral modifier
(0.0584 g, 1.75 ¥ 10-4 mol) in acetonitrile (5 mL) for 15 min.
Styrene (100 mL, 8.73 ¥ 10-4 mol) was added followed by the nitrene
donor (PhINTs, 0.4886 g, or PhINNs, 0.5292 g; 1.31 ¥ 10-3 mol)
and the mixture stirred continuously until all the nitrene donor
had been consumed. The product was isolated using flash column
chromatography (1.5 ¥ 20 cm silica, 10 : 1.5 petroleum ether 40–
60 : ethyl acetate) and analysed by chiral HPLC. The aziridine was
formed as a colourless crystalline solid. For the racemic reaction,
the same procedure was followed, but without the addition of
the chiral modifier. For N-(p-tosylsufonyl)-2-phenyl-aziridine: 1H
NMR (CDCl3, 400 MHz) data agreed with the literature values.4,5
Synthesis of nitrene donors
Synthesis of (N-(p-tosylsulfonyl)imino)phenyliodinane (PhINTs).
The synthesis was carried out following the method described
by Yamada et al.9 Potassium hydroxide (11.2 g, 0.2 mol) was
mixed with p-toluenesulfonamide (13.68 g, 0.08 mmol) in a
500 mL round-bottomed flask containing HPLC grade methanol
(320 mL), and the mixture stirred until complete dissolution had
occurred. This solution was cooled to below 10 ◦C, iodobenzene
diacetate (25.70 g, 0.08 mmol) added slowly and the mixture stirred
over ice until a yellow solution was formed. The ice was removed
and the mixture stirred at room temperature for a further 3 h.
The mixture was then poured into distilled water (~800 mL),
covered and refrigerated overnight. Over a period of 12 h, a yellow
precipitate formed, and this was filtered, washed with distilled
water and dried/stored in a desiccator in the dark until use. The
1H NMR spectroscopic data were in agreement with the literature.
Standard heterogeneous reaction. CuHY (0.326 g, 1.7% weight
Cu, 8.73 ¥ 10-5 mol of Cu) was stirred with the bis(oxazoline) chiral
modifier (0.0584 g, 1.75 ¥ 10-4 mol) in acetonitrile (5 mL) for
15 min. Styrene (100 mL, 8.73 ¥ 10-4 mol) was added followed by
the nitrene donor (PhINTs, 0.4886 g, or PhINNs, 0.5292 g; 1.31 ¥
10-3 mol) and the mixture stirred continuously until the reaction
had reached completion. The catalyst was removed by filtration
and the product isolated using flash column chromatography (1.5 ¥
20 cm silica gel, 10 : 1.5 petroleum ether 40–60 : ethyl acetate) and
analysed by chiral HPLC. Again, for the racemic reaction, the
same procedure was followed but without the addition of the chiral
modifier.
Synthesis
of
(N-(p-nosylsulfonyl)imino)phenyliodinane
(PhINNs). Potassium hydroxide (11.2 g, 0.2 mmol) was
mixed with 4-nitrobenzenesulfonamide (16.16 g, 0.08 mmol) in a
500 mL round-bottomed flask containing HPLC grade methanol
(320 mL) and the mixture stirred until complete dissolution
had occurred. This solution was cooled to below 10 ◦C and
iodobenzene diacetate (25.70 g, 0.08 mmol) added slowly, keeping
the temperature below 10 ◦C at all times. The mixture was stirred
over ice until a cream precipitate was formed, at which point the
ice was removed and the mixture stirred for a further 3 h at room
temperature. The mixture was then poured into distilled water
(~800 mL), covered and refrigerated overnight. The product
was filtered, washed with distilled water and dried/stored in a
Analytical procedures
High pressure liquid chromatography analysis was performed
using a Varian Pro-star HPLC system (PDA detector set to l =
254 nm, a 230 Solvent delivery system and a 410 Autosampler). A
Chiralcel OJ column of size 250 mm ¥ 4.6 mm ID and a packing
composition of cellulose tris(4-methylbenzoate) coated on 10 mm
silica gel was first used to separate the chiral compounds. A solvent
1080 | Org. Biomol. Chem., 2011, 9, 1079–1084
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 1 Crystal data and structure refinement
cyclisation with alkali, with the product mixture from copper-
catalysed aziridination showed that the R-(-)-aziridine was the
enantiomer produced preferentially. This observation, in conjunc-
tion with the findings of Evans et al.3 using PhINTs, shows that
the sense of the stereochemical induction during aziridination
is independent of the 4-substituent in the arenesulfonyl group.
[Note: in some previous publications from this laboratory,3 the
absolute configuration of the aziridines produced from styrene
using S,S- and R,R-bis(4-phenyloxazolines) was erroneously
given as S- and R-N-arenesulfonyl-2-phenylaziridines, respec-
tively].
1
2
Empirical formula
Formula weight
T/K
C14H12N2O4S
304.32
150(2)
C14H12N2O4S
304.32
100(2)
Crystal size/mm3
Crystal system
Space group
0.35 ¥ 0.30 ¥ 0.05
Monoclinic
P21/a
13.4830(5)
7.5430(3)
14.7650(5)
114.997(2)
1360.98(9)
4
0.25 ¥ 0.05 ¥ 0.03
Monoclinic
P21
6.7710(3)
26.8040(15)
7.4480(3)
89.867(3)
1351.73(11)
4
˚
a/A
˚
b/A
˚
c/A
b (◦)
3
˚
In earlier work, the chiral column used for this analysis was a
Chiralcel OJ column with a mixture of 2-propanol (IPA)/hexane
as the mobile phase, analogous to that prescribed in the orig-
inal papers of Evans and co-workers2 for the analysis of N-
tosylaziridines and also used by Sodergren et al. for aziridines with
other substituents.5 This column is packed with cellulose tris(4-
methylbenzoate) coated on 10 mm silica gel. Only alkane and alco-
hol solvents can be used with this type of column; other solvents
commonly used in HPLC eluents such as tetrahydrofuran (THF)
and dichloromethane (DCM) can damage the chiral stationary
phase if they are present, even in residual quantities. Injection of
the mixture of enantiomeric aziridines for analysis was therefore
done in a hexane solution, but we noted that the analyte was often
quite difficult to dissolve. Analysis of the mixture of enantiomeric
N-nosyl-2-phenyl-aziridines using this procedure, with a mobile
phase consisting of hexane (70%) and 2-propanol (IPA, 30%),
indicated the reproducibly of an enantiomeric excess of 90% of the
R-enantiomer. In the present investigation, enantiomeric analyses
were conducted using a more robust Chiralpak IA column.
This column has a packing composition of amylose tris(3,5-
dimethylphenylcarbamate) immobilized on 5 mm silica gel, which
allowed the free choice of any miscible solvent for the injection
and to make up the mobile phase. Using a modified procedure,
in which the analyte was first dissolved in THF and the solution
diluted with four times its volume of hexane prior to injection,
and with hexane (85%) and IPA (15%) as the mobile phase, the ee
was observed to be only 35% R. Polarimetric measurement of the
enantiometric composition gave [a]D = -22.4◦, corresponding to
an ee of 29%, supporting the correctness of the more accurate
HPLC analysis. The ee value can be compared with the 66%
reported by Sodergren et al.4,5 using an analytical procedure
similar to our use of the Chiralcel OJ column, which, as indicated
above, we have now demonstrated over-reports the ee. Other
studies have been published12,13 in which nosyl-2-phenylaziridines
have been made and their ee values determined using similar,
suspect procedures. In all three instances, the reliability of the
ee values cannot be assessed without knowledge of the compo-
sition of the solvent used for injection onto the chiral HPLC
column.
Volume/A
Z
r
cal/Mg m-3
1.485
0.0450
0.0997
1.495
0.0964
0.2224
R1 [I > 2s(I)]
wR2
mixture of hexane 70% : isopropanol 30% was used, pumped at a
rate of 1 mL min-1. The aziridines were prepared for chiral HPLC
analysis by the addition of hexane.
A Chiralpak IA column of size 250 mm ¥ 4.6 mm ID and a pack-
ing composition of amylose tris(3,5-dimethylphenylcarbamate)
immobilized on 5 mm silica gel was used to replace the Chiralcel OJ
column for separating the chiral compounds. A solvent mixture
of hexane 85% : isopropanol 15% was used, pumped at a rate of
1 mL min-1. The aziridines were prepared for chiral HPLC analysis
by dissolving 5 mg in 1 mL THF and adding 4 mL hexane.
X-Ray crystallography
Data were recorded for crystalline racemic N-nosyl-2-
phenylaziridine, 1, and authentic S-enantiomer 2 on a Nonius
Kappa CCD diffractometer equipped with an Oxford Cryosystem
˚
cryostat and a molybdenum source (l = 0.71073 A). The structures
were solved by direct methods with additional light atoms found
by Fourier methods using SHELX-97.11 Hydrogen atoms were
added at calculated positions and refined using a riding model.
Anisotropic displacement parameters were used for all non-H
atoms; H-atoms were given isotropic displacement parameters
equal to 1.2 or 1.5 times the equivalent isotropic displacement
parameter of the atom to which the H-atom is attached. The
asymmetric unit of 2 consists of two independent molecules. The
higher R indices for 2 are due to the weakness of the data resulting
from the small size of the needles obtained. Crystal and refinement
data are shown in Table 1.†
Results and discussion
Enantiomeric excess
The reactions of styrene with PhINNs catalysed by copper(II)
triflate in homogeneous solution in acetonitrile and, heteroge-
neously, by CuHY in the same solvent in the presence of the chiral
modifier S,S-2,2¢-isopropylidene-bis(4-phenyl-2-oxazoline), were
carried out as previously described, the mixtures of enantiomers
isolated and the ee determined by HPLC. Comparison of
the chromatographic behaviour of authentic S-2-phenyl-N-(4-
nitrobenzenesulfonyl)aziridine ([a]D = +77.80), prepared from S-
phenylglycinol and 4-nitrobenzenesulfonyl chloride, followed by
The results of experiments, in which the injection solvent and
mobile phase were varied, are shown in Table 2. It is evident
that the origin of the discrepancy in the observed ee lies in the
use of hexane as the solvent for the injection of the mixture
of enantiomers. We reasoned that, although the enantiomeric
N-nosylaziridines appeared soluble in hexane, a true racemate
might be less soluble so that the solution actually injected onto
the chiral HPLC column could contain largely the enantiomer in
excess.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 1079–1084 | 1081
©

View Article Online
Table 2 HPLC analysis of enantiomeric 2-phenyl-N-(4-nitrobenzenesulfonyl)aziridinesa
Column
Mobile phase
Sample injection solvent
Enantiomeric excess (%)
Chiralcel OJ
Chiralpak IA
Chiralpak IA
Chiralpak IA
70% hexane : 30% IPA
85% hexane : 15% IPA
85% hexane : 15% IPA
20% THF : 80% hexane
100% hexane
100% hexane
20% THF : 80% hexane
20% THF : 80% hexane
90 R
90 R
35 R
36 R
a Reaction conditions used to make the nosyl aziridine: air, RT, 12 h reaction time, MeCN (5 mL), Cu(OTf)2 (4.15 ¥ 10-5 mol of Cu), bis(oxazoline) (1.17 ¥
10-4 mol), PhINNs (1.46 ¥ 10-3 mol), styrene (9.69 ¥ 10-4 mol).
Table 3 Enantiomeric excesses for the solution phase and solid phase in
ternary mixtures hexane–R- and S-N-arenesulfonyl-2-phenylaziridines
ee of aziridine
mixture
Aziridine/hexane/ ee of hexane
-1
mgAz mLC
solution (%)
ee of solid (%)
6 H12
N-Nosylaziridine
28
0.29
0.25
0.20
81 (R)
73 (R)
72 (R)
10.5 (R)
19 (R)
3 (R)
35
26
N-Tosylaziridine
28
28
28
28
27
70 (R)
41 (R)
32 (R)
28 (R)
—
—
—
—
3.6
2.0
1.0
Fig. 1 Observed ee of the hexane solution phase in mixtures of
enantiomeric N-nosyl-2-phenylaziridines.
The ternary system: hexane–R- and
S-2-phenyl-N-(4-nitrobenzenesulfonyl)aziridine
In order to understand the role of the injection solvent on the
enantiomer analysis, we undertook solubility tests in hexane on
N-nosyl- and N-tosyl-2-phenylaziridines, examining the ee for the
aziridines in hexane solution and that for the residual insoluble
aziridine using a Chiralpak IA HPLC column and THF dissolu-
tion of the analyte; the results are shown in Table 3. It is evident
that for N-tosylaziridine, a concentration as high as 1 mg mL-1 of
hexane correctly produced the true ee of the original enantiomeric
mixture. At much higher ratios of enantiomeric aziridines to
hexane, which far exceeded the solubility, the observed ee of the
solution phase did increase but we consider that the published ee
values for N-tosylaziridines are correct. For the much less soluble
N-nosyl-2-phenylaziridines, solid material was always present in
the mixtures in Table 3, and this solid showed a much lower ee than
both the solution phase and the original mixture of enantiomers.
Clearly, the racemate remains largely in the solid phase, indicating
that it is less soluble than either of the enantiomers separately; the
enantiomer in excess is concentrated in the solution phase. The
situation is akin to that described by Blackmond and co-workers14
in the case of R- and S-prolines in dimethyl sulfoxide.
90% ee at a ratio of 1 mg mL-1 hexane, the HPLC analysis of the
solution corresponds to the input composition, because there is
insufficient excess enantiomer or racemate for both solid phases
to be present.
The other set of experiments was concerned with examining
the abilities of different solvents to produce solutions of high
ee from mixtures of enantiomers. Samples (1 mg) of N-nosyl-
2-phenylaziridine of 33% ee were added to a range of solvents and
the resulting liquid phase was analysed by HPLC. The aziridine
was fully soluble in DCM, THF and CH3CN, and the observed ee
of the solution was 33%. The aziridine was less soluble in ethanol,
but the solution still showed a 33% ee, whereas with IPA the
ee was 48%. Aziridine solubility in hydrocarbon solvents is very
Two other sets of experiments were carried out. In the first,
enantiomeric mixtures of N-nosyl-2-phenylaziridines were pre-
pared with ee values ranging from 5 to 100% by mixing the pure
S-enantiomer with the racemic material. The solids (1 mg) were
then equilibrated with hexane (1 mL) and the liquid phase analysed
using a Chiralpak IA HPLC column; the results are shown Fig. 1
and show that HPLC analysis of the hexane solution produced
from enantiomeric mixtures in the range from 10 to 90% ee always
indicate an ee of 82%. This then is the solution composition at
the eutectic point when the saturated solution in hexane is in
equilibrium with the solid racemate and the pure solid enantiomer
in excess. For solid material of less than 10% ee or greater than
Fig. 2 A unit cell of the racemate of N-nosyl-2-phenylaziridine (1).
1082 | Org. Biomol. Chem., 2011, 9, 1079–1084
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Fig. 3 A segment of the structure of (S)-N-nosyl-2-phenylaziridine (2) showing the unit cell.
Table 4 Enantiomeric excesses for N-nosylaziridines from styrene
derivatives
much lower, and the following ee values were observed: hexane,
82%; cyclohexane, 84%; heptane, 91%; pentane, 94%.
Reported % ee
of aziridine10
X-Ray crystallography
Styrene
Corrected % ee % ee of aziridine
Support for the correctness of our interpretation of the pattern
of behaviour described above comes from X-ray crystallographic
studies. Treatment of an enantiomeric mixture of N-nosyl-2-
phenylaziridines with hexane, followed by separation of the
insoluble solid, afforded a material that on recrystallisation from
dichloromethane gave crystals of racemate, 1; the crystallographic
details are in Table 1. The crystal structure of 1 shows a racemic
assembly of R- and S-enantiomeric molecules of N-nosyl-2-
phenylaziridine, as dictated by the crystallographic symmetry.
The unit cell contains two pairs of enantiomeric molecules, as
shown in Fig. 2.
substituent CuHY Cu(OTf)2 of aziridine
dissolved in hexanea
3-F
4-CH3
3-Cl
(S) 58 (S) 83
(S) 67 (S) 66
(S) 95 (S) 72
(R) 25
(S) 25
(R) 30
(R) 94
(S) 89
(R) 87
a 1 mg azirdine : 1 mL hexane.
Conclusions
By synthesising (S)-N-nosyl-2-phenylaziridine from (S)-(+)-
phenylglycinol, it has been shown that the aziridination of
styrene and substituted styrenes by PhINNs in the presence
of the chiral modifier S,S-2,2¢-isopropylidene-bis(4-phenyl-2-
oxazoline), catalysed either by copper(II) triflate in homogeneous
solution in CH3CN or heterogeneously by CuHY, again in
the presence of the same solvent, yields predominantly the R-
enantiomer. Using an improved analytical procedure, it is shown
that previous reports of high enantioselectivity in such reactions
are erroneous. It has been demonstrated that the treatment of
enantiomeric mixtures of N-nosyl-2-phenylaziridine with hexane-
rich solvents leads to the separation of a solid phase that consists
largely of the solid racemic compound and a solution phase that
contains mostly the enantiomer originally present in excess. The
previously reported ee values for N-tosyl-2-phenyl aziridines are
considered to be correct. However, it is apparent that the relative
solubilities of the racemate and the pure enantiomers in hexane
can be used to obtain the enantiomer in high ee.
The corresponding crystallographic results for the pure S-
enantiomer, 2, synthesised from S-phenylglycinol, are shown in
Table 1. The crystal structure of 2 is chiral and a segment
of the structure is shown in Fig. 3. The two independent
molecules in the asymmetric unit assume identical conforma-
tions but are distinguishable by the variable geometry of their
intermolecular contacts. A different crystal structure has also
been reported previously15 for (S)-N-nosyl-2-phenylaziridine, and
therefore structure 2 represents a second polymorphic form.
Enantioselectivity in the aziridination of substituted styrenes
We take this opportunity of correcting the enantiomeric excesses of
aziridines formed by the reaction of PhINNs with ring-substituted
styrenes catalysed by copper(II) triflate and by CuHY.16 Reactions
were conducted in an identical manner to those described by
Ryan et al.,16 but enantiomeric analyses were carried out using
a Chiralpak IA HPLC column with injection of the aziridines
in THF diluted with hexane; the results are shown in Table 4,
which also gives the incorrect ee values reported earlier and
the ee of the saturated solution in hexane produced when the
enantiomeric product mixture (1 mg) was treated with hexane
(1 mL) alone. The corrected ee for each of the substituents is
much less than previously reported, being about 30%. The high
ee values for the hexane-soluble fractions confirm the pattern
of behaviour established for N-nosyl-2-phenylaziridines, namely
that these compounds form a solid racemate that is less soluble
in hexane than the pure enantiomers. Clearly, pure enantiomers
can be readily separated from enantiomeric mixtures of low ee,
particularly by the use of hydrocarbon solvents.
References
1 S. Feast, D. Bethell, P. C. B. Page, F. King, C. H. Rochester, M. R. H.
Siddiqui, D. J. Willock and G. J. Hutchings, J. Chem. Soc., Chem.
Commun., 1995, 2409–2411; R. P. K. Wells, P. Tynjala, J. E. Bailie, D. J.
Willock, G. W. Watson, F. King, C. H. Rochester, D. Bethell, P. C. B.
Page and G. J. Hutchings, Appl. Catal., A, 1999, 182, 75–84.
2 D. A. Evans, M. M. Faul and M. T. Bilodeau, J. Org. Chem., 1991, 56,
6744–6746; D. A. Evans, M. M. Faul, M. T. Bilodeau, B. A. Anderson
and B. M. Barnes, J. Am. Chem. Soc., 1993, 115, 5328–5329; D. A.
Evans, M. M. Faul and M. T. Bilodeau, J. Am. Chem. Soc., 1994, 116,
2742–2753.
3 C. Langham, P. Piaggio, D. Bethell, D. F. Lee, P. McMorn, P. C. B.
Page, D. J. Willock, C. Sly, F. E. Hancock, F. King and G. J. Hutchings,
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 1079–1084 | 1083
©

View Article Online
Chem. Commun., 1998, 1601–1602; C. Langham, S. Taylor, D. Bethell,
P. McMorn, P. C. B. Page, D. J. Willock, C. Sly, F. E. Hancock, F. King
and G. J. Hutchings, J. Chem. Soc., Perkin Trans. 2, 1999, 1043–1049;
C. Langham, D. Bethell, D. F. Lee, P. McMorn, P. C. B. Page, D. J.
Willock, C. Sly, F. E. Hancock, F. King and G. J. Hutchings, Appl.
Catal., A, 1999, 182, 85–89.
4 M. J. Sodergren, D. A. Alonso, A. V. Bedekar and P. G. Andersson,
Tetrahedron Lett., 1997, 38, 6897–6900.
5 M. J. Sodergren, D. A. Alonso and P. G. Andersson, Tetrahedron:
Asymmetry, 1997, 8, 3563–3565.
6 S. Taylor, J. Gullick, P. McMorn, D. Bethell, P. C. B. Page, F. E.
Hancock, F. King and G. J. Hutchings, J. Chem. Soc., Perkin Trans. 2,
2001, 1714–1723; S. Taylor, J. Gullick, P. McMorn, D. Bethell, P. C. B.
Page, F. E. Hancock, F. King and G. J. Hutchings, J. Chem. Soc., Perkin
Trans. 2, 2001, 1724–1728; S. Taylor, J. Gullick, P. McMorn, D. Bethell,
P. C. B. Page, F. E. Hancock, F. King and G. J. Hutchings, Top. Catal.,
2003, 24, 43–50.
7 S. Taylor, J. Gullick, N. Galea, P. McMorn, D. Bethell, P. C. B. Page,
F. E. Hancock, F. King, D. J. Willock and G. J. Hutchings, Top. Catal.,
2003, 25, 81–88.
8 J. Gullick, D. Ryan, P. McMorn, D. Bethell, F. King, F. E. Hancock
and G. J. Hutchings, New J. Chem., 2004, 28, 1470–1478.
9 Y. Yamada, T. Yamamoto and M. Okawara, Chem. Lett., 1975, 361–
362.
10 J. Farra`s, X. Ginesta, P. W. Sutton, J. Taltavull, F. Egeler, P. Romea, F.
Urp´ı and J. Vilarrasa, Tetrahedron, 2001, 57, 7665–7674.
11 G. M. Sheldrick, SHELX-97: Programs for crystal structure analysis
(release 97-2), Institut fu¨r Anorganische Chemie der Universita¨t,
Tammanstrasse 4, D-3400 Go¨ttingen, Germany, 1998.
12 H.-L. Kwong, D. Liu, K.-Y. Chan, C.-S. Lee, K.-H. Huang and C.-M.
Che, Tetrahedron Lett., 2004, 45, 3965–3968.
13 K. Omura, T. Uchida, R. Irie and T. Katsuki, Chem. Commun., 2004,
2060–2061.
14 M. Klussmann, H. Iwamura, S. P. Mathew, D. H. Wells, U. Pandya, A.
Armstrong and D. G. Blackmond, Nature, 2006, 441, 621–623.
15 F. Crestey, M. Witt, K. Frydenvang, D. Stærk, J. W. Jaroszewski and
H. Franzyk, J. Org. Chem., 2008, 73(9), 3566–3569 (see the supporting
information†).
16 D. Ryan, P. McMorn, D. Bethell and G. J. Hutchings, Org. Biomol.
Chem., 2004, 2, 3566–3572.
1084 | Org. Biomol. Chem., 2011, 9, 1079–1084
This journal is
The Royal Society of Chemistry 2011
©