Efficient nitrogen transfer from aldehyde-derived N-acyloxaziridines

Article abstract of DOI:10.1016/S0040-4039(03)01200-0

The effect of solvent polarity on the reaction of 3-aryl-N-carboxamido- and 3-aryl-N-alkoxycarbonyl oxaziridines has been studied and an efficient procedure for high yielding sulfimidation developed by use of polar solvents. The first examples of asymmetric sulfimidation using novel chiral oxaziridines have been carried out with low diastereoselectivity (up to 30% de).

Full text of DOI:10.1016/S0040-4039(03)01200-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 5335–5338
Efficient nitrogen transfer from aldehyde-derived
N-acyloxaziridines
Alan Armstrong,a,* Ian D. Edmondsa and Martin E. Swarbrickb
aDepartment of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
bNeurology & GI CEDD, GlaxoSmithKline, Medicines Research Centre, Stevenage, Herts SG1 2NY, UK
Received 7 April 2003; revised 28 April 2003; accepted 9 May 2003
Abstract—The effect of solvent polarity on the reaction of 3-aryl-N-carboxamido- and 3-aryl-N-alkoxycarbonyl oxaziridines has
been studied and an efficient procedure for high yielding sulfimidation developed by use of polar solvents. The first examples of
asymmetric sulfimidation using novel chiral oxaziridines have been carried out with low diastereoselectivity (up to 30% de).
© 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
easily achieved. However, the N-alkoxycarbonyl-
oxaziridines (e.g. 2a) developed by Vidal and Collet and
co-workers4 afford a mixture of oxidation and amina-
tion products in reaction with heteroatom nucleophiles
such as sulfides. In view of the potential stereochemical
advantages of these compounds, we decided to investi-
gate the variation of reaction conditions to promote
amination over oxidation. Here we describe successful
accomplishment of this goal, as well as the first exam-
The development of efficient reagents for transfer of
electrophilic nitrogen to organic substrates is an impor-
tant contemporary goal.1 We have recently reported2
that the ketomalonate-derived N-alkoxycarbonyl-
oxaziridine 1 effects efficient amination of sulfides and
applied this reagent to the preparation and subsequent
[2,3]-sigmatropic rearrangement of allylic sulfimides.
An asymmetric version of this process would provide a
non-metal mediated alternative to the recent Mn-
catalysed process reported by Katsuki3 and allow access
to valuable chiral amine derivatives. The configuration
at the oxaziridine ring nitrogen would be expected to
exert a major influence on asymmetric sulfimidation
using chiral analogues of 1. However, inversion at
nitrogen is rapid, and there is likely to be little differ-
ence in energy between the two invertomers in ketone-
derived oxaziridines, presenting a challenge for control
of asymmetry in the amination reaction. Aldehyde-
derived oxaziridines display a strong preference for the
N-substituent to be trans- to the substituent on the ring
carbon,4–7 and so stereocontrol is likely to be more
ples of asymmetric sulfimidation using chiral
oxaziridines.
2. Results and discussion
Initial studies focused on the reaction of thioanisole
with N-carboxamidooxaziridine 3 (Scheme 1), previ-
ously developed in the group for electrophilic amina-
tion of carbanions.5 Collet and co-workers had
reported4 that oxaziridine 2a afforded a mixture of
sulfoxide and sulfimide, with the degree of amination
increasing in more polar solvent and at lower tempera-
ture (entries 2–4 of Table 1). However, the range of
Keywords: oxaziridines; amination; sulfimides.
* Corresponding author. Fax: +44 (0)20 75945804; e-mail: a.armstrong@imperial.ac.uk
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01200-0

5336
A. Armstrong et al. / Tetrahedron Letters 44 (2003) 5335–5338
Scheme 1.
Table 1. Reaction of oxaziridines 1, 2a, 2b and 3 with
useful Boc nitrogen protecting group, is an even less
effective aminating agent in medium polarity solvents
(compare entries 18–19 to 2–4). Again the use of 2,2,2-
trifluoroethanol at low temperature results in efficient
amination of thioanisole (entry 21).
thioanisole
Entry
Oxaziridine
Solvent
Temp. (°C)
[N]:[O]a
1
2
3
4
5
6
7
1
CDCl3
CDCl3
19
19
19
−35
19
−40
19
90:10b
34:66c
48:52c
67:33c
<1:10d
1:3
2a
2a
2a
3
3
3
These results suggest that the transition state for amina-
tion is more polar (and hence more stabilised by polar
solvents) than that for oxidation.9 Assuming the reac-
tion proceeds by nucleophilic attack with NꢀO bond
cleavage, these observations can be rationalised by
comparing the developing alkoxy anion in the amina-
tion transition state with the much more stabilised
developing charge on the carboxamido group in the
oxidation transition state (Fig. 1).
CH3CN
CH3CN
Toluene
Toluene
Et2O
1:5
8
3
THF
19
1:4
9
3
3
3
3
3
3
3
THF
CDCl3
Neat
CH3CN
MeOH
MeOH
60% MeOH
(aq)
−40
19
19
19
19
2:3
1:2
1:2
1:1.2
3:1
10
11
12
13
14
15
−30
19
7:1
4:1
These improved conditions for amination were
exploited in the synthesis of a range of sulfimides
(Scheme 2, Table 2) and, in contrast to many amination
reagents, the sulfide was completely and cleanly con-
verted to sulfimide (and sulfoxide) using only 1.05
equivalents of oxaziridine. N-Carboxamidooxaziridine
3 gave good to excellent yields of sulfimide in all cases,
although introduction of bulky substituents on the
sulfide decreased the ratio of amination to oxidation
(entry 3). This steric effect was more pronounced with
N-butoxycarbonyloxaziridine 2b, resulting in lower
yields of sulfimide.
16
17
18
19
20
21
3
3
2b
2b
2b
2b
CF3CH2OH
CF3CH2OH
CDCl3
CH3CN
CF3CH2OH
CF3CH2OH
19
−40
19
−35
19
10:1
>10:1
27:73b
62:38b
5:1
−40
10:1
a Measured by integration of the SCH3 peaks in the 1H NMR
spectrum of the crude reaction mixture.
b From Ref. 2.
c From Ref. 4.
d Sulfoxide isolated in 89% yield.
Chiral sulfimides have considerable potential in
stereoselective synthesis10 and as such we were inter-
ested in developing an asymmetric variant of the above
methodology. Preliminary work has focused on the use
of a chiral amine auxiliary attached as an N-carbox-
amido substituent, namely oxaziridines 4a and 4b.
Preparation of these novel oxaziridines is shown in
Scheme 3. Conversion of commercially available (R,R)-
bis-a-methylbenzylamine to its urea derivative was fol-
lowed by titanium isopropoxide-mediated condensation
with p-chlorobenzaldehyde.11 Oxidation was achieved
using biphasic basic mCPBA to afford a 1:3 mixture of
separable diastereomers 4a and 4b.
solvents used was limited, the most polar being aceto-
nitrile which gave a 67:33 ratio of amination to oxida-
tion at −35°C. Similar trends were observed with our
N-carboxamidooxaziridine 3 (entries 5–17), but by
investigating a wider range of solvent polarity, a
remarkable reversal of chemoselectivity could be
obtained. Almost exclusive oxidation was observed in
toluene (entry 5), but using the highly polar 2,2,2-trifl-
uoroethanol afforded almost exclusive amination
(entries 16–17). Indeed, a good correlation between
solvent polarity (quantified using ET(30) values8) and
percentage amination was observed, with R2=0.99.
In common with the results of Collet and co-workers,
performing the reaction at low temperature increased
the degree of amination (entries 5–6, 8–9, 13–14 and
16–17). Although Collet has only reported the use of
N-methoxycarbonyloxaziridine 2a for the amination of
sulfides, we have previously shown2 that the commer-
cially available N-tert-butoxycarbonyl analogue 2b,
which affords sulfimides bearing the synthetically more
Figure 1. Possible transition states for amination and oxida-
tion.

A. Armstrong et al. / Tetrahedron Letters 44 (2003) 5335–5338
5337
Scheme 2.
Table 2. Scope of the amination of sulfides
Entry
Oxaziridine
R
R%
[N]:[O]a
Yield [N] (%)
Yield [O] (%)
1
2
3
4
5
6
3
3
3
2b
2b
2b
Ph
Ph
tBu
Ph
Ph
tBu
Me
Bn
Me
Me
Bn
>10:1
>10:1
3:1
10:1
3:1
99
94
72
87
75
49
–
6
–
5
22
–
b
b
Me
1:1
a Measured by integration of the SCH2R peaks in the crude 1H NMR spectrum.
b Volatile product not isolated.
Scheme 3. Reagents and conditions: (i) triphosgene (0.5 equiv.), Et3N, DMAP, 93%; (ii) NH3(g), Et2O, 93%; (iii) p-chlorobenzalde-
hyde (1 equiv.), Ti(OiPr)4 (1.2 equiv.), THF; (iv) mCPBA (3 equiv.), K2CO3(aq), CH2Cl2, 63% for two steps.
Since the ring carbon and nitrogen in these oxaziridines
are both stereocentres, four diastereomers could poten-
tially be formed. Two pairs of these could undergo
interconversion by inversion at nitrogen, effectively
resulting in cis- and trans-isomers. However, X-ray
crystallography12 of the separated diastereomers reveals
that they are trans-isomers with opposite configurations
at the ring carbons. The presence of only one set of
peaks in the NMR spectra indicates that the cis-isomers
are also not present in solution. Compounds 4a and 4b
appear to represent the first reported examples of
diastereomerically pure chiral non-racemic N-
carboxamidooxaziridines.13
that the two oxaziridine diastereomers gave opposite
stereoselectivity. As might be expected this suggests that
the ring carbon stereocentre, which also determines the
stereocentre at the ring nitrogen, has much greater
influence on selectivity than the auxiliary chirality.
In summary, we have reported an improved and
efficient procedure for the amination of sulfides using
aldehyde-derived N-alkoxycarbonyl and N-carbox-
amido oxaziridines. Use of polar solvents at low tem-
perature promotes amination, whereas non-polar sol-
vents at room temperature promote oxidation. The
results with chiral non-racemic oxaziridines demon-
strate the dominance of the ring carbon stereocentre in
determining the stereoselectivity of the reaction. This is
important information for ongoing studies aimed at
improving the efficiency of asymmetric sulfimidation.
With the synthesis of the desired non-racemic oxaziridi-
nes accomplished, attention was then turned to their
use in the amination of thioanisole (Scheme 4). These
reactions proceeded with good chemoselectivity but
only moderate diastereoselectivity (30% and 26% d.e.
for 4a and 4b, respectively). Stereochemistry was deter-
mined by oxidation of the separate sulfimide
diastereomers to the corresponding sulfoximines (prece-
dented to proceed with retention of stereochemistry10)
and comparison with authentic samples prepared by
acylation of commercially available (R)- and (S)-S-
methyl, S-phenyl sulfoximine. It is interesting to note
Acknowledgements
We are grateful to the EPSRC (GR/R54668) and GSK
(CASE award to IDE) for their support of this work.

5338
A. Armstrong et al. / Tetrahedron Letters 44 (2003) 5335–5338
Scheme 4.
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