A study of the functional group compatibility of sulfoximination methods

Article abstract of DOI:10.1016/S0040-4039(02)00378-7

The sulfoximination of a range of sulfoxides possessing functionalised side-chains using mesitylene sulfonyl hydroxylamine or iminoiodane reagents is discussed. The use of iminoiodane reagents possessing removable protecting groups (p-nosyl and Ses) is re

Full text of DOI:10.1016/S0040-4039(02)00378-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2749–2751
A study of the functional group compatibility of sulfoximination
methods
Sylvaine Cren, Taryn C. Kinahan, Catharine L. Skinner and Heather Tye*
School of Chemical Sciences, The University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Received 15 January 2002; revised 11 February 2002; accepted 21 February 2002
Abstract—The sulfoximination of a range of sulfoxides possessing functionalised side-chains using mesitylene sulfonyl hydroxyl-
amine or iminoiodane reagents is discussed. The use of iminoiodane reagents possessing removable protecting groups (p-nosyl and
Ses) is reported along with conditions for the deprotection of the sulfoximine adducts. © 2002 Elsevier Science Ltd. All rights
reserved.
1. Introduction
only been employed in aziridination chemistry.6 The
results presented here clearly show that these reagents
are quite generally applicable to sulfoximine synthesis.
During the course of our research into compounds
possessing the sulfoximine functional group we have
had cause to prepare a number of compounds which
also contain other functionalities such as alkenes, alco-
hols, esters and carbamates. Of the methods available
for the introduction of the sulfoximine group1 the
simplest is the imination of the corresponding sulfoxide
either using mesitylene sulfonyl hydroxylamine
(MSH)2,3 or using iminoiodane reagents such as Ph-
IꢀNTs4 under Cu(I)-catalysed conditions. Herein we
report our findings regarding the functional group com-
patibility of MSH and the iminoiodane reagent Ph–
IꢀN–Ts along with use of modified iminoiodane
reagents Ph–IꢀN–Ns5 (Ns=para-nitrophenyl sulfonyl)
and Ph–IꢀN–Ses6 (Ses=trimethylsilylethyl sulfonyl)
possessing removable protecting groups.
In general the iminoiodane reagents appear to be more
versatile than MSH, which fails to react with the vinylic
sulfoxide 1b and the b-bromo sulfoxide 1d, and gives
very poor conversion of the b-sulfinyl propionate 1f
and S-methyl cysteine derivative 1h (in both of these
cases a competing lactamisation of the free sulfoximine
is observed7). Surprisingly MSH and all three iminoio-
dane reagents tolerate the presence of a free hydroxyl
group in sulfoxide 1c giving good to moderate yields of
the corresponding sulfoximines in all cases.
One substrate which could not be iminated by any of
the methods investigated was the a-sulfinyl ethanoate
1e. This lack of reactivity is probably due to the
inductive electron withdrawing effect of the ester group
making the lone pair on sulfur much less nucleophilic
than in the other substrates. However, this sulfoximine
derivative can be prepared by introduction of the ester
group after imination of phenyl methyl sulfoxide 1a.8
2. Results and discussion
The results obtained for the reaction of a range of
sulfoxides 1a–h under differing imination conditions are
summarised in Scheme 1 and Table 1. To date the
modified iminoiodane reagent Ph–IꢀN–Ns has seen lim-
ited use in sulfoximine synthesis5 and Ph–IꢀN–Ses has
Our ultimate synthetic goal was to produce sulfox-
imines possessing side-chain functionalities which could
also be derivatised at nitrogen. In order to achieve this
O
NR3
R2
O
R1,R2 = various
R3 = H, Ts, p-Ns, Ses
Imination
S
S
R1
R2
R1
Scheme 1.
* Corresponding author. Fax: +44 (0)121 414 4403; e-mail: h.tye@bham.ac.uk
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00378-7

2750
S. Cren et al. / Tetrahedron Letters 43 (2002) 2749–2751
Table 1.
Yield (%) of Sulfoximine Using Specified Reagent
Substrate
Ph
MSHa
Ph-I=N-Tsb
Ph-I=N-Nsb Ph-I=N-Sesb
O
S
1a
1b
75
59
69
65
68
30c
59
Me
O
S
0
93
90
Ph
O
S
95
40
1c
Ph
OH
O
S
-
-
0
0
41
0
1d
1e
Ph
Br
O
0
0
S
CO2Me
Ph
O
S
4d
78
55
50
1f
Ph
CO2Me
O
S
Me
70e
48e
-
-
1h
CbzHN
CO2Me
a) MSH (2 eq.), DCM, rt. then Na2CO3 (aq).
b) Iminoiodane (1.1 eq.), CuPF6 (0.05eq), CH3CN, 0oC- rt.
c) Unoptimised yield.
d) Cyclisation to form a lactam derivative was a major side reaction. A similar problem
has been observed in the reaction of methyl cysteine derivatives with MSH (see
reference 7).
e) A single diastereoisomer of sulfoxide was used, however, the configuration at sulfur
is unknown.
the use of MSH (giving free sulfoximines directly) or in
the cases where MSH performed poorly, iminoiodanes
with removable protecting groups, Ph–IꢀN–Ns and Ph–
IꢀN–Ses, would be required. To the best of our knowl-
edge methods for the removal of p-nosyl and Ses
groups from the corresponding protected sulfoximines
have not been previously reported. In our hands the
p-nosyl group could be removed from the phenyl
methyl sulfoximine 2a using Cs2CO3, PhSH in either
acetonitrile or DMF in 59 and 35% yields, respectively
(Scheme 2). However, this reaction did not proceed
cleanly with other functionalised sulfoximines such as
those derived from 1b, 1f and 1h.
50°C giving the free sulfoximine 3 in 86% yield (Scheme
3). Investigations into the compatibility of this method
with other functional groups is ongoing.
Scheme 2.
Scheme 3.
Removal of the Ses group from phenyl methyl sulfox-
imine 2b proceeded smoothly using TBAF in THF at

S. Cren et al. / Tetrahedron Letters 43 (2002) 2749–2751
2751
3. Conclusion
Example procedure for removal of the Ses group from
2b: Sulfoximine 2b (0.63 mmol), was dissolved in THF
(10 ml) under an inert atmosphere (N2) and TBAF
(1.58 mmol, 1 M solution in THF) was added at rt. The
mixture was then heated to 50°C for 72 h. The reaction
mixture was concentrated and the crude product
purified by column chromatography on silica eluted
with ethyl acetate to give sulfoximine 3 as a colourless
oil (88%). lH (300 MHz, CDCl3) 2.67 (1H, s), 3.11 (3H,
s), 7.51–7.68 (3H, m), 7.98–8.06 (2H, m).
The use of iminoiodane reagents for the sulfoximina-
tion of a range of functionalised sulfoxides proceeds in
moderate to good yield. Iminoidoanes are generally
compatible with a wider range of functionality than
MSH. The subsequent removal of N-protecting groups
from the sulfoximine adducts is limited when the p-
nosyl group is used but has potential to be more
generally applicable in the case of the Ses group. This
opens the way to the synthesis of highly functionalised
sulfoximine-containing compounds.
Acknowledgements
4. Experimental
We are grateful to the University of Birmingham,
EPSRC, AstraZeneca and Pfizer for financial support
and to Professor Dodd for helpful advice regarding the
preparation of the Ses protected iminoiodane reagent.
Example procedure for imination of 1f using Ph–IꢀN–
Ses: Sulfoxide 1f (1.0 equiv.) was dissolved in dry
acetonitrile and CuPF6[CH3CN]4 (0.05 equiv.) was
added under an inert atmosphere (N2). The mixture was
cooled to 0°C and Ph–IꢀN–Ses (1.1 equiv.) was added
portionwise. The mixture was allowed to warm to rt
and stirred for a further 48 h. The solvent was evapo-
rated and the residue dissolved in ethyl acetate and
filtered through a silica plug. The product sulfoximine
was then isolated as a waxy solid (50%) by recrystallisa-
tion from ethyl acetate/hexane mixture. lH (300 MHz,
CDCl3) 0.0 (9H, s, TMS), 1.1 (2H, m, CH2), 2.8 (2H,
m, CH2), 3.1 (2H, m, CH2), 3.6 (3H, s, CH3), 4.85 (2H,
m, CH2), 7.6–8.0 (5H, m, ArH); lC (75 MHz, CDCl3)
−1.8 (TMS), 10.4 (CH2), 27.9 (CH2), 52.5 (CH3), 53.5
(CH2), 53.8 (CH2), 128.5 (Ar), 129.8 (Ar), 134.8 (Ar),
136.1 (q, Ar), 169.7 (CꢀO); m/z (ES) 414.0 ([M+Na]+,
100%); HRMS calcd for C15H25NO5S2SiNa (414.0841),
Found (414.0826).
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