Conjugate addition of amines to vinyl sulfoximides: A general method for the synthesis of β-amino sulfoximides

Article abstract of DOI:10.1016/S0040-4039(02)02326-2

The synthesis of a range of β-amino sulfoximide derivatives is described. The conjugate addition of simple amines or amino acids to N-tosyl phenyl vinyl sulfoximide was achieved in moderate to good yield (41-95%). Electron poor nucleophiles such as tosyl amide or benzyl carbamate were found to be unreactive under analogous conditions.

Full text of DOI:10.1016/S0040-4039(02)02326-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9421–9423
Conjugate addition of amines to vinyl sulfoximides: a general
method for the synthesis of b-amino sulfoximides
Heather Tye*
School of Chemical Sciences, The University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK
Received 23 July 2002; accepted 11 October 2002
Abstract—The synthesis of a range of b-amino sulfoximide derivatives is described. The conjugate addition of simple amines or
amino acids to N-tosyl phenyl vinyl sulfoximide was achieved in moderate to good yield (41–95%). Electron poor nucleophiles
such as tosyl amide or benzyl carbamate were found to be unreactive under analogous conditions. © 2002 Published by Elsevier
Science Ltd.
1. Introduction
There are surprisingly few examples of b-amino sulfox-
imides in the literature. Pyne and Reggelin have indepen-
dently described the intramolecular addition of nitrogen
nucleophiles to a,b-unsaturated sulfoximides in order to
generate nitrogen heterocycles.1,2 An example of the
intermolecular addition of amine nucleophiles into vinyl
sulfoximides has been reported by Annunziata et al.,3
who described the kinetic resolution of N-phthaloyl vinyl
sulfoximides using ephedrine (Scheme 1). Taking this
precedent as a starting point we decided to investigate the
generality of the conjugate addition of nitrogen nucleo-
philes into vinyl sulfoximides.
As part of ongoing research projects into the use of
sulfoximide derivatives as ligands in asymmetric synthe-
sis and as building blocks in the synthesis of pepti-
domimetics we required a simple, yet potentially diverse,
method for the preparation of b-amino sulfoximide
derivatives (Fig. 1).
2. Results and discussion
Previous work in our group4 has shown that N-sulfonyl
protected vinyl sulfoximides can be readily prepared
Figure 1.
Scheme 1.
* Present address: Evotec OAI, 151 Milton Park, Abingdon, Oxfordshire, OX14 4SD, UK. Fax +44 (0)1235 441509; e-mail: heather.tye@
evotecoai.com
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02326-2

9422
H. Tye / Tetrahedron Letters 43 (2002) 9421–9423
Table 1.
from the corresponding vinyl sulfoxide using iminoio-
dane reagents as described by Muller et al.5 In this case
we chose to prepare the N-tosyl derivative 1 in racemic
form from commercially available racemic phenyl vinyl
sulfoxide (Scheme 2). The enantiomerically pure sulfox-
ide can be prepared by addition of vinyl magnesium
bromide into a chiral sulfinamide using methodology
developed by Evans,6 however we chose to pursue our
studies using the racemic derivative in the first instance.
Entry
R1
R2
Time (h)
Yield (%)
1
2
3
4
5
H
Et
–(CH2)5–
H
H
Bn
Et
–
Ts
Cbz
24
8
4
24
24
79
78
95
0a
0a
a No reaction was observed.
The addition of a number of amine nucleophiles to
vinyl sulfoximide 1 using the conditions described by
with no evidence of side reactions and the mass balance
could be accounted for by recovery of unreacted 1.
3
Annunziata et al. was carried out (Scheme 3) and the
results are shown in Table 1.
Primary and secondary amines proved to be good
nucleophiles resulting in the formation of the desired
b-amino sulfoximides in excellent yields (78–95%) how-
ever, the electron deficient nucleophiles, tosyl amide
and benzyl carbamate, gave no reaction under these
conditions. The efficient addition of benzylamine was
very encouraging since the benzyl group can potentially
be removed to allow further manipulation of the b-
amino group allowing for the preparation of a wide
range of b-amino sulfoximide derivatives.
3. Conclusion
We have demonstrated that a wide range of amine
nucleophiles can be added to a vinyl sulfoximide to give
the corresponding b-amino sulfoximides in good yield
under mild reaction conditions. The scope of the reac-
tion is likely to be extended by manipulation of the
amine protecting group in the case of the benzylamine
derivative. Reaction at the nitrogen of the sulfoximide
group may also be possible if a removable protecting
group is utilized at this position (e.g. N-SES4). Further
investigations into these synthetic aspects are currently
under way along with enantioselective variants employ-
ing a single enantiomer of vinyl sulfoximide 1.
Our interest in the use of b-amino sulfoximides as
peptidomimetics prompted us to explore the scope of
the amine addition reaction using amino acids as nucle-
ophiles. The addition of a number of amino acid
methyl esters to vinyl sulfoximide 1 was carried out in
a parallel reactor† using the corresponding hydrochlo-
ride salts in the presence of triethylamine with
dichloromethane as solvent (Scheme 4). The results are
presented in Table 2.
4. Experimental
Example procedure for the reaction of an amino acid
methyl ester with vinyl sulfoximide 1: Vinyl sulfoximide
1 (200 mg) was dissolved in dry DCM (5 ml) under an
inert atmosphere of N2. To this was added glycine
methyl ester hydrochloride salt (55 mg) and triethyl-
amine (86 ml). The resulting solution was agitated at
room temperature for a period of 24 h. After this time
The products were isolated in moderate to good yields
(41–78%) as a 1:1 mixture of diastereoisomers except in
the case of the glycine derivative, which lacks a second
stereocentre. In all cases the reactions proceeded cleanly
Scheme 2.
Scheme 3.
† Reactions were carried out using a FirstMate™ parallel synthesizer supplied by Argonaut Technologies.

H. Tye / Tetrahedron Letters 43 (2002) 9421–9423
9423
Scheme 4.
Table 2.
(CH2), 54.4 (CH3), 52.6 (CH2), 45.2 (CH2), 24.0 (CH3);
MS: (Electrospray) 433.0 (100%) [M+Na]+; HRMS:
Entry
Amino acid
Yield (%)
(Electrospray)
Found:
433.0882,
calcd
for
C18H22N2O5NaS2 433.0868.
1
2
3
4
5
6
Glycine
Alanine
Valine
Leucine
Phenylalanine
Proline
41
60a
64a
78a
77a
60a
Acknowledgements
We are grateful to The University of Birmingham and
AstraZeneca for funding. A special thanks to Tanafit
Redjala for carrying out some preliminary investiga-
tions.
a Isolated as a 1:1 mixture of diastereoisomers.
the reaction was washed with saturated aqueous
sodium bicarbonate (5 ml) and the organic phase dried
using sodium sulfate. The solvent was evaporated to
give a clear glass, which was purified by flash column
chromatography on silica eluting with ethyl acetate.
The desired product was isolated as a waxy white solid
(105 mg, 41%). IR: (CHCl3, cm−1) 3330 (w), 3024 (s),
1741 (s), 1317 (s), 1226 (s), 1206 (s), 1154 (s), 1095 (s),
References
1. Pyne, S. G. J. Chem. Soc., Chem. Commun. 1986, 1686.
2. Reggelin, M.; Heinrich, T. Angew. Chem. Int. Ed. 1998, 37,
2883.
1
3. Annunziata, R.; Cinquini, M. J. Chem. Soc., Perkin Trans.
1066 (s); H NMR: (300 MHz, CDCl3) 7.95 (2H, d,
1 1979, 1684.
7.7), 7.79 (2H, d, 8.1), 7.70–7.60 (1H, m), 7.59-7.50
(2H, m), 7.20 (2H, d, 8.1), 3.79–3.51 (2H, m), 3.66 (3H,
s), 3.32–3.22 (2H, m), 3.06–2.89 (2H, m), 2.33 (3H, s),
1.73 (1H, s, NH); 13C NMR: (75.5 MHz, CDCl3) 174.9
(C=O), 145.3 (C), 143.5 (C), 139.0 (C), 136.9 (CH),
132.1 (CH), 131.7 (CH), 130.7 (CH), 129.1 (CH), 60.5
4. Cren, S.; Kinahan, T. C.; Skinner, C. L.; Tye, H. Tetra-
hedron Lett. 2002, 43, 2749.
5. Muller, J. F. K.; Vogt, P. Tetrahedron Lett. 1998, 39, 4805.
6. Evans, D. A.; Faul, M. M.; Colombo, L.; Bisaha, J. J.;
Clardy, J.; Cherry, D. J. Am. Chem. Soc. 1992, 114, 5977.