A convenient method for the alkylation of sulfamides using alkyl bromides and Mitsunobu betaine

Article abstract of DOI:10.1016/S0040-4039(00)02012-8

The alkylation of N-Boc-N′-(2-chloroethyl)sulfamide 1 by electron-deficient alkyl bromides using the Mitsunobu reagent as mild base is described. This method was also applied to the N-glycosylation of various carbohydrates and was anomerically selective.

Full text of DOI:10.1016/S0040-4039(00)02012-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 601–603
A convenient method for the alkylation of sulfamides using alkyl
bromides and Mitsunobu betaine
Jean-Yves Winum, V e´ ronique Barragan and Jean-Louis Montero*
Laboratoire de Chimie Biomol e´ culaire UMR 5032, Universit e´ Montpellier II, Place E. Bataillon, cc073,
34095 Montpellier Cedex 05, France
Received 6 October 2000; accepted 7 November 2000
Abstract—The alkylation of N-Boc-N%-(2-chloroethyl)sulfamide 1 by electron-deficient alkyl bromides using the Mitsunobu
reagent as mild base is described. This method was also applied to the N-glycosylation of various carbohydrates and was
anomerically selective. © 2001 Elsevier Science Ltd. All rights reserved.
In our ongoing research on the synthesis of alkylating
mides were unsuccessful). The reaction proceeds under
mild and neutral conditions. Mitsunobu betaine gener-
2
agents such as N-chloroethylnitrososulfamide (CENS)
1
compounds, we focused our attention on the synthesis
ated in situ from the phosphine and the azodicarboxy-
late plays the role of a base which is sufficiently strong
to deprotonate the NH of the sulfamide prior to alkyla-
tion. Two different redox couples have been tested: (a)
tri-n-butylphosphine (TBP) and 1,1%-(azodicarbonyl)-
dipiperidine and (b) triphenylphosphine (TPP) and
diisopropylazodicarboxylate (DIAD). The former
of a new generation of sugar-derived compounds. The
key step in the preparation of such compounds is the
alkylation of N-Boc-N%-(2-chloroethylsulfamide) 1.
This was followed by the selective removal of the Boc
group on molecule 2, and then by nitrosation to afford
CENS in good overall yields.
(
using 1.5 equiv. of each) appears to be superior to the
To promote efficiently the N-alkylation reaction, we
first used a classical N-alkylation method using a min-
eral base such as potassium or sodium carbonate in an
heterogeneous medium. In each case, we obtained the
desired products in less than 10% yield (data not
shown). These disappointing results led us to investi-
gate another approach in condensing various bromo-
sugars on 1 using a Mitsunobu redox couple (Scheme
latter (using 3 equiv. of each). Table 1 summarizes the
results.
3
The synthesis was carried out in THF for the TPP/
DIAD couple, and in benzene for the TBP/ADDP
couple. A standard sequence of reagent additions was
used. Thus compound 1 (1 equiv.), the phosphine and
alkyl bromide (1 equiv.) were dissolved in the appropri-
ate solvent. After addition of DIAD or ADDP, the
mixture was allowed to stand at room temperature
overnight. The mixture was poured into water, and
extracted with methylene chloride. The combined
organic layers were dried over anhydrous Na SO , and
1).
We first applied the reaction to different alkyl bromides
in which the bromine atom is bonded to electron-
deficient carbon (experiments on inactivated alkyl bro-
2
4
Scheme 1.
Keywords: sulfamides; Mitsunobu betaine; glycosylation; alkyl bromide.
*
Corresponding author. E-mail: montero@univ-montp2.fr
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02012-8

6
02
J.-Y. Winum et al. / Tetrahedron Letters 42 (2001) 601–603
concentrated in vacuo. The resulting residue was then
purified by chromatography on silica gel. The different
products were obtained in moderate to good yields. The
structures of all new compounds were confirmed by the
products. In fact few applications of the Mitsunobu
reaction to glycoside bond formation have been re-
ported in the literature.
5–9
4
usual spectroscopic analysis.
The present approach to N-glycoside synthesis is a mild
and viable procedure which circumvents the need for
deprotection of the anomeric position, and is compat-
ible with various protecting groups (entry 2j).
We then applied the method to the glycosylation reac-
tion (Table 1). Thus the reaction of tetra-O-acetyl-a-
D
-glycopyranosyl bromide with N-Boc-N%-(2-chloro-
ethyl)sulfamide using Mitsunobu reagents afforded
selectively and exclusively the b anomer product in
good or moderate yield with anomeric carbonꢀnitrogen
bond forming (entries 2f–2j). The reaction, applied to
pyranoses (entries 2f–2h) and to furanose (entries 2i
and 2j), demonstrates the potential of our approach.
In conclusion, we have achieved a convenient and
interesting method involving the addition of N-Boc
sulfamide to various alkyl bromide derivatives under
Mitsunobu conditions. This approach provides an
excellent entry into the selective synthesis of N-b-glyco-
syl compounds starting from halogeno sugar.
Our method compares favorably with the Mitsunobu
reaction applied to sugars with anomeric hydroxyl
functions. Its usefulness with such compounds is limited
owing to the formation of various ratios of anomeric
We note that our mild Mitsunobu base might be useful
10
in the synthesis of secondary amines. Work aimed at
the development of this methodology is currently
underway and will be reported in due course.
Table 1. Reaction of 1 with alkyl bromide under Mitsunobu conditions using two different redox couples
*
This compound was synthesized as described in Ref. 11.

J.-Y. Winum et al. / Tetrahedron Letters 42 (2001) 601–603
603
Acknowledgements
m, NH), 5.8 (1H, t, H , J=9.3 Hz), 5.3 (1H, d, H ,
2
1
J=9.3 Hz), 5.15 (1H, t, H , J=9.5 Hz), 5 (1H, t, H ,
3
4
J=9.9 Hz), 4.15 (2H, m, H , H ), 3.7 (1H, m, H ), 3.6
6
6%
5
The authors are grateful to the University of Montpel-
lier II and La Ligue contre le Cancer for financial
support and to Professor F. Menger (Emory Univer-
sity, Atlanta) for critical reading of the manuscript.
(2H, m, CH Cl), 3.3 (2H, m, CH NH), 1.9–2 (12H, 4s,
2
2
CH CO), 1.55 (9H, s, Boc). 2g: 5.85 (2H, m, H , NH);
3
2
5.4 (1H, d, H , J=3 Hz), 5.25 (1H, d, H , J=9.4 Hz), 5
4
1
(
1H, dd, H , J=10.1 Hz, J=3.4 Hz), 4.15 (2H, d, H ,
3
6
H , J=6.5 Hz), 3.95 (1H, t, H , J=6.5 Hz), 3.55 (2H, m,
6%
5
CH Cl), 3.3 (2H, m, CH NH), 1.95–2.1 (12H, 4s,
2
2
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