N-(tert-butoxycarbonyl)-N-[4-(dimethylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]azanide: a new sulfamyolating agent. Structure and reactivity toward amines.

Article abstract of DOI:10.1021/ol0161312

[structure: see text] Synthesis, structure, and reactivity toward amines of the new sulfamoylating reagent 2 are described. Compound 2 allowed sulfamoylation of amines under very mild conditions to give sulfamide derivatives in good yields.

Full text of DOI:10.1021/ol0161312

ORGANIC
LETTERS
2001
Vol. 3, No. 14
2241-2243
N-(tert-Butoxycarbonyl)-N-[4-
(dimethylazaniumylidene)-1,4-
dihydropyridin-1-ylsulfonyl]azanide:
A New Sulfamoylating Agent. Structure
and Reactivity toward Amines
,†
Jean-Yves Winum,* Loic Toupet,‡ Ve´ronique Barragan,† Georges Dewynter,† and
,†,§
Jean-Louis Montero*
Laboratoire de Chimie Biomole´culaire, UMR 5032, UniVersite´ Montpellier II,
Ecole Nationale Supe´rieure de Chimie de Montpellier, 8 rue de l’Ecole Normale,
34296 Montpellier Cedex, France, and Groupe Matie`re Condense´e et Mate´riaux,
UMR 6626, UniVersite´ de Rennes I, Campus de Beaulieu, AVenue du Ge´ne´ral Leclerc
35042 Rennes Cedex, France
winumj@crit.uniV-montp2.fr
Received May 16, 2001
ABSTRACT
Synthesis, structure, and reactivity toward amines of the new sulfamoylating reagent 2 are described. Compound 2 allowed sulfamoylation of
amines under very mild conditions to give sulfamide derivatives in good yields.
The sulfamoyl moiety is an important structural element in
numerous compounds of biological interest.1 During our
efforts toward efficient synthesis of sulfamide or sulfamate
derivatives, we demonstrated that chlorosulfonyl isocyanate
(CSI), the strongest bielectrophile, is the reagent of choice
for the preparation of such compounds.2 Previously, we
demonstrated that according to the difference of reactivity
between both the isocyanate and the chlorosulfonic acid
group, it was possible to synthesize ab initio the unstable
N-(tert-butoxycarbonyl)sulfamoyl chloride 1 (Scheme 1).
This compound was allowed to react in a one-pot reaction
with an amine or an alcohol to lead to a sulfamide or
sulfamate derivatives.1,2 This strategy has already been
successfully applied in the synthesis of new anticancerous
agents such as chloroethylnitrososulfamide2 analogues of the
chloroethylnitrosoureas.
† University of Montpellier II.
‡ University of Rennes I.
§ E-mail: montero@univ-montp2.fr.
The instability of compound 1 and the too strong reactivity
of CSI limited the application of this methodology for
introduction of a sulfamoyl moiety on polyfonctionnal
compounds and its use in solid-phase synthesis of sulfamide
(degradation of the resin by CSI).
(1) Dewynter, G.; Montero, J.-L. C. R. Acad. Sci. Paris, Ser. II 1992,
315, 1675-1682 and references therein.
(2) Abdaoui, M.; Dewynter, G.; Aouf, N.; Favre, G.; More`re, A.;
Montero, J.-L. Bioorg. Med. Chem. 1996, 4, 1227-1235. Abdaoui, M.;
Dewynter, G.; Montero, J.-L. Tetrahedron Lett. 1996, 37, 5695-5698.
Abdaoui, M.; Dewynter, G.; Aouf, N.; Montero, J.-L. Phosphorus, Sulfur
Silicon 1996, 118, 39-47. Dewynter, G.; Abdaoui, M.; Regainia, Z.;
Montero, J.-L. Tetrahedron 1996, 52, 14217-14224. Regainia, Z.; Abdaoui,
M.; Aouf, N. E.; Dewynter, G.; Montero, J.-L. Tetrahedron 2000, 56, 381-
387. Abdaoui, M.; Dewynter, G.; Toupet, L.; Montero, J.-L. Tetrahedron
2000, 56, 2427-2435. Winum, J.-Y.; Barragan, V.; Montero, J.-L.
Tetrahedron Lett. 2001, 42, 601-603.
These problems led us to develop a convenient means to
access a sulfamide and to avoid the use of the sensitive
intermediate 1. Our approach was to try to stabilize com-
pound 1 by treatment with (dimethylamino)pyridine (DMAP)
10.1021/ol0161312 CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/09/2001

1H NMR of compound 2 showed proton chemical shifts
of the aromatic ring and dimethylamino groups which were
more deshielded than those of DMAP. This result was in
accordance with a structure in which the positive charge is
on the nitrogen N1. The X-ray analysis confirmed the
zwitterionic structure of 2 (Figure 1). The structure found
Scheme 1a
Figure 1. X-ray crystal structure of compound 2.
a Reagents and conditions: (i) tBuOH, CH2Cl2; (ii) DMAP, 2
equiv.
gives a maximum distance between the two charges, which
is favorable for the electronic stabilization of the molecule.
All results were correlated by mass spectrometry, which
showed a molecular ion at 301 Da.
It is worth pointing out the structural analogy between 2
and the Burgess reagent12 (methyl N-(triethylammonium
sulfonyl)carbamate), which also presents a zwitterionic form.
As delineated in Table 1, the newly developed reagent 2
(Scheme 1). Indeed, DMAP is well-known for its remarkable
properties in acyl3 or sulfonyl transfer.4 Moreover, some
arylsulfonyl(dimethylamino)pyridinium salts are isolable and
stable.4 Thus, product 2, N-(tert-butoxycarbonyl)-N-[4-(di-
methylazaniumylidene)-1,4-dihydropyridin-1-ylsulfonyl]-
azanide, was obtained in good yield as colorless crystals,
non-moisture sensitive, stable at ambient temperature.
1
The structure of the product 2 was elucidated using H
Table 1. Reactivity of 2 toward Diverse Amines
NMR spectroscopy, mass spectrometry,5 and X-ray crystal
crystallography.6
productsa
amines
time, h
yield,b %
3a
3b
3c
3d
3e
3f
3g
3h
3i
butylamine
4-methlcyclohexylamine
benzylamine
2-adamantanamine
diisobutylamine
diisopropylamine
dibenzylamine
aniline
2
2
4
4
4
4
4
12
12
12
100
80
90
88
94
78
91
50
35
40
(3) Scriven, E. F. V. Chem. Soc. ReV. 1983, 12, 129-161. Katritzky, A.
R.; Burton, R. D.; Shipkova, P. A.; Qi, M.; Watson, C. H.; Eyler, J. R. J.
Chem. Soc., Perkin Trans. 2 1998, 4, 835-840 and references therein.
(4) Guibe-Jampel, E.; Wakselman, M. J. Chem. Soc., Chem. Commun.
1980, 993-994.
(5) Typical procedure for synthesis of compound 2: 1.2 mL (1 equiv)
of CSI was added dropwise to a cold solution of tert-butyl alcohol (1.3
mL, 1 equiv) in anhydrous methylene chloride (10 mL). Then DMAP (3.45
g, 2 equiv) was added. The mixture was stirred for 1 h at room temperature
and washed several times with water. The organic layer was dried on
anhydrous sodium sulfate and concentrated in vacuo. The colorless powder
was then crystallized from acetonitrile to afford compound 2 in 80% yield.
4-bromoaniline
4-methoxyaniline
3j
a The reactions were generally performed on a 0.3-0.5 mmol scale in
1.5 mL of CH2Cl2 using 1 equiv of compound 2 and 1 equiv of amine at
room temperature. b Yield of isolated product.
1
Mp ) 178-180 °C (acetonitrile); H NMR (200 MHz, DMSO-d6) δ 8.5
(d, J ) 7 Hz, 2H), 7.0 (d, J ) 7 Hz, 2H), 3.2 (s, 6H), 1.2 (s, 9H); MS
(FAB positive mode, NOBA), m/z 301 M+, 302 (M + H)+, 324 (M +
Na)+.
(6) Detailed X-ray crystallographic data are available free of charge on
application to the Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB2 1EZ, UK. E-mail: deposit@ccdc.cam.ac.uk (for compound
2 CCDC # 162525). Compound 2: C12H19N3O4S, Mr ) 301.36, ortho-
rhombic, P212121, a ) 10.4262(2), b ) 10.4455(2), and c ) 13.7652(3) Å,
V ) 1498.70(5) Å3, Z ) 4, Dx ) 1.336 Mg‚m-3, λ(Mo KR) ) 0.71073 Å,
µ ) 2.32 cm-1, F(000) ) 640, T ) 293 K. The sample (0.35 × 0.35 ×
0.15 mm) was studied on a NONIUS Kappa CCD with graphite-
monochromatized Mo KR radiation. The cell parameters were obtained by
following methods of Denzo and Scalepack7 with 10 frames (psi rotation:
1° per frame). The data collection8 (2θmax ) 60°, 143 frames via 2° ω
rotation and 80 s per frame, range hkl h ) 0.13, k ) 0.13, l )0.17) gives
10682 reflections. The data reduction by the Denzo and Scalepack7 methods
leads to 1971 independent reflections from which 1860 have I > 2.0σ(I).
The structure was solved with SIR-979, which reveals the non-hydrogen
atoms of structure. After anisotropic refinement, many hydrogen atoms can
was allowed to react with various amines and anilines in
methylene chloride (Scheme 2). The reaction proceeds under
be determined using Fourier difference. The whole structure was refined
using SHELXL9710 by the full-matrix least-squares techniques (use of F
square magnitude; x, y, z, âij for S, O, C, and N atoms, x, y, z in riding
mode for H atoms; 182 variables and 1860 observations with I > 2.0σ(I);
2
2
2
calc w ) 1/[σ2(Fo ) +(0.085P)2 + 0.10P] where P ) (Fo + 2Fc )/3 with
the resulting R )0.036, Rw ) 0.107, and Sw ) 1.009 (residual around solvent
molecules) ∆F < 0.18 e Å-3). Atomic scattering factors are from
International Tables for X-ray Crystallography, 1992. Ortep views were
realized with PLATON98.11 All the calculations were performed on a
Pentium NT Server computer.
2242
Org. Lett., Vol. 3, No. 14, 2001

yields after 12 h. No yield improvement was noted after
thermal activation. The poor nucleophilic nature of the -NH2
function in aniline derivatives can easily explain these results.
Attempted reactions with a series of nitroanilines did not
result in the isolation of the expected sulfamide.
Scheme 2
In summary, we describe here the preparation and the
structure of a new sulfamoylating reagent, 2. Its reactivity
toward amines demonstrates the great potential of this
compound in the synthesis of sulfamides.
very mild conditions at room temperature. The resulting
products are easily isolable by flash chromatography on silica
gel. The different sulfamides have been obtained in good
yields after 2 or 4 h of reaction at room temperature,
independent of the primary or secondary aliphatic amines
used (3a-3g). When the reaction was performed with
anilines (3h-3j), sulfamides were obtained in moderate
Thus, the scope of the reaction (Scheme 2) is broad
because any primary or secondary aliphatic amine can be
converted into a sulfamide by performing a simple and
straightforward synthesis in very mild conditions. Moreover,
the reactivity of compound 2 toward different nucleophiles
is currently in progress and will be reported in due course.
(7) Otwinowski, Z.; Minor, W. In Macromolecular Crystallography, Part
A; Carter, C. W., Sweet, R. M., Eds.; Academic Press: London, 1997; Vol.
276, pp 307-326.
(8) Nonius, B. V. Kappa CCD Software. Nonius BV, Delft, The
Netherlands, 1999.
(9) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.; Giacovazzo,
C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna. G. J. Appl.
Crystallogr. 1998, 31, 74-77.
Acknowledgment. Support of this work by the University
of Montpellier II and Mayoly-Spindler Laboratory is grate-
fully acknowledged.
(10) Sheldrick, G. M. SHELX97, Program for the Refinement of Crystal
Structures, University of Go¨ttingen, Germany, 1997.
(11) Spek, A. L. PLATON, A multipurpose crystallographic tool, Utrecht
University, Utrecht, The Netherlands, 1998.
(12) Burgess, E. M.; Penton, H. R.; Taylor, E. A. J. Org. Chem. 1973,
38, 26-31 and references therein.
Supporting Information Available: Analytical data of
sulfamides 3a-j. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL0161312
Org. Lett., Vol. 3, No. 14, 2001
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