Sulfamide synthesis via Pd-catalysed cross-coupling

Article abstract of DOI:10.1055/s-2004-836052

A novel efficient procedure for the improved synthesis of aryl-substituted sulfamides via a Pd-catalysed arylation of sulfamide is reported.

Full text of DOI:10.1055/s-2004-836052

LETTER
149
Sulfamide Synthesis via Pd-Catalysed Cross-Coupling
S
ulfamide Synthes
i
is via
P
l
d-catal
i
ysed C
a
ross-Coupl
n
ing Muñiz,* Martin Nieger1
Kekulé-Institut für Organische Chemie und Biochemie, Rheinische Friedrich-Wilhelms Universität Bonn, Gerhard-Domagk-Strasse 1,
53121 Bonn, Germany
Fax +49(228)735813; E-mail: kilian.muniz@uni-bonn.de
Received 16 July 2004
combination of tris(tert-butyl)phosphine and a palladi-
Abstract: A novel efficient procedure for the improved synthesis of
um(0) source, the expected amination reaction occurred as
aryl-substituted sulfamides via a Pd-catalysed arylation of sulf-
major pathway. Still, the crude reaction mixture contained
amide is reported.
several compounds which supposedly included N,N- and
Key words: amines, amides, sulfur compounds, catalysis, palladi-
N,N¢-diarylated and higher arylated derivatives as well. In
um
order to accomplish clean mono-phenylation, three equiv-
alents of 1 were employed and the aniline-derivative 3
was obtained in 73% yield after work-up and crystallisa-
Sulfamides (Figure 1) constitute an interesting functional
tion (Scheme 1).11
group for organic chemistry. While on first sight the struc-
ture reminds one of related sulfonamides, its two amino
moieties, which are connected via an electron-acceptor
functionality, render it reminiscent of ureas. In contrast to
the latter, the inherent electronic properties of the sulfonyl
bridge do not induce mesomeric amide interactions.
Scheme 1 Pd-catalysed phenylation of sulfamide 1
Table 1 Hartwig–Buchwald Coupling of Sulfamide 111
Figure 1 General structure of sulfamides
Entry
Ph-X
Ratio 1/
Ph-X
Product
Yield of 3
(%)a
In view of these rather unique properties, there has been a
broad interest on sulfamides including their use in the syn-
thesis of heterocycles2 and incorporation in molecules of
pharmaceutical interest.3
1
2
3
4
5
6
2 (X = Cl)
2 (X = OTf)
2 (X = Br)
2 (X = Br)
2 (X = Br)
2 (X = I)
3:1
3:1
1:1
2:1
3:1
3:1
3
3
3
3
3
3
14
Ca. 10b
Ca. 15b
Ca. 35b
73
While the parent sulfamide (1, R = H) is commercially
available, there does not exist a general access to higher
substituted derivatives of 1.4 Over the last decades, sever-
al reports have appeared which include synthesis from
amination reaction of sulfamoyl chloride5 and sulfamate
57
esters,6 transamidation on sulfamide7 or aminolysis of sta- a Isolated yield after crystallisation.
b Estimated from the NMR spectra of the crude reaction mixture.
ble sulfamoyl salts.8 A solid-phase protocol on the basis of
the latter was reported recently.9
We here describe preliminary results toward a convenient For all these coupling reactions, a catalyst derived from
synthetic procedure for the rapid and high-yielding combination of Pd2(dba)3 and the basic phosphine P(t-
synthesis of these compounds, which is based on a novel Bu)3 turned out to be best. Related catalysts from this pal-
palladium-catalysed amination of arenes.
ladium source and ligands such as BINAP, dppf, dppp or
triphenylphosphine gave more complex reaction mixtures
and yields in the range of 22–51% for the isolated product
3. Preformed tetrakis(triphenylphosphine)palladium(0)
gave comparable results.
Within this context of synthesising aryl sulfamides, a
palladium(0)-catalysed amination of arenes10 was exam-
ined (Scheme 1, Table 1). Preliminary experiments with
triflates and chlorides gave rather low conversion and/or
complex reaction mixtures. However, when bromo- or To the best of our knowledge, these examples represent
iodobenzene were treated with a catalyst derived from a the first successful examples of a Hartwig–Buchwald
coupling employing sulfamide 1 as nitrogen source.12,13
Within this context, the comparable reavtivity of iodo-
and bromobenzene is somewhat surprising. Generally,
bromo arenes tend to give significantly higher reactivity
SYNLETT 2005, No. 1, pp 0149–0151
Advanced online publication: 29.11.2004
DOI: 10.1055/s-2004-836052; Art ID: G27204ST
© Georg Thieme Verlag Stuttgart · New York
0
5.
0
1.
2
0
0
5

150
K. Muñiz, M. Nieger
LETTER
in this type of coupling reactions.10,12 The requirement of
over-stoichiometric amounts of sulfamide in these cou-
plings in order to facilitate mono-arylated sulfamide 3
matches well with a recent report by Moreno-Mañas on
Pd-catalysed Tsuji–Trost reactions with 1 as nucleo-
phile.14 Here, an excess of 4 equivalents was necessary in
order to prevent more than one allylation to occur.
Scheme 3 Arylation of sulfamide 3
previously reported.5a While the nucleophilic direct sub-
stitution at sulfur with amines to yield N-substituted
sulfamides had been established before, we found this
procedure less attractive for the application of more
elaborated amines since an excess of these compounds is
usually required.5,6 The overall synthetic efficiency could
be significantly enhanced when the reaction was carried
out in the presence of 20–25 mol% of DMAP (N,N-di-
methylamino pyridine) and stoichiometric amounts of tri-
ethylamine.15,16
Scheme 2 Pd-catalysed arylation of sulfamide 1
Table 2 General Hartwig–Buchwald Coupling of Sulfamide 111
In view of the convenient process of the described transi-
tion metal coupling, compound 3 was submitted to X-ray
structure determination.17 As expected, the central sulfur
atom displays a nearly tetrahedral environment with the
expected bond lengths and angles for such an arrange-
ment. With regards to the crystal packing, significant
intermolecular hydrogen bonding between the sulfonyl
oxygen and the NH moieties are present.17
Entry
Ar-Br
Ratio 1/ Product Yield
Ar-Br
(%)a
1
2
3
4
2 (Ar = C6H5)
3:1
3
5
7
9
73
4 (Ar = 1-Naph)
6 (Ar = 4-Cl-C6H4)
8 (Ar = 4-MeO-C6H4)
3:1
65
3:1
79
5:1b
61
a Isolated yield after crystallisation.
b Reaction at 75 °C.
In summary, we have reported the use of sulfamide as
substrate for palladium-catalysed amination of halo
arenes. The reaction proceeds under relatively mild condi-
tions to furnish N-aryl sulfamides.
In an identical manner, naphthalene derivative 5 was ob-
tained in 65% yield after crystallisation from the crude re-
action mixture (Scheme 2, Table 2, entry 2). Substitution
pattern at the aromatic ring are tolerated by the present
protocol (Table 2, entries 3, 4), however, a preference for
the electron-acceptor substituent over the electron-donat-
ing one was observed. Apparently, the latter one decreases
the rate for the initial oxidative insertion in the aryl bro-
mide bond leading to lower chemical yields. A satisfying
yield of 61% could only be obtained at a higher 1/8 ratio
of 5:1 and at a temperature of 75 °C. Substituted sulf-
amides such as 3 undergo non-position selective arylation
(Scheme 3). For example, when 3 was submitted to phe-
nylation under the standard conditions, the crude reaction
mixture consisted of the three compounds 3, 10 and 11 in
a ratio of 1:3:2.2. Apparently, steric factors lead to prefer-
ence for the arylation at the free NH2 terminus over the
arylated one. Attempts to improve the respective ratios for
10 and 11 by altering the amounts of phenyl bromide 2 did
only lead to lower reactivity and isolation of larger
amounts of unreacted starting material 3.
Acknowledgment
K. M. is grateful to the German-Israeli Foundation (Young Investor
Grant 2002-2003) and to the Fonds der Chemischen Industrie for
continuous support. Prof. Dr. K. H. Dötz is gratefully acknowled-
ged for his ongoing support and interest.
References
(1) X-Ray Analysis. E-mail: m.nieger@joyx.joensuu.fi.
(2) (a) Gazieva, G. A.; Kravchenko, A. N.; Lebedev, O. Russ.
Chem. Rev. 2000, 69, 221. (b) Lee, C. H.; Kohn, H. J. Org.
Chem. 1990, 55, 6098.
(3) Recent work: (a) Dow, R. L.; Paight, E. S.; Schneider, S. R.;
Hadcock, J. R.; Hargrove, D. M.; Martin, K. A.; Maurer, T.
S.; Nardone, N. A.; Tess, D. A.; DaSilva-Jardine, P. Bioorg.
Med. Chem. Lett. 2004, 14, 3235. (b) Schaal, W.; Karlsson,
A.; Ahlsen, G.; Lindberg, J.; Andersson, H. O.; Danielson,
U. H.; Classon, B.; Unge, T.; Samuelsson, B.; Hulton, J.;
Hallberg, A.; Karlen, A. J. Med. Chem. 2001, 44, 155.
(c) Micklefied, J.; Fettes, K. J. Tetrahedron Lett. 1997, 38,
5387. (d) Jadhar, P. K.; Woerner, F. J. Tetrahedron Lett.
1995, 36, 6383. (e) Casini, A.; Winum, J.-Y.; Montero, J.-
L.; Scozzafava, A.; Supuran, C. T. Bioorg. Med. Chem. Lett.
2003, 13, 837.
All reaction products gave satisfying 1H NMR, 13C NMR,
MS, and HRMS data. These data were compared to the
one from authentical samples obtained through a variation
of standard synthetic procedures. To this end, commer-
cially available chloro sulfonylisocyanate was converted
to chloro sulfonamide by reaction with formic acid as
(4) General reviews: (a) McDermott, S. D.; Spillane, W. J. Org.
Prep. Proced. Int. 1984, 16, 49. (b) Dorlars, A. In Methoden
der Organischen Chemie (Houben-Weyl), Vol. XI.2;
Thieme: Stuttgart, 1958, 645.
Synlett 2005, No. 1, 149–151 © Thieme Stuttgart · New York

LETTER
Sulfamide Synthesis via Pd-Catalysed Cross-Coupling
(13) While this work was under reviewing, a related cross-
151
(5) (a) Graf, R. Chem. Ber. 1959, 92, 509. (b) Spillane, W. J.;
McHugh, F. A.; Burke, P. O. J. Chem. Soc., Perkin Trans. 2
1998, 13. (c) Kloek, J. A.; Leschinsky, K. L. J. Org. Chem.
1976, 41, 4028.
coupling was reported independently: Alcaraz, L.; Bennion,
C.; Morris, J.; Meghani, P.; Thom, S. M. Org. Lett. 2004, 6,
2705.
(6) DuBois, G. E. J. Org. Chem. 1980, 45, 5373.
(14) Cerezo, S.; Cortés, J.; Moreno-Mañas, M.; Pleixats, R.;
Roglans, A. Tetrahedron 1998, 54, 14869.
(15) For a related procedure employing DMA or NMP, see:
Okada, M.; Iwashita, S.; Koizumi, N. Tetrahedron Lett.
2000, 41, 7047.
(7) McDermott, S. D.; Spillane, W. J. Synthesis 1983, 192.
(8) Winum, J.-Y.; Toupet, L.; Barragan, V.; Dewynter, G.;
Montero, J.-L. Org. Lett. 2001, 3, 2241.
(9) Esteve, C.; Vidal, B. Tetrahedron Lett. 2002, 1019.
(10) (a) Murci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002,
219, 133. (b) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37,
2046. (c) Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.;
Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805.
(16) Typical Procedure for DMAP-Mediated Synthesis of
Sulfamides: A solution of sulfamoyl chloride (5 mmol) in
CH2Cl2 (10 mL) is treated with an additional amount of dry
toluene (10 mL) and stirred at 0 °C. To this solution, DMAP
(1.0 mmol) is added in one portion followed by addition of
Et3N (5.5 mmol) and the respective aniline (1.0 mmol). The
resulting yellow solution is stirred first at 0 °C, then at r.t. for
5 h. The solvents are removed to a remaining volume of
approx. 4 mL and extracted with boiling water. Evaporation
of the aqueous phase yields the respective sulfamides.
Alternatively, some of the products can be distilled directly
from the crude reaction mixture.
(17) Data on the X-Ray Analysis of Compound 3.
Crystallographic data (excluding structure factors) for the
structure reported have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC-241627. Copies of the data can be obtained free
of charge on application to the CCDC, 12 Union Road,
Cambridge CB2 1EZ UK (fax: +44(1223)336033; email:
deposit@ccdc.cam.ac.uk).
(11) Typical Synthetic Procedure for Amination of Halo-
arenes via Pd-Coupling: A solution of compound 1 (3.3
mmol) and bromo benzene 2 (1.0 mmol) in freshly distilled
toluene are treated with dipalladium(0)–dba complex (0.075
mmol), tris(tert-butyl)phosphine (0.2 mmol) and caesium
carbonate (1 mmol) and heated to 50 °C overnight. The
reaction mixture is cooled to r.t., filtered over celite and
evaporated under reduced pressure. The pure product was
usually obtained by crystallization from methanol.
Analytical data for compound 3: 1H NMR (DMSO-d6):
d = 4.05 (d, J = 1.2 Hz, 2 H, CH2), 6.55 (br s, 2 H, NH2), 6.92
(t, J = 1.2 Hz, 1 H, NH), 7.11–7.40 (m, 5 H, arom.). 13
C
NMR (DMSO-d6): d = 46.5 (CH2), 127.3, 128.1, 128.5
(arom. CH), 139.0 (Cipso). Anal. Calcd for C7H10N2O2S: C,
45.15; H, 5.41; N, 15.04; S, 17.22. Found: C, 45.29; H, 5.09;
N, 14.81; S, 17.50.
(12) For a related procedure of Hartwig–Buchwald coupling
employing sulfoximines, see: Bolm, C.; Hildebrand, J. P.
J. Org. Chem. 2000, 65, 169.
Synlett 2005, No. 1, 149–151 © Thieme Stuttgart · New York