Novel N-aryl and N-heteroaryl sulfamide synthesis via palladium cross coupling

Article abstract of DOI:10.1021/ol049091l

A novel and efficient synthesis of N-aryl and N-heteroaryl sulfamides via an intermolecular palladium-catalyzed coupling process has been developed. The reactions proceeded with good to excellent yields and were tolerant of a wide range of functional groups.

Full text of DOI:10.1021/ol049091l

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2705-2708
Novel N-Aryl and N-Heteroaryl Sulfamide
Synthesis via Palladium Cross Coupling
Lilian Alcaraz,* Colin Bennion, James Morris, Premji Meghani, and
Stephen M. Thom
Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road,
Loughborough, Leics, LE11 5RH, United Kingdom
lilian.alcaraz@astrazeneca.com
Received May 18, 2004
ABSTRACT
A novel and efficient synthesis of N-aryl and N-heteroaryl sulfamides via an intermolecular palladium-catalyzed coupling process has been
developed. The reactions proceeded with good to excellent yields and were tolerant of a wide range of functional groups.
In the area of combinatorial library synthesis for medicinal
agents there is a constant need for new methodologies. The
sulfamide moiety is a ubiquitous entity in many therapeutic
agents in medicinal chemistry.1,2 Acyclic sulfamides bearing
an electron-withdrawing group such as carbonyl 1 or
aromatic heterocycles 2 can produce weakly acidic com-
pounds capable of acting as bioisosteres, for example, of
carboxylic acids and phenols.3
The transition metal-catalyzed formation of C-N bonds
between an amine/amide and an aryl/heteroaryl halide has
been the topic of much research over the past few years,
resulting in the development of mild conditions accom-
(1) For selected examples from recent literature, see: (a) Zhong, J.; Gan,
X. Bioorg. Med. Chem. 2004, 12, 589-593. (b) Collins, I. J.; Cooper, L.
C. WO-2003093264, 2003; Chem. Abstr. 2003, 139, 381492. (c) Kadow,
J. F.; Regueiro-Ren, A.; Xue, Q. M. WO-2004000210, 2003; Chem. Abstr.
2003, 140, 59662. (d) Cherney, R. J.; King, B. W. WO-2002028846, 2002;
Chem. Abstr. 2002, 136, 309923. (e) Schaal, W.; Karlsson, A.; Ahlse´n, G.;
Lindberg, J.; Andersson, H. O.; Danielson, U. H.; Classon, B.; Unge, T.;
Samuelsson, B.; Hulte´n, J.; Hallberg, A.; Karle´n, A. J. Med. Chem. 2001,
44, 155-169. (f) Groutas, W. C.; He, S.; Kuang, R.; Ruan, S.; Tu, J.; Chan,
H.-K. Bioorg. Med. Chem. 2001, 9, 1543-1548. (g) Shih, N.-Y.; Shue,
H.-J.; Reichard, G. A.; Paliwal, S.; Blynthin, D. J.; Piwinski, J. J.; Xiao,
D.; Chen, X. WO-2001044200, 2001; Chem. Abstr. 2001, 135, 61331. (h)
Kuang, R.; Epp, J. B.; Ruan, S.; Chong, L. S.; Venkataraman, R.; Tu, J.;
He, S.; Truong, T. M.; Groutas, W. C. Bioorg. Med. Chem. 2000, 8, 1005-
1016. (i) He, S.; Kuang, R.; Venkataraman, R.; Tu, J.; Truong, T. M.; Chan,
H.-K.; Groutas, W. C. Bioorg. Med. Chem. 2000, 8, 1713-11717. (j)
Martinez, A.; Gil, C.; Perez, C.; Castro, A.; Prieto, C.; Otero, J.; Andrei,
G.; Snoeck, R.; Balazarini, J.; De Clerk, E. J. Med. Chem. 2000, 43, 3267-
3273. (k) Benson, G. M.; Rutledge, M. C.; Widdowson, K. L. WO-
2000076501, 2000; Chem. Abstr. 2001, 134, 56675. (l) Lee, C. H.; Kohn,
H. J. Pharm. Sci. 1990, 79, 716-718.
Wider use of 2 in this context has been largely impeded
by their relatively difficult synthetic accessibility. Indeed,
to date, the only available methods for the preparation of 2
are the thermal displacement of activated heterocyclic halides
with the alkaline salt of the dersired N-mono- or N,N-
disubstituted sulfamide2,4 and the sulfonylation of the
heterocyclic aniline with a suitable sulfamoyl chloride
derivative.5 In our hands, these reactions have usually been
low yielding and have not involved readily accessible
reagents. In addition, they were relatively unstable under the
required reaction conditions.
(2) Bolli, M.; Boss, C.; Fischli, W.; Clozel, M.; Weller, T. WO-
2002053557, 2002; Chem. Abstr. 2002, 137, 93766.
(3) (a) The Practice of Medicinal Chemistry, 2nd ed; Wermuth, C. G.,
Ed.; Academic Press: London, 2003. (b) Albright, J. D.; DeVries, V. G.;
Du, M. T.; Largis, E. E.; Miner, T. G.; Reich, M. F.; Shepherd, R. G. J.
Med. Chem. 1983, 26, 1393-1411.
(4) Levchenko, E. S.; Budnik, L. V. J. Org. Chem. USSR (Engl. Transl.)
1975, 11, 2077-2082.
10.1021/ol049091l CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/10/2004

modating a wide range of functional groups.6,7 Most recently
the emergence of new phosphine ligands has led to the
incorporation of sulfonamides into these processes.8 Buch-
wald and co-workers were first to report a palladium-
catalyzed coupling of aryl bromides with primary and
secondary sulfonamides.9 Wu et al. have also described
N-aryl sulfonamide formation via a copper(I)-catalyzed
process through the use of microwave irradiation,10 and Cao
et al. have reported a related palladium-catalyzed process
employing several sulfonamides and aryl/heteroaryl chlo-
rides.11
Scheme 1. Pd-Catalyzed N-Heteroarylation of
N,N-Disubstituted Sulfamide15
a Conditions: 2.5 mol % Pd2(dba)3, 7.5 mol % ligand, 1.4 mol
equiv of Cs2CO3, dioxane, 80 °C, 18 h.
To the best of our knowledge, the formation of N-aryl
sulfamides by transition metal-catalyzed processes is un-
precedented in the literature. We hereby report the first
palladium-catalyzed process for the formation of these
potentially biologically interesting molecules.
and Cs2CO3 (1.4 equiv) in dioxane heated to 80 °C for 18 h
(Scheme 1).15 The results of this study are summarized in
Table 1.
N,N-Disubstituted sulfamides are readily available by
reaction of amines with sulfamide12 or alternatively by
stepwise addition of an alcohol (e.g., tert-butyl alcohol or
benzyl alcohol) and an amine to chlorosulfonyl isocyanate,
followed by deprotection of the carbamate moiety.13 More
recently, Montero et al. have reported a procedure related
to the latter using a stable DMAP complex.14
To establish the optimum reaction conditions, a limited
screen was undertaken focusing on seven phosphine-based
ligands (Figure 1) commonly used in palladium-catalyzed
Table 1. Ligand Effect on the Pd-Catalyzed N-Heteroarylation
of 6-Chloronicotinonitrile 4
entry
ligand
conversion (%)a
1
2
3
4
5
6
7
BINAP
dppf
6
(t-Bu)3P
Xantphos
XPHOS
7
0
0
0
65
90
95
95
1
a Conversion determined by crude H NMR.
A control experiment showed that omission of palladium
catalyst leads to no reaction. Reactions employing BINAP,
dppf, and ligand 6 also failed to catalyze any reaction (Table
1, entries 1-3). Electron-rich sterically crowded monophos-
phine (t-Bu)3P only led to moderate conversion (Table 1,
entry 4), whereas Xantphos, XPHOS, and N,P ligand 7 all
gave near complete conversion to the N-heteroaryl sulfamide
(8) (a) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653-6655. (b) Strieter, E.
R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
13978-13980.
(9) (a) Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101-1104. (b) Yin,
J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043-6048.
(10) He, H.; Wu, Y.-J. Tetrahedron Lett. 2003, 44, 3385-3386.
(11) Burton, G.; Cao, P.; Gang, L.; Rivero, R. Org. Lett. 2003, 5, 4373-
4376.
Figure 1. Ligands assessed for the Pd-catalyzed N-heteroarylation
of 6-chloronicotinonitrile 4.
(12) (a) McManus, J. M.; McFarland, J. W.; Gerber, C. F.; McLamore,
W. M.; Laubach G. D. J. Med. Chem. 1965, 8, 766-776. (b) Aeberli, P.;
Gogerty, J.; Houlihan, W. J. J. Med. Chem. 1967, 10, 636-642.
(13) (a) Abdaoui, M.; Dewynter, G.; Aouf, N.; Favre, G.; Morere, A.;
Montero, J.-L. Bioorg. Med. Chem. 1996, 4, 1227-1235. (b) Kavalek, J.;
Kralikova, U.; Machacek, V.; Sedlak, M.; Sterba, V. Collect. Czech. Chem.
Commun. 1990, 55, 203-222.
C-N bond-forming processes. The standard reaction condi-
tions subjected sulfamide 3 and 6-chloronicotinonitrile 4 to
Pd2(dba)3 (2.5 mol %), the ligand (7.5 mol %, Figure 1),
(14) Winum, J.-Y.; Toupet, L.; Barragan, V.; Dewynter, G.; Montero,
J.-L. Org. Lett. 2001, 3, 2241-2243.
(5) (a) Esteve, C.; Vidal, B. Tetrahedron Lett. 2002, 43, 1019-1021.
(b) Hogberg, M.; Engelhart, P.; Vrang, L.; Zhang, H. Bioorg. Med. Chem.
Lett. 2000, 10, 265-268. (c) Goya, P.; Lissavetzky, J.; Rozas, I. Synthesis
1989, 280-282. (d) Wheeler, W. K.; Degering, F. J. Am. Chem. Soc. 1944,
66, 1242-1243 and references cited herein.
(6) For a recent review on copper-catalyzed C-N bond formation, see:
Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400-5449.
(7) For recent reviews on palladium-catalyzed C-N bond formation,
see: (a) Muci, A. B.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131.
(b) Hartwig, J. F. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, 2002; p 1051.
(15) General Procedure. A 25 mL round-bottom flask was charged with
sulfamide 3 (166 mg, 1 mmol), 6-chloronicotinonitrile 4 (138 mg, 1 mmol),
Cs2CO3 (456 mg, 1.4 mmol), N,P ligand 7 (30 mg, 75 µmol), and Pd2-
(dba)3 (23 mg, 25 µmol). The flask was flushed with N2 for 30 s and charged
with anhydrous dioxane (2.5 mL). The flask was heated at 80 °C for 18 h
under a nitrogen atmosphere. The reaction mixture was then allowed to
cool to room temperature and diluted with dichloromethane (5 mL), and
acetic acid was added (500 µL). After filtration through a cotton wool plug,
the crude mixture was concentrated under vacuum and purified by reverse-
phase HPLC to afford the product 5 in 74% yield.
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Org. Lett., Vol. 6, No. 16, 2004

Table 2. Pd-Catalyzed N-Aryl/Heteroarylation of N,N-Disubstituted Sulfamides15
a Isolated yields. b Xantphos. c X-PHOS. d N,P 7. e Purified by reverse-phase HPLC. f Purified by flash chromatography. g Purified by crystallization
(DCM/Et2O). h Conversion determined by LC/MS.
5 (Table 1, entries 5-7). Further exploration of the reaction
conditions showed toluene to be an alternative solvent, while
more polar solvents such as DMF, NMP, MeCN, and
t-BuOH gave poor conversions or complex product mixtures.
This was also the case when employing KOt-Bu16 or tertiary
amines as bases.
With the optimum conditions identified (Table 1, entries
6 and 7), the reaction scope was investigated by variation
of the sulfamide and halide components (Table 2).
In most cases, conversions were greater than 90% when
employing one of the three catalytically active ligands
(Xantphos, XPHOS, and N,P ligand 7). A range of sulfa-
Org. Lett., Vol. 6, No. 16, 2004
2707

mides were first coupled with 6-chloronicotinonitrile 4.
N-Alkyl, benzyl, and phenyl sulfamides all coupled well in
the process (Table 2, entries 1-6). However, a monosub-
stituted sulfamide failed to afford any product (Table 2, entry
7). Other pyridines activated in the 3-position were also found
to be good substrates for this reaction. Nitro, ester, and
aldehyde functional groups were all tolerant to the reaction
conditions, although only 70% conversion was achieved in
the aldehyde case (Table 2, entries 8-10). In contrast,
unactivated 2-bromopyridine undergoes no reaction when
employing our best conditions (Table 2, entry 11). Substituted
chloro-pyrimidines and 1,4-pyrazines also coupled well to
afford the required sulfamides in acceptable yields (Table
2, entries 12-17). Finally, aryl bromides activated by
electron-withdrawing groups in the para position also proved
to be good substrates in this reaction. Complete, or near
complete, conversion was observed for ester-, aldehyde-,
nitrile-, and nitro-substituted phenyl bromides (Table 2,
entries 18-21). However, the corresponding ortho isomers
were more sluggish under the reaction conditions and
represent a limitation of this methodology (Table 2, entry
22). Furthermore, the importance of the activation was
underlined when attempting to couple bromobenzene with
3. Poor conversion resulted along with the isolation of
byproduct 817 (Table 2, entry 23).
In summary, we have reported an efficient Pd-catalyzed
synthesis of N-aryl/heteroaryl sulfamides that tolerates a
range of secondary sulfamides and functionalized hetero-
cycles. Application of this reaction toward the synthesis of
sulfamides libraries is currently underway.
Acknowledgment. We are grateful to Hema Pancholi for
her expert assistance with MS studies.
Supporting Information Available: 1H and 13C NMR
and HRMS data for the products illustrated in Table 2. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL049091L
(17) During the course of our work with N,N-disubstituted sulfamides,
we have observed that they can undergo base-catalyzed thermal decomposi-
tion to release the corresponding amine. This has previously been reported
in the literature: Kavalek, J.; Kralikova, U.; Machacek, V.; Seldlak, M.;
Sterba, V. Collec. Czech. Chem. Commun. 1990, 55, 202-222. We thus
suspect that 8 is the result of a palladium-catalyzed coupling between
morpholine and bromobenzene.
(16) This is consistent with previous reports of the limited functional
group compatibility of KOt-Bu when used as a stoichiometric base in a
palladium coupling reaction: Wolfe, J. P.; Buchwald, S. L. Tetrahedron
Lett. 1997, 38, 6359-6362,
2708
Org. Lett., Vol. 6, No. 16, 2004