heterocyclic cores, the nature of the halide, and/or its position
on the ring have been observed. The copper-catalyzed mono-
N-arylation of primary sulfonamides is known;5 however,
the use of heteroaryl donors in these reactions still remains
uncharted ground,6 and the potential for product inhibition
is a major concern.7 Indeed, the conjugate base of the
N-heteroarylation product, formed easily as a result of the
increased acidity of the sulfonamide NH, may form a stable
complex with the catalyst, thus impeding its turnover.7b In
general, a N-heteroarylation procedure that covers a broad
spectrum of heteroaryl halides (many have not been explored)
is still needed.
Table 1. Reaction Scope with Respect to Heteroaryl Halides
The recent mechanistic insights that enabled the Hiyama
and Suzuki couplings of 2-pyridyl nucleophiles,8 along with
the N-amidation works reported in the literature,3 gave us
greater confidence that copper catalysts may be applied for
the N-sulfonamidation of 2-heteroaryl halides.9 We also
believed that a solution to the coupling of this capricious
subclass of heteroaryl donors may be broadly applicable to
other systems. Herein, we detail the reduction of these
hypotheses to practice.
We initiated our investigations by examining conditions
under which 4-toluene sulfonamide and 2-bromopyridine
can be coupled. We examined the effect of ligand, base,
solvent, and copper salts.10 The initial screening experi-
ments were performed in dioxane with CuI (5 mol %),
and cesium carbonate as base, and the best parameter was
included in the next round of optimization. We observed
(5) For the coupling between aryl boronic acids and sulfonamides see:
(a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron
Lett. 1998, 39, 2933–2936. (b) Combs, A. P.; Rafalski, M. J. Comb. Chem.
2000, 2, 29–32. (c) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.;
Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415–3418. For the coupling of
aryl halides and sulfonamides under the classic Goldberg reaction conditions
see: (d) He, H.; Wu, Y.-J. Tetrahedron Lett. 2003, 44, 3385–3386. For
examples of catalytic coupling of aryl halides and sulfonamides see: (e)
Deng, W.; Wang, Y.-F.; Zou, Y.; Liu, L.; Guo, Q.-X. Tetrahedron Lett.
2004, 45, 2311–2315. (f) Deng, W.; Liu, L.; Zhang, C.; Liu, M.; Guo, Q.-
X. Tetrahedron Lett. 2005, 46, 7295–7298.
(6) During the course of the preparation of this manuscript, the coupling
of pyridine derivatives and sulfonamides was reported: Han, X. Tetrahedron
Lett. 2010, 51, 360–362.
(7) For examples of use of 2-aminopyridine as ligands in copper
catalysis, see: (a) Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A.
J. Am. Chem. Soc. 2000, 122, 5043–505. For an example of product
inhibition associated with the use of primary sulfonamides see: (b) Toto,
P.; Gesquiere, J.-C.; Cousaert, N.; Deprez, B.; Willand, N. Tetrahedron
Lett. 2006, 47, 4973–497. For an example of sulfonamide chromium ligand
see: (c) Liu, X.; Henderson, J. A.; Sasaki, T.; Kishi, Y. J. Am. Chem. Soc.
2009, 131, 16678–16680.
a Isolated yield after silica gel chromatography. b Reaction was heated
to 130 °C. c Purified by tritutation.
(8) CuI as additives in the Hiyama and Suzuki cross-coupling of
2-borono and trimethylsilane pyridine, see: (a) Pierrat, P.; Gros, P.; Fort,
Y. Org. Lett. 2005, 7, 697–700. (b) Jones, N. A.; Antoon, J. W.; Bowie,
A. L., Jr.; Borak, J. B.; Stevens, E. P. J. Heterocycl. Chem. 2007, 44, 363–
367. (c) Deng, J. Z.; Paone, D. V.; Ginetti, A. T.; Kurihara, H.; Dreher,
S. D.; Weissman, S. A.; Stauffer, S. R.; Burgey, C. S. Org. Lett. 2009, 11,
345–347. (d) Gutz, C.; Lutzen, A. Synthesis 2010, 1, 85–90.
that glycine,11 N,N′-dimethylethane-1,2-diamine, and trans-
N,N′-dimethylcyclohexane-1,2-diamine12 ligands afforded
the desired product in 5%, 20%, and 26% yield, respec-
tively. Phenanthroline,13 2-pyrrole carboxylic acid,14 and
(benzotriazol-1-yl)methanol15 ligands did not afford any
(9) For recent reviews on copper catalysis, see: (a) Monnier, F.; Taillefer,
M. Angew. Chem., Int. Ed. 2009, 48, 6954–6971. (b) Carril, M.; SanMartin,
R.; Dominguez, E. Chem. Soc. ReV. 2008, 37, 639–647. (c) Ma, D. W.;
Cai, Q. Acc. Chem. Res. 2008, 41, 1450–1460. (d) Kienle, M.; Dubbaka,
S. R.; Brade, K.; Knochel, P. Eur. J. Org. Chem. 2007, 4166–4176. (e)
Frlan, R.; Kikelj, D. Synthesis 2006, 2271–2285. Corbet, J.-P.; Mignani,
G. Chem. ReV. 2006, 106, 2651–2710. (f) Beletskaya, I. P.; Cheprakov,
A. V. Coord. Chem. ReV. 2004, 248, 2337–2364. (g) Ley, S. V.; Thomas,
A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449. (h) Kunz, K.; Scholz,
U.; Ganzer, D. Synlett 2003, 2428–2439.
(11) Ma, D. W.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453–2455.
(12) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 11684–11688.
(13) (a) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron
Lett. 1999, 40, 2657–2660. (b) Goodbrand, H. B.; Hu, N.-X. J. Org. Chem.
1999, 64, 670–674.
(14) Altman, R. A.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem.
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(10) The screening results are summarized in Table 1 in the SI.
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