ORGANIC
LETTERS
2011
Vol. 13, No. 10
2564–2567
Mild Pd-Catalyzed N-Arylation of
Methanesulfonamide and Related
Nucleophiles: Avoiding Potentially
Genotoxic Reagents and Byproducts
Brandon R. Rosen, J. Craig Ruble,* Thomas J. Beauchamp,* and Antonio Navarro
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285,
United States
Received March 11, 2011
ABSTRACT
A convenient, general, and high yielding Pd-catalyzed cross-coupling of methanesulfonamide with aryl bromides and chlorides is reported. The
use of this method eliminates concern over genotoxic impurities that can arise when an aniline is reacted with methanesulfonyl chloride. The
application of this method to the synthesis of dofetilide is also reported.
The N-arylsulfonamide substructure is quite common
among medicinally interesting molecules.1 Molecules of
this type have most frequently been prepared via the
reaction of an aniline with a sulfonyl chloride. While
generally effective, this approach is less than ideal when
one considers it from the perspective of potential genotoxic
impurities in the product.2 Both the aniline and the sulfo-
nyl chloride raise alerts for genotoxicity. Furthermore,
exposure of the reaction mixtures to alcohols during work-
up can yield alkyl sulfonates, which can also be genotoxic.3
Given these concerns, a more attractive alternative for
the construction of N-arylsulfonamides is the metal-cata-
lyzed cross-coupling of an aryl halide with a sulfonamide,
Scheme 1. Although couplings under Ullman-type condi-
tions have been known for many years,4,5 the harsh
conditions required for such couplings rendered them
impractical for many applications. A major breakthrough
came in 1996 when the Pd-catalyzed intramolecular aryla-
tion of sulfonamides was described by Buchwald.6 Since
then, significant progress has been made with both Cu and
Pd catalysis, but noteworthy issues still exist, including the
frequent use of Cs2CO3 as the base,7 relatively high reac-
tion temperatures, and high catalyst loadings.8ꢀ11
(6) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996,
52, 7525–7546.
(7) We choose to avoid Cs2CO3 where possible due, in part, to its high
molar cost when compared to several other common bases.
(8) For examples employing Cu catalysis, see: (a) He, H.; Wu, Y.-J.
Tetrahedron Lett. 2003, 44, 3385–3386. (b) Steinhuebel, D.; Palucki, M.;
Askin, D.; Drolling, U. Tetrahedron Lett. 2004, 45, 3305–3307. (c)
ꢀ
Baffoe, J.; Hoe, M. Y.; Toure, B. B. Org. Lett. 2010, 12, 1532–1535.
(d) Han, X. Tetrahedron Lett. 2010, 51, 360–362.
(9) For examples employing Pd catalysis, see: (a) Yin, J.; Buchwald,
S. L. Org. Lett. 2000, 2, 1101–1104. (b) Burton, G.; Cao, P.; Li, G.;
Rivero, R. Org. Lett. 2003, 5, 4373–7376. (c) Steinhuebel, D.; Palucki,
M.; Askin, D.; Drolling, U. Tetrahedron Lett. 2004, 45, 3305–3307. (d)
Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2007, 129, 13001–13009. (e) Anjanappa, P.; Mullick, D.;Selvakumar,
K.; Sivakumar, M. Tetrahedron Lett. 2008, 49, 4585–4587. (f) Hicks, J. D.;
Hyde, A. M.; Cuezva, A. M.; Buchwald, S. L. J. Am. Chem. Soc. 2009,
131, 16720–16734.
(1) For a list of marketed drugs containing a sulfonamide, see: Smith,
D. A.; Jones, R. M. Curr. Opin. Drug Discovery Dev. 2008, 11, 72–79.
(2) (a) Snodin, D. J. Org. Process Res. Dev. 2010, 14, 960–976. (b)
Pierson, D. A.; Olsen, B. A.; Robbins, D. K.; DeVries, K. M.; Varie,
D. L. Org. Process Res. Dev. 2009, 13, 285–291.
(3) Teasdale, A.; Delaney, E. J.; Eyley, S. C.; Jacq, K.; Taylor-Worth,
K.; Lipczynski, A.; Hoffmann, W.; Reif, V.; Elder, D. P.; Facchine,
K. L.; Golec, S.; Oestrich, R. S.; Sandra, P.; David, F. Org. Process Res.
Dev. 2010, 14, 999–1007.
(4) Ullmann, F.; Junghans, W. Annalen 1913, 399, 330–345.
(5) For a review, see: Lindley, J. Tetrahedron 1984, 40, 1433–1456.
(10) For Cu-catalyzed arylation of sulfonamides with boronic acids,
see: (a) Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav,
P. K. Tetrahedron Lett. 2001, 42, 3415–3418. (b) Pan, C.; Cheng, J.; Wu,
H.; Ding, J.; Liu, M. Synth. Commun. 2009, 39, 2082–2092.
(11) For arylation of sulfonamides via reaction with benzynes, see:
Liu, Z.; Larock, R. C. Org. Lett. 2003, 5, 4673–4675.
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10.1021/ol200660s
Published on Web 04/21/2011
2011 American Chemical Society