ORGANIC
LETTERS
2012
Vol. 14, No. 6
1432–1435
Palladium-Catalyzed N-Arylation
of 2-Aminothiazoles
Meredeth A. McGowan, Jaclyn L. Henderson, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States
Received January 21, 2012
ABSTRACT
A method for the Pd-catalyzed coupling of 2-aminothiazole derivatives with aryl bromides and triflates is described. Significantly, for this class of
nucleophiles, the coupling exhibits a broad substrate scope and proceeds with a reasonable catalyst loading. Furthermore, an interesting effect of
acetic acid as an additive is uncovered that facilitates catalyst activation.
The 2-arylaminothiazole motif has appeared with in-
creasing frequency throughout the medicinal chemistry
literature over the past decade. It features prominently in
compounds implicated for the treatment of cancer1 and
psoriasis,2 and recently there have been several reports of
2-arylaminothiazole derivatives which show promising
activity in assays targeting neurodegenerative disorders
such as Alzheimer’s disease3 (Figure 1). Typically, these
compounds are synthesized by combining a monoaryl
thiourea and an ortho-bromo ketone to form the thiazole
ring. However, as often SAR and lead optimization studies
require the evaluation of multiple 2-aminoaryl groups,3,4
an efficient method for the direct arylation of 2-aminothia-
zole would significantly expedite the synthesis of analogs.
Palladium-catalyzed CÀN bond-forming methods are
widely recognized as convenient and efficient means for
obtaining N-arylation products.5 However, primary amine
derivatives of five-membered heterocycles, particularly
2-aminoazoles, have historically been problematic sub-
strates for Pd-catalyzed N-arylation. While some methods
for the Pd-catalyzed coupling of these amines have been
reported,5a,6 they generally require high Pd loadings
(2À18%), long reaction times, and in most cases the use
of an activated aryl electrophile.7 For example, the most
comprehensive report to date is that of Yin,6a in which
Xantphos and 2À8% Pd are used to form select 2-aryla-
minothiazole derivatives in moderate to good yields.
(1) (a) Das, J.; Chen, P.; Norris, D.; Padmanabha, R.; Lin, J.;
Moquin, R. V.; Shen, Z.; Cook, L. S.; Doweyko, A. M.; Pitt, S.; Pang,
S.; Shen, D. R.; Fang, Q.; de Fex, H. F.; McIntyre, K. W.; Shuster, D. J.;
Gillooly, K. M.; Behnia, K.; Schieven, G. L.; Wityak, J.; Barrish, J. C.
J. Med. Chem. 2006, 49, 6819. (b) Ghaemmaghami, S.; May, B. C. H.;
Renslo, A. R.; Prusiner, S. B. J. Virol. 2010, 84, 3408. (c) Borzilleri,
R. M.; Bhide, R. S.; Barrish, J. C.; D’Arienzo, C. J.; Derbin, G. M.;
Fargnoli, J.; Hunt, J. T.; Jeyaseelan, R.; Kamath, A.; Kukral, D. W.;
Marathe, P.; Mortillo, S.; Qian, L.; Tokarski, J. S.; Wautlet, B. S.;
Zheng, X.; Lombardo, L. J. J. Med. Chem. 2006, 49, 3766.
ꢀ
(2) Giltaire, S.; Herphelin, F.; Frankart, A.; Herin, M.; Stoppie, P.;
Poumay, Y. Brit. J. Dermatol. 2009, 160, 505.
(5) For selected reviews and examples: (a) Maiti, D.; Fors, B. P.;
Henderson, J. L.; Nakamura, Y.; Buchwald, S. L. Chem. Sci. 2011, 2, 57.
(b) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338.
(c) Marion, N.; Nolan, S. P. Acc. Chem. Res. 2008, 41, 1440. (d) Hartwig,
J. F. Acc. Chem. Res. 2008, 41, 1534. (e) Tasler, J. M.; Langa, N. Adv.
Synth. Catal. 2007, 349, 2286. (f) Torborg, C.; Beller, M. Adv. Synth.
Catal. 2009, 351, 3027. (g) Buchwald, S. L.; Muager, C.; Mignani, G.;
Scholz, U. Adv. Synth. Catal. 2006, 348, 23. (h) Kantchev, E. A. B.;
O’Brien, C. J.; Organ, M. G. Angew. Chem., Int. Ed. 2007, 46, 2768.
(6) (a) Yin, J.; Zhao, M. M.; Huffman, M. A.; McNamara, J. M. Org.
Lett. 2002, 4, 3481. (b) Tweedie, S. R. S.; James, P., II. Synlett 2007,
2331. (c) Jonckers, T. H. M.; Maes, B. U. W.; LemiEre, G. L. F.;
Dommisse, R. Tetrahedron 2001, 57, 7027. (d) For an example in the
context of a synthesis of a kinase inhibitor: Zhao, M.; Yin, J.; Huffman,
M. A.; McNamara, J. M. Tetrahedron 2006, 62, 1110.
(3) (a) Lubbers, T.;Flohr, A.;Jolidon, S.; David-Pierson, P.;Jacobsen,
H.; Ozmen, L.; Baumann, K. Bioorg. Med. Chem. Lett. 2011, 21, 6554. (b)
Kounnas, M. Z.; Danks, A. M.; Cheng, S.; Tyree, C.; Ackerman, E.;
Zhang, X.; Ahn, K.; Nguyen, P.; Comer, D.; Mao, L.; Yu, C.; Pleynet, D.;
Digregorio, P. J.; Velicelebi, G.; Stauderman, K. A.; Comer, W. T.;
Mobley, W. C.; Li, Y.-M.; Sisodia, S. S.; Tanzi, R. E.; Wagner, S. L.
Neuron 2010, 67, 769. (c) Gallardo-Godoy, A.; Gever, J.; Fife, K. L.;
Silber, B. M.; Prusiner, S. B.; Renslo, A. R. J. Med. Chem. 2011, 54, 1010.
(4) (a) Lu, Y.; Li, C.-M.; Wang, Z.; Chen, J.; Mohler, M. L.; Li, W.;
Dalton, J. T.; Miller, D. D. J. Med. Chem. 2011, 54, 4678. (b) Andersen,
C. B.; Wan, Y.; Chang, J. W.; Riggs, B.; Lee, C.; Liu, Y.; Sessa, F.; Villa,
F.; Kwiatkowski, N.; Suzuki, M.; Nallan, L.; Heald, R.; Musacchio, A.;
Gray, N. S. ACS Chem. Biol. 2008, 3, 180.
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10.1021/ol300178j
Published on Web 03/06/2012
2012 American Chemical Society