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After developing a new copper-catalyzed cross-coupling
Ligand-Free Copper-Catalyzed Arylation of
Amidines
reaction suitable for the preparation of N,N0-disubstituted
guanidines,7 we believed that aryl amidines could also be
prepared by direct arylation methods. Amidines of this type
could provide structural mimics of the diaryl guanidines we
are currently investigating as calcium channel blockers in
ischemic stroke therapy with biological collaborators.8
Standard methods for the synthesis of substitued amidines
often utilize Pinner reaction protocols.9 These reactions are
generally performed by the addition of amines to nitriles
substituted with electron-withdrawing groups.10 The nitrile
activation is usually promoted through the use of relatively
costly catalysts,11 aluminum amides,12 high temperatures,13
or stoichiometric amounts of CuCl.14 Chang presented a
three-component synthesis using azides, alkynes, and amines
for the formation of N-sulfonylamidines using CuI as
catalyst.15 Other amidines were prepared using sulfonyl
azides in order to diminish the production of toxic byproducts
when CuCl was used as catalyst.16 It is also possible to arylate
amidines to form benzimidazoles with N,N0-dimethylethylene-
diamine as a ligand with temperatures ranging from 100 to
165 °C.17
Michelle Cortes-Salva, Corey Garvin, and Jon C. Antilla*
Department of Chemistry, University of South Florida, 4202
East Fowler Avenue CHE 205A, Tampa, Florida 33620,
United States
Received November 9, 2010
Ullmann18 (C-C, C-N, or C-O bond formation) and
Goldberg19 (C-N amide bond formation) reactions are very
Copper-catalyzed cross-coupling reactions of amidine
salts were utilized to synthesize monoarylated amidines
in moderate to high yields with ligand-free conditions.
DMF was the superior solvent for the N-arylation of
benzamidines, while MeCN was used in the formation of
N-aryl amidines in moderate to high yield.
(8) (a) Herrera, Y.; Katnik, C.; Rodriguez, J. R.; Hall, A. A.; Willing, A.;
Pennypacker, K. R.; Cuevas, J. J. Pharmacol. Exp. Ther. 2008, 327, 491.
(b) Ajmo, C. T., Jr.; Vernon, D. O.; Collier, L.; Pennypacker, K. R.; Cuevas,
J. Curr. Neurovasc. Res. 2006, 3, 89. (c) Katnik, C.; Guerrero, W. R.;
Pennypacker, K. R.; Herrera, Y.; Cuevas, J. J. Pharmacol. Exp. Ther.
2006, 319, 1355. (d) Zhang, H.; Cuevas, J. J. Pharmacol. Exp. Ther. 2005,
313, 1387.
(9) Caron, S.; Wei, L.; Douville, J.; Ghosh, A. J. Org. Chem. 2010, 75,
945.
(10) Grivas, J. C.; Taurins, A. Can. J. Chem. 1961, 39, 761.
(11) (a) Cai, T.; Chen, X.; Xu, F.; Zhang, Y.; Yao, Y.; Shen, Q.
J. Organomet. Chem. 2009, 694, 3167. (b) Wang., J.; Xu, F.; Cai, T.; Shen,
Q. Org. Lett. 2008, 10, 445.
(12) Garigipati, R. Tetrahedron Lett. 1990, 31, 1969.
(13) Hisano, T.; Tasaki, M.; Tsumoto, K.; Matsuoka, T.; Ichikawa, M.
Chem. Pharm. Bull. 1983, 31, 2484.
Amidines are moieties found in current antiviral,1 anti-
inflammatory,2 and antithrombotic3 drugs presumably be-
cause of their unique structural properties. Amidines are
also important precursors used in the formation of qui-
nazolinones,4 benzimidazoles,5 and obesity treatment
drugs.6
(14) Rousselet, G.; Capdervielle, P.; Maumy, M. Tetrahedron Lett. 1993,
34, 6395.
(15) (a) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038.
(b) Kim, J.; Lee, J.; Do, Y.; Chang, S. J. Org. Chem. 2008, 73, 9454.
(16) (a) Xu, X.; Li, X.; Ma, L.; Ye, N.; Weng, B. J. Am. Chem. Soc. 2008,
130, 14048. (b) Zhao, Q.; Li, L.; Fang, Y.; Sun, D.; Li, C. J. Org. Chem. 2009,
74, 459. (c) Xu, X.; Ge, Z.; Cheng, D.; Ma, L.; Lu, C.; Zhang, Q.; Yao, N.; Li,
X. Org. Lett. 2010, 12, 897.
(17) Deng., X.; McAllister, H.; Mani, N. S. J. Org. Chem. 2009, 74, 5742.
(18) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382.
(19) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691.
(20) For reviews of copper-catalyzed cross-coupling reactions, see: (a)
Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (b) Kunz,
K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428. (c) Beletskaya, I. P.; Cheprakov,
A. V. Coord. Chem. Rev. 2004, 248, 2337. (d) Surry, D. S.; Buchwald, S. L.
Chem. Sci. 2010, 1, 13. For copper-catalyzed cross-coupling reactions, see:
(e) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. J. Am. Chem. Soc.
2001, 123, 7727. (f) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett.
2002, 4, 581. (g) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128,
8742.
(1) Grienke, U.; Schmidtke, M.; Kirchmair, J.; Pfarr, K.; Wutzler, P.;
€
Durrwarld, R.; Wolber, G.; Liedl, K. R.; Stuppner, H.; Rollinger, J. M.
J. Med. Chem. 2010, 53, 778.
(2) Kort, M. E.; Drizin, I.; Gregg, R. J.; Scanio, M. J. C.; Shi, L.; Gross,
M. F.; Atkinson, R. N.; Johnson, M.; Pacofsky, G. J.; Thomas, J. B.; Carroll,
W. A.; Krambis, M. J.; Liu, D.; Shieh, C.-C.; Zhang, X.; Hernandez, G.;
Mikusa, J. P.; Zhong, C.; Joshi, S.; Honore, P.; Roeloffs, R.; Marsh, K. C.;
Murray, B. P.; Liu, J.; Werness, S.; Faltynek, C. R.; Krafte, D. S.; Jarvis,
M. F.; Chapman, M. L.; Marron, B. E. J. Med. Chem. 2008, 51, 407.
ꢀ
(3) Ilas, J.; Jakopin, Z.; Brostnar, T.; Stegnar, M.; Kikelj, D. J. Med.
Chem. 2008, 51, 5617.
(4) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009, 48,
348.
(5) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932.
(6) Pan, K.; Scott, M. K.; Lee, D. H. S.; Fitzpatrick, L. J.; Crooke, J. J.;
Rivero, R. A.; Rosenthal, D. I.; Vaidya, A. H.; Zhao, B.; Reitz, A. B. Bioorg.
Med. Chem. 2003, 11, 185.
(7) (a) Cortes-Salva, M.; Nguyen, B.-L.; Cuevas, J.; Pennypacker, K. R.;
Antilla, J. C. Org. Lett. 2010, 12, 1316. (b) Cortes-Salva, M.; Antilla, J.;
Behensky, A.; Cuevas, J.; Pennypaker, K. Design, synthesis and evaluation
of guanidine analogs as potential drugs for stroke therapeutics. Abstract of
Papers, 237 National Meeting of the American Chemical Society, Salt Lake
City, Utah, March 22-26, 2009.
(21) (a) Quach, T. D.; Batey, R. Org. Lett. 2003, 5, 4397. (b) Saha, P.;
Ramana, T.; Purkait, N.; Ali, M. A.; Paul, R.; Punniyamurthy, T. J. Org.
Chem. 2009, 74, 8719. (c) Ali, M. A.; Saha, P.; Punniyamurthy, T. Synthesis
2010, 6, 908. (d) Xu, H.-J.; Zheng, F.-Y.; Liang, Y.-F.; Cai, Z.-H.; Feng,
Y.-S.; Che, D.-Q. Tetrahedron Lett. 2010, 51, 669. (e) Liu, Z.-J.; Vors; J.-P.;
Gesimg, E. R. F.; Bolm, C. Green Chem. 2011, 13, 42. (f) Correa, A.; Bolm, C.
Adv. Synth. Catal. 2007, 349, 2673.
(22) Sperotto, E.; Vries, J. G.; Van Klink, G. P. M.; Van Koten, G.
Tetrahedron Lett. 2007, 48, 7366.
1456 J. Org. Chem. 2011, 76, 1456–1459
Published on Web 01/20/2011
DOI: 10.1021/jo102235u
r
2011 American Chemical Society