ORGANIC
LETTERS
2011
Vol. 13, No. 12
3262–3265
Synthesis of Unsymmetrical Diarylureas
via Pd-Catalyzed CꢀN Cross-Coupling
Reactions
Simon Breitler, Nathan J. Oldenhuis, Brett P. Fors, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States
Received May 6, 2011
ABSTRACT
A facile synthesis of unsymmetrical N,N0-diarylureas is described. The utilization of the Pd-catalyzed arylation of ureas enables the synthesis of an
array of diarylureas in good to excellent yields from benzylurea via a one-pot arylationꢀdeprotection protocol, followed by a second arylation.
Unsymmetrical N,N0-diarylureas are found in a variety
of biologically active molecules, and their efficient synthe-
sis is of great importance,1 especially to medicinal
chemists.2 They are most commonly prepared via a
nucleophilic attack of an aniline on an isocyanate.1,3
Unfortunately, isocyanates are unstable and typically
require the use of phosgene for their synthesis. To circum-
vent these issues, several methods have been developed to
allow in situ generation of the isocyanates from different
precursors, such as carbamates,4 carbamic acids,5 hydro-
xamic acids,6 or acetoacetanilide.7 However, these meth-
ods do not provide general and efficient syntheses of
diarylureas.
In efforts to develop more general routes to make unsym-
metrical diarylureas, several metal-catalyzed N-arylations of
urea or monosubstituted ureas have been reported.8ꢀ10
However, all of these procedures give either symmetrically
substituted products (when using urea as the N-nucleophile),8
rely on a commercially available monosubstituted starting
material (for which one aryl group is “purchased,” e.g.,
phenylurea),9 or require the preparation of the monosubsti-
tuted urea by traditional methods (vide supra).10
(1) (a) Gallou, I. Org. Prep. Proced. Int. 2007, 4, 355. (b) Bankston,
D.; Dumas, J.; Natero, R.; Riedl, B.; Monahan, M.; Sibley, R. Org.
Proc. Res. Dev. 2002, 6, 777.
(2) (a) Morgan, B. P.; Muci, A.; Lu, P.-P.; Qian, X.; Tochimoto, T.;
Smith, W. W.; Garard, M.; Kraynack, E.; Collibee, S.; Suehiro, I.;
Tomasi, A.; Valdez, S. C.; Wang, W.; Jiang, H.; Hartman, J.; Rodriquez,
H. M.; Kawas, R.; Sylvester, S.; Elias, K. A.; Godinez, G.; Lee, K.;
Anderson, R.; Sueoka, S.; Xu, D.; Wang, Z.; Djordjevic, N.; Malik, F. I.;
Morgans, D. J., Jr. ACS Med. Chem. Lett. 2010, 1, 472. (b) Zhang, Y.;
Anderson, M.; Weisman, J. L.; Lu, M.; Choy, C. J.; Boyd, V. A.; Price,
J.; Sigal, M.; Clark, J.; Connelly, M.; Zhu, F.; Guiguemde, W. A.;
Jeffries, C.; Yang, L.; Lemoff, A.; Lious, A. P.; Webb, T. R.; DeRisis,
J. L.; Guy, R. K. ACS Med. Chem. Lett. 2010, 1, 460. (c) Zhang, J.;
Zhou, J.; Ren, X.; Diao, Y.; Li, H.; Jiang, H.; Ding, K.; Pei, D. Invest.
New Drugs 2010, 28, 35. (d) Anandan, S.-K.; Webb, H. K.; Do, Z. N.;
Gless, R. D. Bioorg. Med. Chem. Lett. 2009, 19, 4259.
Herein, we report the development of an efficient and
general method for the synthesis of unsymmetrical
ꢀ
(6) Dube, P.; Nathel, N. F. F.; Vetelino, M.; Couturier, M.; Aboussafy,
C. L.; Pichette, S.; Jorgensen, M. L.; Hardink, M. Org. Lett. 2009, 11,
5622.
(7) Wei, Y.; Liu, J.; Lin, S.; Ding, H.; Liang, F.; Zhao, B. Org. Lett.
2010, 12, 4220.
(8) (a) Artamkina, G. A.; Sergeev, A. G.; Beletskaya, I. P. Tetrahe-
dron Lett. 2001, 42, 4381. (b) Sergeev, A. G.; Artamkina, G. A.;
Beletskaya, I. P. Tetrahedron Lett. 2003, 44, 4719.
(3) Ozaki, S. Chem. Rev. 1972, 72, 457.
ꢀ
~
(4) (a) Gallou, I.; Eriksson, M.; Zeng, X.; Senanayake, C.; Farina, V.
J. Org. Chem. 2005, 70, 6960. (b) Matsumura, Y.; Satoh, Y.; Onomura,
O.; Maki, T. J. Org. Chem. 2000, 65, 1549. (c) Gastaldi, S.; Weinreb,
S. M.; Stien, D. J. Org. Chem. 2000, 65, 3239. (d) Han, C.; Porco, J. A.
Org. Lett. 2007, 9, 1517. (e) Liu, Q.; Luedtke, N. W.; Tor, Y. Tetrahedron
Lett. 2001, 42, 1445.
(9) (a) Abad, A.; Agullo, C.; Cunat, C.; Vilanova, C. Synthesis 2005,
6, 915. (b) Willis, M. C.; Snell, R. H.; Fletcher, A. J.; Woodward, R. L.
Org. Lett. 2006, 8, 5089. (c) Kotecki, B. J.; Fernando, D. P.; Haight,
A. R.; Lukin, K. A. Org. Lett. 2009, 11, 947.
(10) (a) McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett. 2006,
8, 3311. (b) Clayden, J.; Hennecke, U. Org. Lett. 2008, 10, 3567. (c) Yu,
S.; Haight, A.; Kotecki, B.; Wang, L.; Lukin, K.; Hill, D. R. J. Org.
Chem. 2009, 74, 9539.
(5) Peterson, S. L.; Stucka, S. M.; Dinsmore, C. J. Org. Lett. 2010, 12,
1340.
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10.1021/ol201210t
Published on Web 05/23/2011
2011 American Chemical Society