ORGANIC
LETTERS
2010
Vol. 12, No. 13
3090-3092
Facile Double-Lithiation of a Transient
Urea: Vicarious ortho-Metalation of
Aniline Derivatives
Chris E. Houlden, Guy C. Lloyd-Jones,* and Kevin I. Booker-Milburn*
School of Chemistry, UniVersity of Bristol, Cantock’s Close, Bristol BS8 1TS, U.K.
k.booker-milburn@bristol.ac.uk; guy.lloyd-jones@bris.ac.uk
Received May 13, 2010
ABSTRACT
A convenient one-pot method for the conversion of phenylisocyanate into ortho-functionalized aniline derivatives has been developed. The
reaction proceeds via the selective ortho-metalation of a transient labile urea, which can be considered as a synthetic equivalent of 2-lithio-
phenylisocyanate, a highly improbable intermediate.
A number of efficient methods are available for the regi-
oselective ortho-functionalization of aniline derivatives,1
including catalytic methodologies proceeding via C-H
activation.2 Nonetheless, for the past 3 decades the stoichio-
metric directed ortho-metalation (DoM) reaction has reigned
supreme as the most reliable and broad-ranging procedure.3
DoM of anilines requires a directed metalation group
(DMG), for example, N-pivaloyl,4 N-Boc,5 or urea6,7 moi-
eties, to facilitate the ortho-metalation. Herein we report on
the DoM of highly hindered, N,N-dialkyl-N′-aryl ureas. Not
only are these moieties potent DMGs, but they also provide
a unique advantage: upon protonation, isocyanate-like reac-
tivity is restored, allowing rapid access to a range of ortho-
functionalized aniline derivatives.
We recently reported that a “proton switch” mechanism
allows protic nucleophiles to liberate and then capture aryl
isocyanates from N,N-dialkyl-N′-aryl ureas under neutral
conditions, provided that there is substantial steric hindrance
(5) (a) Muchowski, J. M.; Venuti, M. C. J. Org. Chem. 1980, 45, 479.
(b) Stanetty, P.; Koller, H.; Mihovilovic, M. J. Org. Chem. 1992, 57, 6833.
(6) (a) Cram, D. J.; Dicker, I. B.; Lauer, M.; Knobler, C. B.; Trueblood,
K. N. J. Am. Chem. Soc. 1984, 106, 7150. (b) Smith, K.; El-Hiti, G. A.;
Shukla, A. P. J. Chem. Soc., Perkin Trans. 1 1999, 2305. (c) Meigh, J. P.;
(1) For examples see: (a) Sugasawa, T.; Toyoda, T.; Adachi, M.;
Sasakura, K. J. Am. Chem. Soc. 1979, 100, 4842. (b) Friedel-Crafts and
Related Reactions; Olah, G., Ed.; Interscience: New York, 1963; Vols. I-IV.
(c) Zoltewicz, J. Top. Curr. Chem. 1975, 59, 33. (d) Ferrini, S.; Ponticelli,
F.; Taddei, M. Org. Lett. 2007, 9, 69. (e) Tremont, S. J.; Rahman, H. U.
J. Am. Chem. Soc. 1984, 106, 5759. (f) Horino, H.; Inoue, N. J. Org. Chem.
1981, 46, 4416.
´
Alvarez, M.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1 2001, 2012. (d)
Smith, K.; El-Hiti, G. A.; Hawes, A. C. Synlett 1999, 945. (e) Resek, J. E. P.;
Beak, P. J. Am. Chem. Soc. 1994, 116, 405. (f) Smith, K.; El-Hiti, G. A.;
Hegazy, A. S. Synthesis 2010, 1371. (g) Smith, K.; El-Hiti, G. A.; Hegazy,
A. S. Chem. Commun. 2010, 46, 2790.
(2) (a) Selective functionalization of C-H bonds. Chem. ReV 2010, 110.
(b) Kakiuchi, F.; Kochi, T. Synthesis 2008, 19, 3013. (c) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (d) Li, B. J.; Yang, S. D.;
Shi, Z. J. Synlett 2008, 7, 949. (e) Campeau, L.-C.; Stuart, D. R.; Fagnou,
K. Aldrichimica Acta 2007, 40, 35.
(7) The utility of ureas for directed metallation has been recently been
substantially expanded by Clayden and co-workers: (a) Bach, R.; Clayden,
J.; Hennecke, U. Synlett 2009, 421. (b) Clayden, J.; Turner, H.; Helliwell,
M.; Moir, E. J. Org. Chem. 2008, 73, 4415. (c) Clayden, J.; Hennecke, U.
Org. Lett. 2008, 10, 3567. (d) Clayden, J.; Dufour, J.; Grainger, D. M.;
Helliwell, M. J. Am. Chem. Soc. 2007, 129, 7488. (e) Clayden, J.; Dufour,
J. Tetrahedron Lett. 2006, 47, 6945. (f) Clayden, J.; Turner, H.; Pickworth,
M.; Adler, T. Org. Lett. 2005, 7, 3147.
(3) (a) Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon:
Oxford, 2002. (b) Snieckus, V. Chem. ReV. 1990, 90, 879. (c) Beak, P.;
Zajdel, W. J. Chem. ReV. 1984, 84, 471.
(4) Fuhrer, W.; Gschwend, H. W. J. Org. Chem. 1979, 44, 1133.
10.1021/ol101102y 2010 American Chemical Society
Published on Web 06/08/2010