C O M M U N I C A T I O N S
Table 2. Highly Selective C-Arylation of Free (NH)-Azolesa
Figure 2. Arylation of imidazole. Complete orthogonality.
ligand (e.g., DPPF, tBu3P, 2-biaryl-dialkylphosphine, N-heterocyclic
carbene ligands), the azolyl anion is able to undergo N-arylation.6
Imidazole represents a substrate that best illustrated the remark-
able selectivity of the methodology developed herein (Figure 2).
In fact, we have found that imidazole may be functionalized with
complete chemo- and regiocontrol via fully orthogonal arylation
methods. These novel C-arylation methods described herein serve
to complement the selective N-arylation developed previously by
other groups.9,10
Acknowledgment. Funding was provided by the National
Institute of Health (NIGMS: R01 GM60326), GlaxoSmithKline,
Johnson & Johnson, and Merck. D.S. is a recipient of the Alfred
P. Sloan Fellowship, and the Camille Dreyfus Teacher-Scholar
Award. We thank Dr. J. B. Schwarz (editorial assistance) and Vitas
Votier Chmelar (intellectual contribution).
a Conditions: (a) PhI (1.2 equiv), Pd(OAc)2 (5 mol %), PPh3 (20 mol
%), MgO (1.2 equiv), dioxane, 150 °C, 12-15 h. PhBr afforded 52-60%
yield of the corresponding products.
observed with pyrrole (C-2) and imidazole (C-4) is consistent with
an electrophilic substitution mechanism. However, in the case of
pyrazole, C-3 arylation stands in contrast to electrophilic substitution
reactions which occur at C-4. As in the indole case (see discussion
above), either the addition-elimination mechanism or the activating
effect of the neighboring nitrogen on the metalation step may be
responsible for the observed “nucleophilic” selectivity.7
Supporting Information Available: Experimental procedures,
spectral data for all products (PDF). This material is available free of
References
(1) Sezen, B.; Franz, R.; Sames, D. J. Am. Chem. Soc. 2002, 124, 13372-
13373.
(2) (a) Akita, Y.; Itagaki, Y.; Takizawa, S.; Ohta, A. Chem. Pharm. Bull.
1989, 37, 1477-1480. (b) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura,
M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467-473. (c) A review
on arylation of arenes: Miura, M.; Nomura, M. Top. Curr. Chem. 2002,
219, 211-241.
(3) (a) For solid phase-assisted selective arylation of azoles: Kondo, Y.;
Komine, T.; Sakamoto, T. Org. Lett. 2000, 2, 3111-3113. (b) For a recent
improved method for selective 2-arylation of thiazole: Mori, A.; Sekiguchi,
A.; Masui, K.; Shimada, T.; Horie, M.; Osakada, K.; Kawamoto, M.; Ikeda,
T. J. Am. Chem. Soc. 2003, 125, 1700-1701.
(4) Sundberg, R. J. Indoles; Academic Press: London, 1996; pp 105-109.
(5) (a) Glover, B.; Harvey, K. A.; Liu, B.; Sharp, M. J.; Tymoschenko, M. F.
Org. Lett. 2003, 5, 301-304. (b) Hughes, C. C.; Trauner, D. Angew.
Chem., Int. Ed. 2002, 41, 1569-1572.
(6) Pd-catalyzed N-arylation of heteroarenes: (a) Mann, G.; Hartwig, J. F.;
Driver, M. S.; Ferna´ndez-Rivas, C. J. Am. Chem. Soc. 1998, 120, 827-
828. (b) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575-5580. (c) Old, D.
W.; Harris, M. C.; Buchwald, S. L. Org. Lett. 2000, 2, 1403-1406. (d)
Grasa, G. A.; Viciu, M. S.; Huang, J.; Nolan, S. P. J. Org. Chem. 2001,
66, 7729-7737.
(7) Jones, W. D.; Dong, L.; Myers, A. W. Organometallics 1995, 14, 855.
(8) (a) Okuro, K.; Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J. Org.
Chem. 1993, 58, 4716-4721 and references therein. (b) See also ref 2b.
(c) A discussion on possible roles of Cu(I) in Pd/Cu catalytic systems:
Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55, 5359-5364.
(9) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727-7729.
(10) (a) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.;
Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-2944. (b)
Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233-1236. (c) Lam, P. Y.
S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett.
2001, 42, 3415-3418.
(11) Hartwig et al. demonstrated (ref 6a) that (Ph3P)2Pd(Ph)(N-pyrrolyl)
underwent slow reductive elimination providing a low yield of the
N-phenylpyrrole.
The selectivity obtained in the arylation of free imidazole
prompted us to explore whether the regio-course of this reaction
could be altered. We considered Cu(I) salts as a potential cocatalyst/
additive because of their ability to catalyze arylation of active
methylene and methine groups.8 However, the issue of C- versus
N-arylation emerged again in this context as copper salts have also
been shown to catalyze the selective N-arylation of heterocycles.9,10
To our great delight, addition of CuI to the new Pd/Ph3P/MgO
system resulted in exclusive arylation of position 2 in 83% yield.
Hence, a complete switch from 4-arylation to 2-arylation of
imidazole was brought about by a simple alteration of the arylation
protocol (entries 4 and 5, Table 2). Furthermore, efficient arylation
of benzimidazole and purine was demonstrated, furnishing high
yields of the anticipated monoarylation products (Table 2).
These new results raise many interesting mechanistic questions
regarding the selectivity of these orthogonal methods. Certainly,
the selective arylation of C-H bonds may be attributed to the
formation of magnesium salts [cf., (XMg-N)-azole] in the presence
of MgO. We reason that the strong magnesium-nitrogen bond not
only protects the nitrogen from attack by other electrophiles [in
this instance, Ph-Pd-X(L2)] but also increases the nucleophilicity
of the heteroarene nucleus. In contrast, alkali ions, preferring the
solvation sphere, release the azolyl anion which in turn inhibits
the palladium catalyst. This scenario provides a rationale for low
reactivity of free (NH)-azoles under arylation conditions employing
standard alkali bases.11 However, in the presence of an appropriate
JA034848+
9
J. AM. CHEM. SOC. VOL. 125, NO. 18, 2003 5275