Journal of the American Chemical Society
COMMUNICATION
Table 4) by using a smaller acetic acid co-catalyst (converted
in situ to acetate ligand) instead of bulky 2,2-dimethylhexanoic
or pivalic acid (from 50% to 70% yield improvement).
2009, 65, 10269. (d) Roger, J.; Gottumukkala, A. L.; Doucet, H.
ChemCatChem 2010, 2, 20.
(6) (a) Berman, A. M.; Lewis, J. C.; Bergman, R. G.; Ellman, J. A.
J. Am. Chem. Soc. 2008, 130, 14926. (b) Tobisu, M.; Hyodo, I.; Chatani,
N. J. Am. Chem. Soc. 2009, 131, 12070.
(7) C2-arylation of pyridine N-oxides and N-iminopyridinium
ylides. (a) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem.
Soc. 2005, 127, 18020. (b) Larivꢀee, A.; Mousseau, J. J.; Charette, A. B.
J. Am. Chem. Soc. 2008, 130, 52. (c) Cho, S. H.; Hwang, S. J.; Chang, S.
J. Am. Chem. Soc. 2008, 130, 9254. (d) Xi, P.; Yang, F.; Qin, S.; Zhao, D.;
Lan, J.; Gao, G.; Hu, C.; You, J. J. Am. Chem. Soc. 2010, 132, 1822. (e)
Gong, X.; Song, G.; Zhang, H.; Li, X. Org. Lett. 2011, 13, 1766. (f)
Yamaguchi, A. D.; Mandal, D.; Yamaguchi, J.; Itami, K. Chem. Lett. 2011,
40, 555. (g) Wang, Z.; Li, K.; Zhao, D.; Lan, J.; You, J. Angew. Chem., Int.
Ed. 2011, 50, 5365.
Furthermore, we found that the presence of a cyano group is
not compatible with the catalytic protocol using silver carbonate,
most likely due to the coordination of the cyano group with
the silver salts. We overcame this limitation by reoptimizing
the catalytic protocol in the absence of Ag2CO3 (Table 5).
The silver-free conditions enabled CÀH arylation of cyanopyridines
with predictable regioselectivity. In particular, 4-cyanopyridine
was a better substrate than the 3-cyano isomer (19 versus 23).
The method is not effective for pyridines bearing ester or ketone
functionality at C-3/C-4 positions.
In conclusion, we have developed a new catalytic protocol for
highly selective CÀH arylation of pyridines containing common
and versatile electron-withdrawing substituents. The new protocol
significantly expands the scope of catalytic azine functionalization
as the excellent regioselectivity at the 3- and 4-positions well
complements the existing methods for CÀH arylation as well as
the Ir-catalyzed borylation of pyridines. Another important feature
of the new methodisits flexibilitytoadapttochallengingsubstrates
by a modification of the carboxylic acid ligand or the use of silver
salts. The regioselectivity can be rationalized on the basis of the key
electronic effects (repulsion between the nitrogen lone pair and
polarized CÀPd bond and acidity of the CÀH bond) in combina-
tion with steric effects (sensitivity to bulky substituents). Further
exploration of new methods for CÀH arylation of complex azines
is underway in our laboratory.
(8) Wasa, M.; Worrell, B. T.; Yu, J.-Q. Angew. Chem., Int. Ed. 2010,
49, 1275.
(9) (a) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.;
Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc. 2010,
132, 13194. (b) Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org.
Lett. 2008, 10, 4673.
(10) For examples of Lewis acid-promoted selective functionaliza-
tion of pyridines, see: (a) Tsai, C.-C.; Shih, W.-C.; Fang, C.-H.; Li, C.-Y.;
Ong, T.-G.; Yap, G. P. A. J. Am. Chem. Soc. 2010, 132, 11887. (b) Nakao,
Y.; Yamada, Y.; Kashihara, N.; Hiyama, T. J. Am. Chem. Soc. 2010,
132, 13666. (c) Jaric, M.; Haag, B. A.; Unsinn, A.; Karaghiosoff, K.;
Knochel, P. Angew. Chem., Int. Ed. 2010, 49, 5451. High C3-selectivity
was achieved for palladium-catalyzed pyridine alkenylation in the
presence of silver carbonate. (d) Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am.
Chem. Soc. 2011, 133, 6964.
(11) C3/C4-selective Ir-catalyzed borylation of pyridine may also be
rationalized by either the electronic repulsion between the nitrogen lone
pair and the developing CÀIr bond or steric blockade of C2/C6
positions by coordinated Ir-complex. (a) Takagi, J.; Sato, K.; Hartwig,
J. F.; Ishiyama, T.; Miyaura, N. Tetrahedron Lett. 2002, 43, 5649. (b)
Mkhalid, I. A. I.; Coventry, D. N.; Albesa-Jove, D.; Batsanov, A. S.;
Howard, J. A. K.; Perutz, R. N.; Marder, T. B. Angew. Chem., Int. Ed.
2006, 45, 489. (c) Vanchura, B. A., II; Preshlock, S. M.; Roosen, P. C.;
Kallepalli, V. A.; Staples, R. J.; Maleczka, R. E., Jr.; Singleton, D. A.;
Smith, M. R., III. Chem. Commun. 2010, 46, 7724. (d) Li, B.-J.; Shi, Z.-J.
Chem. Sci. 2011, 2, 488.
(12) For transformation of the nitro group in nitropyridines into
amino, halogen, hydroxy, methoxy groups as well as azaindoles, see: (a)
Rahaim, R. J., Jr.; Maleczka, R. E., Jr. Synthesis 2006, 3316. (b) Stockmann,
V.; Bakke, J. M.; Bruheim, P.; Fiksdahl, A. Tetrahedron 2009, 65,
3668. (c) Kuduk, S. D.; DiPardo, R. M.; Bock, M. G. Org. Lett. 2005,
7, 577. (d) O’Shea, P. D.; Gauvreau, D.; Gosselin, F.; Hughes, G.;
Nadeau, C.; Roy, A.; Shultz, C. S. J. Org. Chem. 2009, 74, 4547. (e) Bay,
E.; Timony, P. E.; Leone-Bay, A. J. Org. Chem. 1988, 53, 2858. (f) Zhang,
Z.; Yang, Z.; Meanwell, N. A.; Kadow, J. F.; Wang, T. J. Org. Chem. 2002,
67, 2345. (g) Bartoli, G.; Palmieri, G.; Bosco, M.; Dalpozzo, R.
Tetrahedron Lett. 1989, 30, 2129. For transformation of the fluoride
group of fluoropyridines into hydrogen, methoxy, phenoxy, aryl groups
as well as imidazoles, see: (h) Kuhl, S.; Schneider, R.; Fort, Y. Adv. Synth.
Catal. 2003, 345, 341. (i) Lloung, M.; Loupy, A.; Marque, S.; Petit, A.
Heterocycles 2004, 63, 297. (j) Mongin, F.; Mojovic, L.; Guillamet, B.;
Trꢀecourt, F.; Quꢀeguiner, G. J. Org. Chem. 2002, 67, 8991. (k) Ackermann,
L.; Born, R.; Spatz, J. H.; Meyer, D. Angew. Chem., Int. Ed. 2005, 44, 7216.
(l) Denton, T. T.; Zhang, X.; Cashman, J. R. J. Med. Chem. 2005, 48, 224.
(m) Cherng, Y.-J. Tetrahedron 2002, 58, 4931.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
characterization data for all new compounds. This material is
’ AUTHOR INFORMATION
Corresponding Author
’ ACKNOWLEDGMENT
We thank the National Institute of General Medical Sciences
(GM60326) for support of this work.
’ REFERENCES
(1) (a)Comprehensive Heterocyclic Chemistry;Katritzky, A. R.;Ramsden,
C. A.; Scriven, E. F. V.; Taylor, R. J. K. Eds.; Elsevier: Oxford, 2008; Vol. 7.
(b) Henry, G. D. Tetrahedron 2004, 60, 6043. (c) Michael, J. P. Nat. Prod.
Rep. 2005, 22, 627.
(2) Godula, K.; Sames, D. Science 2006, 312, 67.
(3) CÀH arylation of indoles and pyrroles. (a) Lane, B. S.; Sames, D.
Org. Lett. 2004, 6, 2897. (b) Lane, B. S.; Brown, M. A.; Sames, D. J. Am.
Chem. Soc. 2005, 127, 8050. (c) Wang, X.; Lane, B. S.; Sames, D. J. Am.
Chem. Soc. 2005, 127, 4996. (d) Wang, X.; Gribkov, D. V.; Sames, D.
J. Org. Chem. 2007, 72, 1476.
(4) CÀH arylation of imidazoles and pyrazoles. (a) Tourꢀe, B. B.;
Lane, B. S.; Sames, D. Org. Lett. 2006, 8, 1979. (b) Goikhman, R.;
Jacques, T. L.; Sames, D. J. Am. Chem. Soc. 2009, 131, 3042. (c) Joo,
J. M.; Tourꢀe, B. B.; Sames, D. J. Org. Chem. 2010, 75, 4911.
(5) Reviews on catalytic CÀH arylation of heteroarenes. (a) Alberico,
D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (b) Satoh, T.;
Miura, M. Chem. Lett. 2007, 36, 200. (c) Bellina, F.; Rossi, R. Tetrahedron
(13) Complexation of pyridines to silver ions is known to increase
the solubility of the resulting salts in organic solvents. For an
example, see: Gulevskaya, A. V.; Maes, B. U. W.; Meyers, C.; Herrebout,
W. A.; van der Veken, B. J. Eur. J. Org. Chem. 2006, 5305.
(14) C4-arylation of 3-fluoropyridine with 4-iodotoluene was re-
ported using a copper catalyst and t-BuOLi base (40%). Do, H.-Q.;
Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128.
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