C O M M U N I C A T I O N S
Table 2. Scope of Picoline N-Oxide sp2/sp3-Arylationa
should prompt its evaluation for similar selectivity switches with
other substrates and reaction classes.
Acknowledgment. We thank NSERC, the University of Ottawa,
the Research Corporation, Boehringer Ingelheim (Laval), Merck
Frosst Canada, Merck Inc., and Astra Zeneca Montreal are thanked
for support of this work.
Supporting Information Available: Experimental procedures and
spectroscopic characterization of all new products. This material is
References
(1) For reviews, see: (a) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35,
826. (b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731.
(c) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211. (d) Kakiuchi,
F.; Chatani, N. AdV. Synth. Catal. 2003, 345, 1077. (e) Campeau, L.-C.;
Fagnou, K. Chem. Commun. 2005, 1253. (f) Espino, C. G.; Du Bois, J.
In Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.;
Wiley-VCH: Weinheim, 2005; pp 379-416. (g) Davies, H. M. L. Angew.
Chem., Int. Ed. 2006, 45, 6422. (h) Daugulis, O.; Zaitsev, V. G.;
Shabashov, D.; Pham, Q.-N.; Lazareva, A. Synlett 2006, 3382. (i) Dick,
A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. (j) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (k) Seregin, I. V.;
Gevorgyan, V. J. Chem. Soc., Chem. ReV. 2007, 36, 1173. (l) Campeau,
L.-C.; Stuart, D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35. (m)
Godula, K.; Sames, D. Science 2006, 312, 67.
(2) (a) Grimster, N. P.; Gauntlett, Godfrey, C. R. A.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2005, 44, 3125. (b) Beck, E. M.; Grimster, N. P.; Hatley,
R.; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128, 2528. (c) Lane, B. S.;
Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050. (d) Mori,
A.; Sekiguchi, A.; Masui, K.; Shimada, T.; Horie, M.; Oskada, K.;
Kawamoto, M.; Ikeda, T. J. Am. Chem. Soc. 2003, 125, 1700. (e) Glover,
B.; Harvey, K.A.; Lui, b.; Sharp, M.J.; Tymoschenko, M.F. Org. Lett.
2003, 5, 301. (f) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem.
Soc. 2007, 128, 12072.
(3) For recent examples involving metallacyclic intermediates, see: (a)
Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046. (b)
Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem.
Soc. 2005, 127, 7330. (c) Kakiuchi, F.; Kan, S.; Igi, K.; Chatani, N.; Murai,
S. J. Am. Chem. Soc. 2003, 125, 1698. (d) Bedford, R. B.; Coles, S. J.;
Hursthouse, M. B.; Limmert, M. E. Angew. Chem., Int. Ed. 2003, 42,
112. For recent advances with electron rich arenes, see : (e) Lane, B. S.;
Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050. (f) Park,
C. H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org.
Lett. 2004, 6, 1159. (g) Li, W. J.; Nelson, D. P.; Jensen, M. S.; Hoerrner,
R. S.; Javadi, G. J.; Cai, D.; Larsen, R. D. Org. Lett. 2003, 5, 4835. (h)
Mori, A.; Sekiguchi, A.; Masui, K.; Shimada, T.; Horie, M.; Osakada,
K.; Kawamoto, M.; Ikeda, T. J. Am. Chem. Soc. 2003, 125, 1700. (i)
Yanagisawa, S.; Sudo, T.; Noyori, R.; Itami, K. J. Am. Chem. Soc. 2006,
128, 11749. For recent examples with simple and electron-deficient arenes,
see: (j) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K., K. J. Am.
Chem. Soc. 2006, 128, 8754. (k) Lafrance, M.; Shore, D.; Fagnou, K.
Org. Lett. 2006, 22, 5097. (l) Lafrance, M.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 16496.
(4) For examples at sp3 C-H bonds, see: (a) Giri, R.; Maugel, N.; Li, J.-J.;
Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem.
Soc. 2007, 129, 3510. (b) Chen, X.; Goodhue, C. E.; Yu, J.-Q. J. Am.
Chem. Soc. 2006, 128, 12634. (c) Hitce, J.; Retailleau, P.; Baudoin, O.
Chem. Eur. J. 2007, 13, 792. (d) Zaitsev, V. G.; Shabashov, D.; Daugulis,
O. J. Am. Chem. Soc. 2005, 127, 13154. (e) Shaabashov, D.; Daugulis,
O. Org. Lett. 2005, 7, 3657. (f) Barder, T. E.; Walker, S. D.; Martinelli,
J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685. (g) DeBoef,
B.; Pastine, S. J.; Sames, D. J. Am. Chem. Soc. 2004, 126, 6556. (h)
Baudoin, O.; Herrbach, A.; Gueritte, F. Angew. Chem., Int. Ed. 2003, 42,
5736. (i) Chen, H.; Schlecht, S.; Semple, T.C.; Hartwig, J. F. Science
2000, 287, 1995. For examples at benzylic C-H bonds, see: (j) Ren, H.;
Knochel, P. Angew. Chem., Int. Ed. 2006, 45, 3462. (k) Dong, C.-G.; Hu,
Q.-G. Angew. Chem., Int. Ed. 2006, 45, 2289. (l) Kalyani, D.; Deprez, N.
R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330. For
examples at sp3C-H bonds next to heteroatoms, see: (m) Pastine, S. J.;
Gribkov, D. V.; Sames, D. J. Am. Chem. Soc. 2006, 128, 14220. (n) Dyker,
G. J. Org. Chem 1993, 58, 6426.
a Conditions A: N-oxide (2 equiv), aryl halide (1 equiv), Pd(OAc)2 (5
mol %), PtBu3HBF4 (5 mol %), K2CO3 (1.5 equiv) dissolved in toluene
and heated to 110 °C. Conditions B: N-oxide (1.5 equiv), aryl halide (1
equiv), Pd2dba3 (2.5 mol %), X-Phos (5 mol %) and NaOtBu (3 equiv)
dissolved in PhMe and heated in a microwave reactor at 110 °C for 45
min. b Isolated yield. c Using 1.1 equiv of N-oxide. d Using Ru-Phos (10
mol %). e Using S-Phos (10 mol %) and 3 equiv of the N-oxide.
superior yields (entries 7, 8). Other alkyl groups can also be arylated
where use of the corresponding alkyl organometallic may be
problematic due to â-hydride elimination at the alkylpalladium
intermediate (entries 14, 15).
This methodology has been validated in both divergent sp2/sp3
arylation and in sequential sp2/sp3 arylation which should be useful
for the rapid derivatization of heterocyclic compounds (Scheme
1). Furthermore, the N-oxide moiety can be used to introduce a
wide range of other functional groups or easily de-oxygenated under
mild conditions if desired.9,10 Consequently, these reactions should
be useful for the derivatization of heterocyclic compounds in
medicinal chemistry. Finally, the ability of palladium to selectively
react at both sp2 and sp3 centers under different reaction conditions
(5) Campeau, L. C.; Fagnou, K. J. Chem. Soc., Chem. ReV. 2007, 36, 1058
and references therein.
(6) (a) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005,
127, 18020. (b) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int. Ed. 2006,
45, 7781.
(7) Reaction of 4-picoline N-oxide under Conditions B yields only sp2 arylation
in 21% yield
(8) Niwa, T.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 2373.
(9) For example, see ref 6a,b and references therein.
(10) See Supporting Information for examples of product deoxygenation.
JA710451S
9
J. AM. CHEM. SOC. VOL. 130, NO. 11, 2008 3267