to prepare, especially in highly functionalized form.6 In the
context of direct arylation, a C2 arylation of 7-azaindole has
been described,7 but methods for the direct functionalization
of the azine ring have not been forthcoming.
studies point to new opportunities for the site-selective
functionalization of useful organic building blocks and may
find application in the preparation of novel medicinal
compounds.
Initial optimization studies were performed with N-methyl-
7-azaindole N-oxide 5 and 4-bromotoluene 6a as cross-
coupling partners. Under previously reported conditions for
azine N-oxides,8f only 5% NMR yield was obtained favoring
the formation of regioisomer 7a (Table 1, entry 1). In
Because azaindoles have electron-rich azole and electron-
deficient azine ring systems, we wondered if it might be
possible to capitalize on recent advances in direct arylation
methods to selectively functionalize both rings in a controlled
fashion. Herein, we describe that, by employing N-oxide
azine activation,8 both 7- and 6-azaindoles undergo regiose-
lective direct arylation at the azine ring. We have also found
that, by modifying the Larrosa arylation protocol9 slightly
(heating to 80 °C), highly selective C2 arylation can be
induced, offering a divergent method for the preparation of
polyaromatic compounds based on an azaindole core. These
Table 1. Optimization of Azine Arylation on
N-Methyl-7-azaindole N-Oxide 5a
(2) For recent examples, see: (a) Seregin, I. V.; Gevorgyan, V. Chem.
Soc. ReV. 2007, 36, 1173. (b) Lewis, J. C.; Berman, A. M.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 2493. (c) Phipps, R. J.; Grimster,
N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172. (d) Yanagisawa,
S.; Sudo, T.; Noyori, R.; Itami, K. Tetrahedron 2008, 64, 6073. (e)
Ackermann, L.; Vicente, R.; Born, R. AdV. Synth. Catal. 2008, 350, 741.
(f) Bellina, F.; Cauteruccio, S.; Rossi, R. Eur. J. Org. Chem. 2006, 1379.
(g) Bellina, F.; Benelli, F.; Rossi, R. J. Org. Chem. 2008, 73, 5529. (h)
Flegeau, E. F.; Popkin, M. E.; Greaney, M. F. Org. Lett. 2008, 10, 2717.
(i) Martin, T.; Verrier, C.; Hoarau, C.; Marsais, F. Org. Lett. 2008, 10,
2909. (j) Ban, I.; Sudo, T.; Taniguchi, T.; Itami, K. Org. Lett. 2008, 10,
3607. (k) Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72,
1476. (l) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am.
Chem. Soc. 2006, 128, 4972. (m) Wang, J. X.; McCubbin, J. A.; Jin, M.;
Laufer, R. S.; Mao, Y.; Crew, A. P.; Mulvihilland, M. J.; Snieckus, V.
Org. Lett. 2008, 10, 2923. (n) Yang, S.-D.; Sun, C.-L.; Fang, Z.; Li, B.-J.;
Li, Y.-Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2007, 47, 1473. (o) Ackermann,
L.; Althammer, A.; Fenner, S. Angew. Chem., Int. Ed. 2009, 48, 201.
(3) (a) Nakao, Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama, T. J. Am.
Chem. Soc. 2008, 130, 16170. (b) Do, H.-Q.; Kahn, R. M. K.; Daugulis,
O. J. Am. Chem. Soc. 2008, 130, 15185. (c) Caron, L.; Campeau, L.-C.;
Fagnou, K. Org. Lett. 2008, 10, 4533. (d) Do, H.-Q.; Daugulis, O. J. Am.
Chem. Soc. 2008, 130, 1128. (e) Berman, A. M.; Lewis, J. C.; Bergman,
R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 14296.
equiv
of 5
yield
entry
base
additive
molarity
(7a:8:9)b
1
2
3
4
5
6
7
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
none
none
none
none
PivOH
none
PivOH
1
1
1
1
1
2
2
0.3
0.3
0.3
0.5
0.5
0.5
0.5
5:1:0c
24:2:1
37:4:6
52:4:5
57:1:4
65:6:4
87:7:0d
(4) (a) Qin, C.; Lu, W. J. Org. Chem. 2008, 73, 7424. (b) Lafrance, M.;
Fagnou, K. J. Am. Chem. Soc. 2006, 128, 16496. (c) Wen, J.; Zhang, J.;
Chen, S.-Y.; Li, J.; Yu, X.-Q. Angew. Chem., Int. Ed. 2008, 47, 8897. (d)
Ackermann, L.; Mulzer, M. Org. Lett. 2008, 10, 5043. (e) Ackermann, L.;
´
Born, R.; Alvarez-Bercedo, P. Angew. Chem., Int. Ed. 2007, 46, 6364. (f)
Ackermann, L.; Althammer, A.; Born, R. Angew. Chem., Int. Ed. 2007,
45, 2619.
a Conditions: aryl halide (1 equiv), N-oxide (1 or 2 equiv), base (2 equiv),
Pd(OAc)2 (5 mol %), ligand (15 mol %), and PivOH (0 or 30 mol %) were
weighed into a vial, purged with argon, charged with toluene (0.3 or 0.5
M), and stirred at 110 °C overnight. b Determined by NMR analysis relative
to 1,3,5-trimethoxybenzene as an internal standard. c Compound 10 used
as ligand. d Isolated yields, 35% recovered 5.
(5) (a) Rodriguez, J.; Feraud, M. Spec. Chem. Mag. 2005, 25, 16–17.
(b) Fernandez, D.; Ahaidar, A.; Danelon, G.; Cironi, P.; Marfil, M.; Perez,
O.; Cuevas, C.; Albericio, F.; Joule, J. A.; Alvarez, M. Monatsh. Chem.
2004, 135, 615. (c) Fresneda, P. M.; Delgado, S.; Francesch, A.; Manzanares,
I.; Cuevas, C.; Molina, P. J. Med. Chem. 2006, 49, 1217. (d) Beswick, P.;
Gleave, R.; Swarbrick, M. Patent WO 0169241, 2005. (e) Tang, P. C.; Sun,
L.; McMahon, G. Patent US 6849641, 2005. (f) David, L.; Hansen, P. Patent
WO 099205, 2004. (g) Wang, T.; Wallace, O. B.; Zhang, Z.; Meanwell,
N. A.; Bender, J. A. Patent WO 0622551, 2001. (h) Benoit, S.; Gingras,
S.; Soundararajan, N. Patent WO 0822891, 2003.
subsequent work, particularly promising results were ob-
tained when utilizing palladium(II) acetate, Buchwald phos-
phine ligands,10 and carbonate bases. For example, by
employing DavePhos 1111 in a 3:1 ligand-to-metal ratio, the
NMR yield of 7a could be increased to 24% (entry 2). The
use of cesium carbonate instead of potassium carbonate as
base was found to further increase the yield to 37% (entry
3). Increasing the concentration from 0.3 to 0.5 M also
provided an improvement to 52% NMR yield (entry 4), and
a 57% yield could be reached by the addition of 30 mol %
(6) Reviews on azaindoles: (a) Prokopov, A. A.; Yakhontov, L. N.
Pharm. Chem. J. 1994, 28, 1573. (b) Song, J. J; Reeves, J. T.; Gallou, F.;
Tan, Z.; Yee, N. K.; Senanayake, C. H. Chem. Soc. ReV. 2007, 36, 1120.
(c) Yakhontov, L. N. Russ. Chem. ReV. 1968, 37, 551.
(7) Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897.
(8) (a) Campeau, L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-Laperle,
M.; Villemure, E.; Sun, H.-Y.; Lasserre, S.; Guimond, N.; Lecavallier, M.;
Fagnou, K. J. Am. Chem. Soc. 2009, in press, DOI: 10.1021/ja808332k.
(b) Schipper, D. J.; Campeau, L.-C.; Fagnou, K. Tetrahedron, in press, DOI:
10.1016/j.tet.2008.12.004. (c) Campeau, L.-C.; Schipper, D. J.; Fagnou, K.
J. Am. Chem. Soc. 2008, 130, 3266. (d) Campeau, L.-C.; Bertrand-Laperle,
M.; Leclerc, J.-P.; Villemure, E.; Gorelsky, S.; Fagnou, K. J. Am. Chem.
Soc. 2008, 130, 3276. (e) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int.
Ed. 2006, 45, 7781. (f) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am.
Chem. Soc. 2005, 127, 18020. A related strategy with N-iminopyridinium
ylides: (g) Larive´e, A.; Mousseau, J. J.; Charette, A. B. J. Am. Chem. Soc.
2008, 130, 52. (h) Mousseau, J. J.; Larive´e, A.; Charette, A. B. Org. Lett.
2008, 10, 1641.
(10) For a review of these ligands in Pd-catalyzed amination, see: Surry,
D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338.
(11) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722.
(9) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926.
1358
Org. Lett., Vol. 11, No. 6, 2009