synthesis of biaryls.6 Fagnou and DeBoef independently
reported that Pd(II) can catalyze the oxidative cross-
coupling between a heteroarene and a carbocyclic
arene.7 In particular, recent studies by the groups of
Fagnou,8 Hiyama,9 Chang,10 Hu and You,11 and Cui
and Wu12 have shown that N-oxides of pyridines and
quinolines can undergo C-H functionalization at the
2-position in a Pd- and Ni-catalyzed cross-coupling with
arenes, heteroarenes, arylhalides, and olefins. Here
bench-stable pyridine N-oxides can be regarded as a
useful surrogate of 2-pyridyl organometallics and they
function as an activated form of pyridine.13 Given the
significance of 2-aryl- and 2-vinylpyridines in mate-
rial and medicinal chemistry, these processes represent
powerful and atom-economic methods to access func-
tionalized pyridines. Despite an increasing number
of reports, 2-fold oxidative C-H functionalization re-
mains a great challenge, especially when one of the
coupling partners is an indole. This is because indoles
are electron-rich heteroarenes that often undergo de-
composition under oxidative conditions.7d In addition,
azoles are also susceptible to oxidative homo-
coupling.14 For example, DeBoef reported that the
reaction conditions optimal for the Pd(II)-catalyzed
oxidative coupling of benzofuran were inapplicable
for indoles.7d We now report an oxidative cross-cou-
pling between pyridine N-oxides and N-substituted
indoles, where the functionalization occurred at the
3-position of indoles.
You, Hu, and co-workers recently reported a Pd(II)-
catalyzed, copper(I)-promoted oxidative cross-coupling
between pyridine N-oxides and electron-rich heteroarenes
such as furans and thiophenes, where Cu(OAc)2 H2O was
3
used as an oxidant (eq 1).11 When we applied these
conditions and attempted to extend the heteroarene part-
ners toindoles suchasN-benzyl indole, the desired product
3aa was obtained in only 12% NMR yield, together with
decomposition products (Table 1, entry 1). Thus further
screening of the reaction conditions is necessary. When
Pd(OAc)2 (10 mol %) was used as a catalyst and Ag2CO3
(2.3 equiv) as an oxidant (DMF, 135 °C), this reaction
proceeded to give the coupled product in 35% NMR yield
(entry 2, Table 1). The addition of 4 equiv of pyridine
proved to be beneficial, and the yield was improved to
45%. Pyridine has been often used as an additive in
palladium-catalyzed oxidation reactions,15 and it likely
serves to stabilize the palladium(II) catalyst.
Table 1. Synthesis of a 3-(2-Pyridyl)-indolea
(6) For recent reviews, see: (a) Colby, D. A.; Bergman, R. G.; Ellman,
J. A. Chem. Rev. 2010, 110, 624. (b) Chen, X.; Engle, K. M.; Wang,
D. H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (c) Xu, L.-M.;
Yang, Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712. (d) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 3013. (e) Satoh, T.;
Miura, M. Top. Organomet. Chem. 2008, 24, 61. (f) Ritleng, V.; Sirlin, C.;
Pfeffer, M. Chem. Rev. 2002, 102, 1731. (g) Kakiuchi, F.; Murai, S. Acc.
Chem. Res. 2002, 35, 826. (h) Sun, C.-L.; Shi, Z.-J. Chem. Commun. 2010,
46, 677.
(7) (a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (b)
Liegault, B.; Lee, D.; Huestis, M. P.; Stuart, D. S.; Fagnou, K. J. Org.
Chem. 2008, 73, 5022. (c) Stuart, D. S.; Villemure, E.; Fagnou, K. J. Am.
Chem. Soc. 2007, 129, 12072. (d) Liegault, B.; Fagnou, K. Organo-
metallics 2008, 27, 4841. (e) Dwight, T. A.; Rue, N. R.; Charyk, D.;
Josselyn, R.; DeBoef, B. Org. Lett. 2007, 9, 3137. (f) Potavathri, S.;
Pereira, K. C.; Gorelsky, S. I.; Pike, A.; LeBris, A. P.; DeBoef, B. J. Am.
Chem. Soc. 2010, 132, 14676.
(8) (a) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem.
Soc. 2005, 127, 18020. (b) Campeau, L.-C.; Schipper, D. J.; Fagnou, K.
J. Am. Chem. Soc. 2008, 130, 3266. (c) 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, 131, 3291. (d) Leclerc, J.-P.; Fagnou, K. Angew. Chem., Int.
Ed. 2006, 45, 7781. (e) Huestis, M. P.; Fagnou, K. Org. Lett. 2009, 11,
1357. (f) Lapointe, D.; Markiewicz, T.; Whipp, C. J.; Toderian, A;
Fagnou, K. J. Org. Chem. 2010, 76, 749. (g) Schipper, D. J.; El-Salfiti,
M.; Whipp, C. J.; Fagnou, K. Tetrahedron 2009, 65, 4977.
(9) Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Angew. Chem., Int. Ed.
2007, 46, 8872.
additive
(mol %)b
yield
(%)c
oxidant
base
1d
2
Cu(OAc)2 H2O
pyridine
none
CuBr (10%)
none
12
35
45
18
22
3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
3
pyridine
Cs2CO3
K2CO3
none
4
none
5
none
6
pyridine
pyridine
pyridine
pyridine
pyridine
none
TBAB (20%)
TBAF (20%)
TBAC (20%)
TBAB (10%)
TBAB (40%)
PivOH (30%)
TBAB (20%)
88 (83e, 81f)
7
<10
<10
48
8
9
10
11
54
70
a Conditions: N-benzyl indole (0.5 mmol), pyridine N-oxides (4
equiv), Pd(OAc)2 (10 mol %), oxidant (2.3 equiv), base (4 equiv),
additive, DMF (3 mL), 135 °C, 20 h. b TBAB = tetrabutylammonium
bromide, TBAF = tetrabutylammonium fluoride, TBAC = tetrabuty-
lammonium chloride. c NMR yield using 1,3,5-trimethoxybenzene as
(10) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130,
9254.
(11) Xi, P.; Yang, F.; Qin, S.; Zhao, D.; Lan, J.; Gao, G.; Hu, C.;
You, J. J. Am. Chem. Soc. 2010, 132, 1822.
(12) Wu, J.; Cui, X.; Chen, L.; Jiang, G.; Wu, Y. J. Am. Chem. Soc.
a standard. d Cu(OAc)2 H2O (2.5 equiv), CuBr (10 mol %), pyridine
3
(1 equiv), 1,4-dioxane (3 mL). e 5 mol % Pd(OAc)2. f Isolated yield using
5 mol % Pd(OAc)2.
2009, 131, 13888.
(13) Deng, G.; Ueda, K.; Yanagisawa, S.; Itami, K.; Li, C.-J.
Chem.;Eur. J. 2009, 15, 333.
(14) (a) Li, Y.; Jin, J.; Qian, W.; Bao, W. Org. Biomol. Chem. 2010, 8,
326. (b) Monguchi, D.; Yamamura, A.; Fujiwara, T.; Somete, T.; Mori,
A. Tetrahedron Lett. 2010, 51, 850. (c) Truong, T.; Alvarado, J.; Tran,
L. D.; Daugulis, O. Org. Lett. 2010, 12, 1200.
We noted that when pyridine was replaced with other
basic additives suchasK2CO3 andCs2CO3, aloweryield of
3aa was obtained (entries 4 and 5). Further improvement
Org. Lett., Vol. 13, No. 7, 2011
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