the solvent (entries 8 and 9). As to the catalyst working
mode,14 it is notable that well-defined ruthenium(II) car-
boxylate complex [Ru(O2CMes)2(p-cymene)] (6) turned
out to becatalytically competentaswell(entries 10and 11).
With optimized reaction conditions in hand, we ex-
plored the scope of the in situ generated catalyst in direct
arylations with differently substituted indole derivatives 1
(Scheme 1). The catalytic system proved broadly applic-
able and tolerated various valuable functional groups as
well as additional heteroaromatic moieties. Decoration on
Table 1. Optimization Studies for the Direct Arylation of Indole
1aa
entry
L
yield
(4) For representative recent reports on transition-metal-catalyzed
direct arylations of heteroarenes, see: (a) Kirchberg, S.; Tani, S.; Ueda,
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Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2010, 75, 7863–7868. (k)
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Buttner, L. Org. Lett. 2010, 12, 2056–2059. (l) Roy, D.; Mom, S.;
Beauperin, M.; Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2010,
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1
---
---
2
KOAc (30 mol %)
57%
72%
61%
68%
71%
84%
---b
3
(1-Ad)2P(O)H (4) (10 mol %)
MesCO2H (5a) (30 mol %)
4
5
t-BuCO2H (5b) (30 mol %)
6
(1-Ad)CO2H (5c) (10 mol %)
7
(1-Ad)CO2H (5c) (30 mol %)
8
(1-Ad)CO2H (5c) (30 mol %)
9
(1-Ad)CO2H (5c) (30 mol %)
---c
10
11
[Ru(O2CMes)2(p-cymene)]d (6) (5.0 mol %)
[Ru(O2CMes)2(p-cymene)]d (6) (2.0 mol %)
78%
51%
a Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), [RuCl2-
(p-cymene)]2 (2.5 mol %), L, m-xylene (2.0 mL), 120 °C, 22 h, yields of
isolated products. b In NMP (2.0 mL). c With H2O (2.0 mL). d Instead of
[RuCl2(p-cymene)]2.
€
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the indole backbone was not detrimental to catalytic
efficacy, which even allowed for high-yielding direct aryla-
tions of sterically demanding 1,3-disubstituted indoles.
However, lower yields of isolated products3 were obtained
when using ortho-substituted aryl halides. With respect to
the preparation of bioactive compounds it is noteworthy
that the high catalytic activity set the stage for direct CÀH
€
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(11) For remarkable progress in palladium-catalyzed CÀH bond
functionalizations through the use of removable directing groups, see:
ꢀ
´
ꢀ
ꢀ~
ꢀ
(a) GarcUa-Rubia, A.; Fernandez-Ibanez, M. A.; Arrayas, R. G.;
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(8) For representative subsequent contributions, see: Direct alkyla-
ꢀ
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ꢀ
ꢀ
aromatic heterocycles using boron-based reagents, see: (h) Prokopcova,
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(12) Intermolecular competition experiments between 2-pyridyl-sub-
stituted benzene and N-2-pyridyl-substituted indole revealed the latter
to be functionalized preferentially (ratio: 9/91; Scheme S-1 in the
Supporting Information). Attempted ruthenium-catalyzed direct aryla-
tions of free (NH)-indole did not meet with success.
(13) Reviews: (a) Ackermann, L. Isr. J. Chem. 2010, 50, 652–663.
(b) Ackermann, L. Synthesis 2006, 1557–1571.
(14) Reactions with isotopically labeled starting materials and inter-
molecular competition experiments suggested the CÀH bond metalation
to be reversible in nature (Schemes S-2 and S-3 in the Supporting
Information).
Lett. 2009, 11, 4966–4969. An elegant application on scale: (c) Ouellet,
S. G.; Roy, A.; Molinaro, C.; Angelaud, R.; Marcoux, J.-F.; O’Shea,
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(10) For select reviews on the preparation of indoles, see: (a) Cacchi,
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€
Kruger, K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008, 350, 2153–
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therein.
(15) For palladium-catalyzed direct arylations of electron-deficient
pyridines through chelation assistance, see: Wasa, M.; Worrell, B. T.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2010, 49, 1275–1277.
Org. Lett., Vol. 13, No. 13, 2011
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