Communications
DOI: 10.1002/anie.201005874
À
C H Activation
À
À
One-Pot Formation of C C and C N Bonds through Palladium-
Catalyzed Dual C H Activation: Synthesis of Phenanthridinones**
À
Guan-Wu Wang,* Ting-Ting Yuan, and Dan-Dan Li
À
Palladium-catalyzed C H activation has emerged in recent
years as one of the most sustainable and intriguing protocols
Aryl iodides have been widely employed in palladium-
catalyzed ligand-directed arylation reactions.[6] Therefore, we
chose the reaction of N-methoxybenzamide (1a) with phenyl
iodide (2a) catalyzed by Pd(OAc)2 as the model reaction to
verify our assumption and to screen the optimal conditions.
Silver salts have been widely used as oxidants in palladium-
catalyzed arylation and lactamization reactions.[2,3,6] We first
examined the model reaction with AgOAc as the oxidant and
CF3COOH as the solvent. However, the desired product 3aa
was not obtained (Table 1, entry 1). Other solvents such as
1,4-dioxane, 1,2-dichloroethane, and toluene were also inef-
fective. When AcOH was used as the solvent, product 3aa
À
À
À
À
À
to construct C C, C O, C N, C S, and C X (X = halogen)
bonds, and has been employed in the synthesis of pharma-
ceuticals and natural products.[1] A directing group is com-
monly required to achieve high regioselectivity in a C H
activation reaction. Among the directing groups, the utiliza-
À
3
À
tion of the CONHOMe group in the arylation of sp C H
À
bonds through palladium-catalyzed C C bond formation was
first discovered by Yu and co-workers.[2] Subsequently, Wasa
and Yu exploited the same directing group in intramolecular
cyclization reactions, thus affording lactam derivatives
through the palladium-catalyzed formation of C N bonds.
Nevertheless, the cascade formation of C C and C N bonds
[3]
À
À
À
Table 1: Screening conditions for the palladium-catalyzed reaction of
N-methoxybenzamide and phenyl iodide.[a]
À
through palladium-catalyzed C H activation in one pot is
quite challenging.[4] In continuation of our interest in the C H
À
activation of N-methoxybenzamides,[5] we envision that a
À
palladium-catalyzed intermolecular C C bond formation
could be coupled with another palladium-catalyzed intra-
À
molecular C N bond formation for a rapid synthesis of
biologically important phenanthridinones (Scheme 1). Herein
we report the one-pot cascade synthesis of phenanthridinones
by the palladium-catalyzed reaction of N-methoxybenza-
mides and aryl iodides with this strategy. This reaction results
in the breaking of four bonds and formation of two bonds.
Entry
Oxidant
Yield [%]
Entry
Oxidant
Yield [%]
1[b]
2
3
4
5
AgOAc
AgOAc
Ag2SO4
AgOTf
Ag2O
Trace
61
29
23
76
6[c]
7[d]
8
9
10
Ag2O
Ag2O
K2S2O8
Oxone
Cu(OAc)2
68
66
13
13
12
[a] Unless otherwise specified, all reactions were carried out with 1a
(0.5 mmol), 2a (1.0 mmol), Pd(OAc)2 (0.025 mmol), and oxidant
(1.0 mmol) in AcOH (5 mL) at 1208C for 36 h. [b] CF3COOH was used
as the solvent. [c] 0.5 mmol of 2a was used. [d] 0.5 mmol of Ag2O was
used.
was isolated in 61% yield (entry 2). Silver salts Ag2SO4 and
AgOTf could also promote the reaction, albeit in much lower
yields (entries 3 and 4). It turned out that Ag2O performed
best; the yield was improved to 76% (entry 5). Decreasing
the quantity of 2a or Ag2O from 2 equivalents to 1 equivalent
resulted in a lower yield of 68% and 66%, respectively
(entries 6 and 7 vs. entry 5). Disappointingly, when K2S2O8,
oxone, or Cu(OAc)2 was employed as the oxidant, the product
was isolated in very low yield (entries 8–10). In addition, the
reaction did not occur without oxidant or with PhI(OAc)2 and
benzoquinone as the oxidant. Therefore, 1 equivalent of 1a,
2 equivalents of 2a, and 2 equivalents of Ag2O were chosen as
the best conditions for the palladium-catalyzed reaction of 1a
with 2a in AcOH at reflux.
Scheme 1. Retrosynthesis of phenanthridinones.
[*] Prof. Dr. G.-W. Wang, T.-T. Yuan, D.-D. Li
Hefei National Laboratory for Physical Sciences at Microscale, CAS
Key Laboratory of Soft Matter Chemistry, Joint Laboratory of Green
Synthetic Chemistry, and Department of Chemistry, University of
Science and Technology of China
Hefei, Anhui 230026 (P. R. China)
Fax: (+86)551-360-7864
E-mail: gwang@ustc.edu.cn
[**] We are grateful for the financial support from the National Basic
Research Program of China (2006CB922003) and the National
Natural Science Foundation of China (20772117)
With the optimal conditions in hand, we next explored
other N-methoxybenzamides and aryl iodides to examine the
scope and limitation of the current reaction. The results are
summarized in Scheme 2. Benzamides with either electron-
Supporting information for this article is available on the WWW
1380
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 1380 –1383