Published on the web September 5, 2011
1047
Synthesis of Phenanthridinones and Phenanthridine Derivatives
through Palladium-catalyzed Oxidative C-H Coupling of Benzanilides
Naoki Ishida, Yuuta Nakanishi, Taisaku Moriya, and Masahiro Murakami*
Department of Synthetic Chemistry and Biological Chemistry, Kyoto University, Katsura, Kyoto 615-8510
(Received June 30, 2011; CL-110551; E-mail: murakami@sbchem.kyoto-u.ac.jp)
A palladium-catalyzed oxidative C-H coupling reaction of
benzanilides using molecular oxygen as the oxidant furnishes
phenanthridinones. The palladium-catalyzed reaction in combi-
nation with simple derivatization provides an efficient access to
a phenanthridine skeleton starting from readily available benzoic
acids and anilines.
Phenanthridine is an important structural motif which is
found in a number of natural products1 and fluorescent
chromophores.2 Although a number of reactions to construct a
Scheme 1. Synthetic pathway to phenanthridines.
phenanthridine skeleton have been reported,3,4 the search for
better properties with such compounds requires more efficient
synthetic methods equipped with structural diversity using
Table 1. Optimization of reaction conditionsa
readily available building blocks. This led us to envisage a
synthetic pathway starting from benzoic acids and anilines
leading to phenanthridines via phenanthridinones, as shown in
Scheme 1. Benzanilide is readily synthesized by condensation
of benzoic acid and aniline. Phenanthridinone is obtained by an
oxidative C-H coupling reaction of benzanilide, for which a
palladium/tin cocatalyst system is known to be effective.5-7 The
secondary amide moiety of phenanthridinone can be activated
by triflation for further transformations, leading to the synthesis
of 6-substituted phenanthridines. Since a wide variety of anilines
and benzoic acids are available from commercial sources, this
synthetic pathway would give rise to significant structural
diversity. In this paper, we describe the tin-free palladium-
catalyzed oxidative C-H coupling reaction of N-H benzanilides
and its application to the synthesis of phenanthridine derivatives.
We initially reexamined the reaction conditions for
palladium-catalyzed oxidative C-H coupling of benzanilide
(Table 1). When 1a was heated at 120 °C for 24 h in the presence
of Pd(OAc)2 (5 mol %) under an oxygen atmosphere (1 atm) in
acetic acid, phenanthridinone 2a was formed in 14% NMR yield
(Entry 1). Palladium(II) trifluoroacetate was more reactive than
Pd(OAc)2, giving 2a in 27% yield under otherwise identical
conditions (Entry 2). The yield varied depending on the solvents
and we found that melted benzoic acid afforded a relatively good
result. In particular, when benzanilide 1a was heated at 150 °C
for 48 h in the presence of 7 mol % of Pd(OCOCF3)2 under an
oxygen atmosphere (1 atm) in melted benzoic acid, phenanthri-
dinone 2a was obtained in 91% isolated yield (Entry 6). In
contrast, only a small amount of 2a was produced when other
nonprotic solvents such as toluene, DCE (1,2-dichloroethane),
and NMP (N-methylpyrrolidone) were employed and 5 equiv of
benzoic acid was added therein.
Entry
Pd
Solvent
Yield/%b
1
2
3
4
5
6c
Pd(OAc)2
AcOH
AcOH
t-BuCOOH
CF3COOH
PhCOOH
PhCOOH
14
27
12
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
Pd(OCOCF3)2
not detected
42
92 (91)
aReaction conditions: 0.10 mmol 1a, 5 mol % Pd, 1.0 mL
solvent or 1.0 g PhCOOH, 120 °C, 24 h, O2 atmosphere
(1 atm) unless otherwise noted. NMR yield. Isolated yield is
b
c
in parentheses. 7 mol % Pd(OCOCF3)2, 150 °C, 48 h.
systems for cross-coupling of anilides with benzenes developed
by Shi (5 mol % Pd(OAc)2, 10 mol % Cu(OTf)2, EtCOOH, O2,
120 °C, 24 h)6a and Buchwald (5 mol % Pd(OAc)2, 10 mol %
DMSO, 5 equiv CF3COOH, benzene, O2, 120 °C, 24 h)6b gave
2a in 11% and <5% yields, respectively. No reaction was
observed when 1a was subjected to the reaction conditions
reported by Dong7 (10 mol % Pd(OAc)2, 4 equiv Na2S2O8, 5
equiv CF3COOH, DCE, 70 °C). Thus, our conditions proved to
be efficient and environmentally friendly in comparison with the
reported conditions.
Next, the palladium-catalyzed oxidative C-H coupling
reaction of 1a was carried out in melted PhCOOD in order to
gain mechanistic insight (eq 1). When the reaction at 150 °C
was stopped after 10 h, a mixture of benzanilide 1a (46%
recovery) and phenanthridinone 2a (48% yield) was obtained.
Deuterium incorporation was detected by integration values
in the 1H NMR spectra of both compounds. With recovered
benzanilide 1a, 33% deuterium incorporation was observed at
For comparison, we conducted oxidative C-H coupling
of 1a under the reaction conditions which were previously
reported for analogous oxidative C-H coupling of anilides.5-7
With a Pd(OCOCF3)2/Sn(OAc)2 cocatalyst system reported by
¡kermark,5b 2a was obtained in 38% yield. The catalytic
Chem. Lett. 2011, 40, 1047-1049
© 2011 The Chemical Society of Japan