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Published on the web June 12, 2010
Rhodium-catalyzed Oxidative Coupling/Cyclization of Benzamides
with Alkynes via C-H Bond Cleavage
Satoshi Mochida, Nobuyoshi Umeda, Koji Hirano, Tetsuya Satoh,* and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871
(Received April 28, 2010; CL-100415; E-mail: satoh@chem.eng.osaka-u.ac.jp, miura@chem.eng.osaka-u.ac.jp)
Oxidative coupling of primary, secondary, and tertiary
synthesis of more complex molecules.9 Recently, transition-
metal-catalyzed coupling reactions of o-substituted benzamides
have been shown to be applicable to the simple construction of
isoquinolinone frameworks.10 Our protocol provides a more
straightforward approach from readily available parent benz-
amides.
benzamides with internal alkynes proceeds efficiently under
rhodium catalysis to selectively give the corresponding 1:1 and
1:2 coupling products, accompanied by C-H and/or N-H bond
cleavages. Some of the products exhibit intense fluorescence in
the solid state.
In addition to such primary and secondary benzamides,
tertiary compounds also underwent the rhodium-catalyzed
oxidative coupling with alkynes via two C-H bond cleavages.
These new findings are described herein.
The transition-metal-catalyzed C-C bond formation reac-
tions via C-H bond cleavage have attracted much attention from
the atom- and step-economical point of view, and have been
significantly developed in recent years.1 Particularly, the
reactions of aromatic substrates possessing a directing group
such as carbonyl and imino functions are powerful synthetic
tools, because they allow regioselective C-H activation and
functionalization at the ortho-positions. Besides the directing
groups containing a neutral heteroatom, an amide group can also
act as a good anchor to exhibit the proximate effect.2,3 Thus, we
previously reported the palladium-catalyzed arylation2a-2c and
vinylation reactions2d of aromatic amides with aryl halides and
alkenes, respectively. In the context of our further study of
regioselective C-H functionalization,4 we have undertaken the
coupling of amides with alkynes. As a result, the oxidative
coupling of N-free benzamide with diphenylacetylene has been
found to proceed smoothly accompanied by regioselective C-H
bond cleavage by using a rhodium catalyst and a copper oxidant.
In this case, to our surprise, not their 1:1 but unexpected 1:2
coupling product was obtained predominantly (R = H in
Scheme 1). The tetracyclic structure, constructed via the 1:2
coupling, can be seen in various naturally occurring and
synthetic compounds that exhibit a broad range of interesting
biological and optoelectronic properties.5 Its construction usu-
ally needs complicated multisteps with huge effort.5,6
In an initial attempt, benzamide (1a) (0.5 mmol) was treated
with diphenylacetylene (2a) (0.5 mmol) in the presence of
[Cp*RhCl2]2 (0.005 mmol, Cp* = pentamethylcyclopentadien-
yl) and Cu(OAc)2¢H2O (1 mmol) as catalyst and oxidant,
respectively, in o-xylene at 100 °C for 10 h under N2. As
described above, the 1:2 coupling product, 5,6,13-triphenyl-8H-
dibenzo[a,g]quinolizin-8-one (3a), was obtained in 39% isolated
yield (Entry 1 in Table 1). It was confirmed by GC-MS analysis
of the resulting mixture that the corresponding 1:1 coupling
product, N-free isoquinolinone [I (R = H) in Scheme 1], was
also formed (ca. 30%). The latter was sparingly soluble in
organic solvents. Therefore, it is possible that part of this
intermediate precipitated during the reaction to result in the
moderate yield of 3a. Expectedly, the reactions using alkyl-
substituted diphenylacetylenes 2b and 2c in place of 2a gave
more soluble products 3b and 3c, respectively, in enhanced
yields (Entries 2 and 3). Methoxy-substituted product 3d was
also obtained under similar conditions (Entry 4). Similarly, 4-
substituted benzamides 1b-1d also coupled with 2c in the ratio
of 1:2 to produce the corresponding product 3e-3g (Entries 5-7).
A plausible mechanism for the 1:2 coupling of 1a with 2a
via directed metalation involving intermediates A-E is illus-
trated in Scheme 2, in which neutral ligands are omitted. In
the cyclorhodation steps from A and D, coordination of the
nitrogen atom to a RhIII species appears to be the key for the
regioselective C-H bond cleavage.
We next examined the reaction of a secondary amide,
benzanilide (4a) with 2a under similar conditions to those for
the reaction of 1. Thus, in the presence of the [Cp*RhCl2]2/
Cu(OAc)2¢H2O catalyst system, the 1:1 coupling efficiently took
place to afford 2,3,4-triphenylisoquinolin-1(2H)-one (5a) in
75% yield (Entry 1 in Table 2). The reaction of 4a with
diarylacetylenes 2c-2e also proceeded smoothly to produce the
corresponding 3,4-diaryl-2-phenylisoquinolin-1(2H)-one 5b-5d
in good yields (Entries 2-4). 1-Phenyl-1-propyne (2f) reacted
with 4a to give 4-methyl-2,3-diphenylisoquinolin-1(2H)-one
(5e) predominantly, along with a minor amount of a regioisomer
(Entry 5). Similarly, from the reaction of 1-phenyl-1-hexyne
(2g) with 4a, 4-butyl-2,3-diphenylisoquinolin-1(2H)-one (5f)
was obtained along with its regioisomer (Entry 6).11 N-Aryl (4b
and 4c) as well as N-butylbenzamides (4d) underwent the
In the reaction of N-monosubstituted benzamides (R º H in
Scheme 1) with alkynes under similar conditions, on the other
hand, the expected 1:1 coupling products, isoquinolin-1(2H)-one
derivatives, could be obtained selectively.7 Such a fused
heteroaromatic skeleton is also of interest because it is found
in various natural products such as dorianine and ruprechstyril8
and has been utilized in versatile building blocks for the total
O
O
O
R
H
N
R
N
N
H
R = H
H
S
I (1:1)
P (1:2)
Scheme 1.
Chem. Lett. 2010, 39, 744-746
© 2010 The Chemical Society of Japan
Mochida, Satoshi
