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useful benzyne precursors 2d and 2e reacted with 1e, giving
products 4k and 4l in 70% and 63% yields, respectively.
The catalytic reaction was further tested with other N-methyl
benzamides (Scheme 3). N-Methyl benzamide (6a) underwent
cyclization with 2a, providing N-methyl phenanthridinone 7a in
49% yield, in which ortho C–H bond activation takes place
selectively at the sterically less hindered side. Further, N-methyl
4-methoxy benzamide (6b) and N-methyl benzamide (6c) reacted
with 2a or 2c affording cyclization products 7b–d in 45%, 43% and
38% yields, respectively. Treatment of N-methyl benzamide 6d
with 1a gave natural product N-methylcrinasiadine9b (7e) in 30%
yield and other regioisomer 7e0 in 25% yield. It is important to
point out that natural product N-methylcrinasiadine (7e) shows
several biological activities.1
Scheme 5 Mechanistic investigation.
N–H arylation of benzamide with benzyne providing compound 3
followed by intramolecular dehydrogenative aryl–aryl coupling are
also possible.7 To support the proposed mechanism in Scheme 4,
the following reactions were done (Scheme 5). ortho-Arylated
benzamide 12 was prepared separately and treated with Pd(OAc)2,
CsF and K2S2O8 in CH3CN at 100 1C for 12 h. In the reaction, no
cyclization product 4a was observed. Subsequently, N-arylated
benzamide 3a was treated with Pd(OAc)2 and K2S2O8 under similar
reaction conditions. However, no cyclization product 4a was
observed. Further, a five-membered palladacycle intermediate 5b
was prepared separately and treated with benzyne precursor 2a in
the presence of CsF in CH3CN at 100 1C for 12 h. As expected, the
cyclization product 4f was observed in 75% yield. These results
clearly revealed that the present reaction proceeds via a coordina-
tive insertion pathway. To support the hypothesis that benzyne is
involved in the cyclization reaction, the reaction of benzamide 1e
with unsymmetrical benzyne precursor 2g was performed. In the
reaction, a mixture of regioisomeric compounds 4n and 4n0 was
observed in 53% combined yield in a 2 : 1 ratio. The lack of
regioselectivity of the reaction is consistent with insertion of
unsymmetrical benzyne into a Pd–carbon bond in intermediate 5.
In conclusion, we have demonstrated a palladium-catalyzed
oxidative cyclization of N-substituted benzamides with benzynes
providing phenanthridinones with diverse substituents.
(2)
Later, OMe groups on the cyclic amides of 4c and 4d were
cleaved into the natural product phenaglydon9a,b 8a in 69%
yield and 6(5H)-phenanthridinone 8b in 67% yield under the
photochemical irradiation conditions7a,b (eqn (2)). Later, com-
pound 8b underwent nitration at the C-5 position of phenan-
thridinone in the presence of HNO3/H2SO4, providing 5-nitro
phenanthridinone 9 in 75% yield. It is important to note that
compound 9 is a key precursor for the preparation of anti-
cancer drug PJ34.9c
A possible reaction mechanism is proposed in Scheme 4 to
account for the present cyclization reaction. Coordination of
the amide nitrogen of benzamide 1 to the palladium species
followed by ortho-metalation provides a five-membered pallada-
cycle intermediate 5. Coordinative insertion of benzyne 10 into
intermediate 5 yields a seven-membered palladacycle intermediate
11. Subsequent C–N bond formation and reductive elimination
afford product 4 and regenerate the active palladium species in the
presence of RCOOH and K2S2O8.
We thank the DST (SR/S1/OC-26/2011), India for the support
of this research. S. P. thanks the BRNS for a fellowship.
Apart from the above proposed mechanism, other possible
pathways such as ortho-arylation of benzamide with benzyne yield-
ing product 12 followed by intramolecular C–N bond formation or
Notes and references
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H. Abe and Y. Takeuchi, J. Chem. Soc., Perkin Trans. 1, 2001, 523;
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Scheme 4 Proposed mechanism.
12118 | Chem. Commun., 2014, 50, 12116--12119
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