pubs.acs.org/joc
is very important due to their wide biological and photo- and
Rh-Catalyzed Oxidative Coupling between Primary
and Secondary Benzamides and Alkynes: Synthesis
of Polycyclic Amides
electrochemical applications.2 Among them, isoquinolones are
important structural motifs in various natural products.3
Recent seminal work on the synthesis of isoquinolones by the
group of Murakami4 and the group of Kurahashi and
Matsubara5 focused on nickel-catalyzed denitrogenative inser-
tion of alkynes into benzotriazin-4(3H)-ones and the decarbo-
nylative insertion of alkynes into phthalimides, respectively. In
these systems, five-membered metalacycles have been proposed
as key intermediates. We envision that an atom-economic
synthesis of isoquinolones from simple benzamides and
alkynes can be advantageous by way of chelation-assisted
C-H activation under rhodium-catalyzed oxidative condi-
tions. Recently, Fagnou,6 Satoh and Miura,7 Jones,8 and
Glorius9 have independently reported the important and useful
Rh-catalyzed oxidative coupling reactions between arenes or
heteroarenes and alkynes or alkenes, wherein the active five- or
six-membered organorhodium species were generated with the
assistance of directing groups such as amides,6b,9a carboxyls,7e
hydroxyls,7g,i imines,7a and other N atoms.7b,f,h Considering
that amides are readily available, the ortho Caryl-H activation
of secondary acetanilides has been well documented in oxida-
tive coupling with alkenes or alkynes catalyzed by Pd(II)10 and
Rh(III).6b,9a In the case of benzamides bearing N-aryl groups
such as 1, complication of selectivity of C-H activation can
arise as to which arene undergoes C-H activation. To the best
of our knowledge, no such selectivity has been examined,11
Guoyong Song,† Dan Chen,† Cheng-Ling Pan,†
Robert H. Crabtree,§ and Xingwei Li*,†,‡
†Dalian Institute of Chemical Physics, Chinese Academy of
Sciences, Dalian, China 116023, ‡The Scripps Research
Institute, Scripps Florida, Jupiter, Florida 33458,
§
United States, and Chemistry Department, Yale University,
New Haven, Connecticut 06520, United States
Received August 23, 2010
(2) For selected examples, see: (a) Abet, V.; Nunez, A.; Mendicuti, F.;
Burgos, C.; Alvarez-Builla, J. J. Org. Chem. 2008, 73, 8800. (b) Ahmed, E.;
Briseno, A. L.; Xia, Y.; Jenekhe, S. A. J. Am. Chem. Soc. 2008, 130, 1118.
(c) Parenty, A. D. C.; Song, Y.-F.; Richmond, C. J.; Cronin, L. Org. Lett.
2007, 9, 2253. (d) Barrio, J. R.; Sattsangi, P. D.; Gruber, B. A.; Dammann,
L. G.; Leonard, N. J. J. Am. Chem. Soc. 1976, 98, 7408.
(3) (a) Le, T. N.; Gang, S. G.; Cho, W.-J. J. Org. Chem. 2004, 69, 2768.
(b) Ruchelman, A. L.; Houghton, P. J.; Zhou, N.; Liu, A.; Liu, L. F.; LaVoie,
E. J. J. Med. Chem. 2005, 48, 792.
(4) Miura, T.; Yamaushi, M.; Murakami, M. Org. Lett. 2008, 10, 3085.
(5) Kajita, Y.; Matsubara, S.; Kurahashi, T. J. Am. Chem. Soc. 2008, 130, 6058.
(6) (a) Guimond, N.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050.
(b) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K.
J. Am. Chem. Soc. 2008, 130, 16474.
(7) (a) Fukutani, T.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Chem.
Commun. 2009, 5141. (b) Umeda, N.; Hirano, K.; Satoh, T.; Miura, M.
J. Org. Chem. 2009, 74, 7094. (c) Ueura, K.; Satoh, T.; Miura, M. J. Org.
Chem. 2007, 72, 5362. (d) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9,
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74, 6295. (f) Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010,
12, 2068. (g) Uto, T.; Shimizu, M.; Ueura, K.; Tsurugi, H.; Satoh, T.; Miura,
M. J. Org. Chem. 2008, 73, 298. (h) Umeda, N.; Tsurugi, H.; Satoh, T.;
Miura, M. Angew. Chem., Int. Ed. 2008, 47, 4019. (i) Mochida, S.; Shimizu,
M.; Hirano, K.; Satoh, T.; Miura, M. Chem. Asian J. 2010, 5, 847.
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12414.
A methodology for the high yield and facile synthesis of
isoquinolones from benzamides and alkynes via the oxidative
ortho C-H activation of benzamides has been developed.
Ag2CO3 proved to be an optimal oxidant when MeCN was
used as a solvent, and [RhCp*Cl2]2 was utilized as an efficient
catalyst. Both N-alkyl and N-aryl secondary benzamides can
be applied as effective substrates. Furthermore, primary
benzamides react with two alkyne units, leading to tricyclic
products via double C-H activation and oxidative coupling.
The reactivity of the structurally related 1-hydroxyisoquino-
line was also demonstrated, where both N- and O-containing
rhodacyclic intermediates can be generated, leading to the
construction of different O- or N-containing heterocycles.
In the past decade, catalytic activation of C-H bonds has
become an increasingly important strategy for the elaboration
of readily available simple substrates to complex products in an
atom-economic fashion.1 In this context, the construction of
nitrogen-containing heterocycles via (directed) C-H cleavage
(9) (a) Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9982.
(b) Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132,
9585.
(10) (a) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew. Chem., Int. Ed.
2008, 47, 1115. (b) Wan, X.; Ma, Z.; Li., B.; Zhang, K.; Cao, S.; Zhang, S.;
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Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.;
van Leeuwen, P.W. N. M. J. Am. Chem. Soc. 2002, 124, 1586. (d) Giri, R.;
Lam, J. K.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 686.
(11) During the preparation of this manuscript, similar studies leading to
isoquinolone synthesis catalyzed by Rh(III) were reported by the groups of T.
Rovis and M. Miura; see: (a) Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010,
132, 10565. (b) Mochida, S.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M.
Chem. Lett. 2010, 39, 744.
(1) For leading reviews, see: (a) Colby, D. A.; Bergman, R. G.; Ellman, J. A.
Chem. Rev. 2010, 110, 624. (b) Sun, C.-L.; Shi, Z.-J. Chem. Commun. 2010, 46,
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2009, 48, 5094. (d) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int.
Ed. 2009, 48, 9792. (e) Xu, L.-M.; Yang, Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39,
712. (f) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (g) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. Rev. 2007, 107, 3013. (h) Satoh, T.; Miura, M. Top.
Organomet. Chem. 2008, 24, 61. (i) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev.
2002, 102, 1731. (j) Kakiuchi, F.; Murai, S. Acc. Chem. Res. 2002, 35, 826.
(k) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698.
DOI: 10.1021/jo101596d
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Published on Web 10/05/2010
J. Org. Chem. 2010, 75, 7487–7490 7487
2010 American Chemical Society