access to the target molecules. Thus, from the point of view
of synthetic simplicity, the synthesis of R-substituted, het-
eroatom-substituted enones from simple arenes and readily
available heteroatom-substituted enones via twofold CꢀH
bond functionalization would be an ideal strategy. However,
the transition-metal-catalyzed intermolecular dehydrogena-
tive cross-coupling of heteroatom-substituted enones with
simple arenes via this strategy has not been reported to date,6
and to the best of our knowledge, only Pd-catalyzed direct
R-CꢀH functionalization of such enones with arylmetals7 or
alkenes8 has been developed. This strategy still faces intrinsic
challenges, suppressing undesired homocouplings. Consid-
ering the nucleophilic character of heteroatom-substituted
enones, we hypothesized that if electron-deficient polyfluor-
oarenes were chosen as the coupling partner, the difference
between the reactivities of the heteroatom-substituted en-
ones and polyfluoroarenes would facilitate the two metala-
tion steps of the catalytic cycle, and thus the dehydrogena-
tive cross-coupling of heteroatom-substituted enones with
simple arenes would be possible (Scheme 1). Furthermore,
polyfluoroarenes are a key structural motif found in various
functional molecules, such as pharmaceuticals, agrochem-
icals, liquid crystals, and electronic devices.9 Consequently,
the development of transition-metal-catalyzed methods for
introducing polyfluoroaryl groups into organic molecules
has been the subject of intense research. Despite significant
progress in the direct arylation of polyfluoroarenes,10,5hꢀj
there are few examples for introducing vinyl substituents.11
Given that C3 substituted 4-quinolones not only are
used for the antimicrobial and anticancer therapies but
also display significant antimalarial activity,12 we began
this study by choosing 1-methyl-4(1H)-quinolone 1a and
pentafluorobenzene 2a as model substrates (eq 1).
Initially, the reaction was carried out with 1a (1.0 equiv),
2a (3.0 equiv), Ag2CO3 (1.5equiv),andPd(OAc)2 (10mol%)
in DMF þ DMSO (5 equiv) at 120 °C, providing no desired
product 3a (see Table S1 in the Supporting Information).
Further switching of the solvent to DMSO also failed to
give 3a. After screening a series of reaction mediums, we
found that DMSO and dioxane are critical for the reaction
efficiency. The absence of DMSO or the use of a mixed
DMSO in other solvents was totally ineffective. Different
Pd-catalysts and oxidants were also examined (see Table
S2 in the Supporting Information), and Pd(OAc)2 and
Ag2CO3 were found to be the best choice, although only a
reasonable yield was obtained. Inspired by the importance
of DMSO in the reaction, a series of sulfides previously
demonstrated to have a beneficial effect on the dehydro-
genative cross-coupling of two simple arenes5j were tested
to further improve the reaction efficiency (see Table S1 in
the Supporting Information). To our delight, a 56%
isolated yield of 3a was obtained when 5.0 equiv of iPr2S13
and 3.0 equiv of Ag2CO3 were employed. Increasing the
reaction concentration or the Pd-catalyst loading gave no
further improvements in yield due to the difficulty in
suppressing the homocouplings of both coupling partners.
To improve the reaction efficiency further, we found the
optimal isolated yield (68%) and homocouplings of 1a and
2a (14%, based on 1a;11%, based on 2a) were afforded by
three consecutive additions of Pd(OAc)2 (5 mol %) and
Ag2CO3 (1.0 equiv) over a period of 5 h.
Scheme 1. Pd-Catalyzed Dehydrogenative Cross-Coupling of
Polyfluoroarenes with Heteroatom-Substituted Enones
Herein, we present the first example of intermolecular
regioselective R-arylation of heteroatom-substituted en-
ones with polyfluoroarenes via twofold CꢀH bond func-
tionalization using a palladium catalyst. This reaction
provides an efficient and straightforward protocol for the
preparation of R-fluoroarylated enones of interest in life
science.
(9) For selected recent reviews, see: (a) Meyer, E. A.; Castellano,
R. K.; Diederich, F. Angew. Chem., Int. Ed. 2003, 42, 1210. (b) Muller,
K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (c) Murphy, A. R.;
ꢀ
Frechet, J. M. J. Chem. Rev. 2007, 107, 1066. (d) Babudri, F.; Farinola,
G. M.; Naso, F.; Ragni, R. Chem. Commun. 2007, 1003. (e) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320. (f) Amii, H.; Uneyama, K. Chem. Rev. 2009, 109, 2119.
(10) For selected recent papers, see: (a) Lafrance, M.; Rowley, C. N.;
Woo, T. K.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, 8754. (b) Lafrance,
ꢀ
M.; Shore, D.; Fagnou, K. Org. Lett. 2006, 8, 5097. (c) Rene, O.;
(6) For transition-metal-catalyzed intramolecular dehydrogenative
R-arylation of heteroatom-substituted enones, see: (a) Wurtz, S.;
Rakshit, S.; Neumann, J. J.; Droge, T.; Glorius, F. Angew. Chem., Int.
Ed. 2008, 47, 7230. (b) Bernini, R.; Fabrizi, G.; Sferrazza, A.; Cacchi, S.
Angew. Chem., Int. Ed. 2009, 48, 8078. (c) Guan, Z.-H.; Yan, Z.-Y.; Ren,
Z.-H.; Liu, X.-Y.; Liang, Y.-M. Chem. Commun. 2010, 46, 2823. (d)
Neumann, J. J.; Rakshit, S.; Droge, T.; Wurtz, S.; Glorius, F. Chem.;
Eur. J. 2011, 17, 7298.
(7) (a) Ge, H.; Niphakis, M. J.; Georg, G. I. J. Am. Chem. Soc. 2008,
130, 3708. (b) Bi, L.; Georg, G. I. Org. Lett. 2011, 13, 5413. For classical
Suzuki cross-coupling, see: (c) Cross, R. M.; Manetsch, R. J. Org. Chem.
2010, 75, 8654. (d) Mugnaini, C.; Falciani, C.; Rosa, M. D.; Brizzi, A.;
Pasquini, S.; Corelli, F. Tetrahedron 2011, 67, 5776.
Fagnou, K. Org. Lett. 2010, 12, 2116. (d) Do, H.-Q.; Daugulis, O.
J. Am. Chem. Soc. 2008, 130, 1128. (e) Do, H.-Q.; Khan, R. M. K.;
Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185.
(11) (a) Nakao, Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama, T. J. Am.
Chem. Soc. 2008, 130, 16170. (b) Zhang, X.; Fan, S.; He, C.-Y.; Wan, X.;
Min, Q.-Q.; Yang, J.; Jiang, Z.-X. J. Am. Chem. Soc. 2010, 132, 4506. (c)
Chen, F.; Zhang, X. Chem. Lett. 2011, 40, 978. (d) Sun, Z.-M.; Zhang, J.;
Manan, R. S.; Zhao, P. J. Am. Chem. Soc. 2010, 132, 6935. (e) Fan, S.;
Chen, F.; Zhang, X. Angew. Chem., Int. Ed. 2011, 50, 5918.
(12) (a) Winter, R. W.; Kelly, J. X.; Smilkstein, M. J.; Dodean, R.;
Hinrichs, D.; Riscoe, M. K. Exp. Parasitol. 2008, 118, 487. (b) Cross,
R. M.; Monastyrskyi, A.; Mutka, T. S.; Burrows, J. N.; Kyle, D. E.;
Manetsch, R. J. Med. Chem. 2010, 53, 7076.
(8) (a) Hirota, K.; Isobe, Y.; Kitade, Y.; Maki, Y. Synthesis 1987,
495. (b) Cheng, D.; Gallagher, T. Org. Lett. 2009, 11, 2639. (c) Li, M.; Li,
L.; Ge, H. Adv. Synth. Catal. 2010, 352, 2445. (d) Kim, D.; Hong, S. Org.
Lett. 2011, 13, 4466.
(13) The amount of iPr2S is important for the reaction efficiency.
Using less than 5.0 equiv of iPr2S led to a lower yield; see Table S2 in
the Supporting Information.
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