generated by substitution of tert-butoxide of the ortho-
CꢀF bond because of the electron-withdrawing
oxazoline group. In agreement with our assumption,
switching the directing group from oxazoline to
2-pyridinyl resulted in significant improvement of the
yield to 93%. Interestingly, other directing groups such
as an imine or amide were ineffective under these condi-
tions (eq 1).
Scheme 1. Strategies for Transition Metal-catalyzed CꢀF Bond
Activation
activation of the undesired but kinetically more favorable
CꢀH bond of the polyfluoroarene substrates. We now
report a direct palladium-catalyzed cross-coupling reac-
tion of polyfluoroarenes with heteroarenes. Our report is
the first example of a transition metal-catalyzed carbonꢀ
carbon bond formation via a concurrent CꢀF/CꢀH bond
activation process (Scheme 1).10,11
We recently developed a palladium catalyzed Suzuki-
Miyaura coupling reaction of polyfluorophenyl oxazo-
lines, in which the selective ortho-CꢀF activation was
directed by the oxazoline group.12 In light of these pre-
liminary studies, we initially chose to examine the reaction
of pentafluorophenyl oxazoline and benzoxazole as the
second coupling partner, in an effort to achieve the con-
current CꢀF/CꢀH bond activation. After careful inves-
tigation, we were excited to find that the desired carbonꢀ
carbon bond forming product could be obtained in 30%
yield when pentafluorophenyl oxazoline and 2.0 equiv of
benzoxazole were heated in xylene at 130 °C for 10 h with
lithium tert-butoxide as the base and a catalyst generated
in situ from Pd(MeCN)2Cl2 and DPPBz (1,2-bis(diphenyl-
phosphino)benzene). The major side product was iden-
tified as 2-(2-tert-butoxy-3,4,5,6-tetrafluorophenyl)-4,5-
dihydrooxazole. We reasoned that the side product was
Encouraged by these initial results, we further optimized
the reaction parameters such as the palladium precursors,
ligands, bases and solvents (See Supporting Information
for details). It was found that ligand is critical for the
reaction efficiency. For example, electron-rich, sterically
hindered monodentate trialkyl ligands such as PtBu3, PCy3
and RuPhos that have been widely used for the coupling of
aryl chlorides were ineffective. Bidentate ligands with large
bite angles such as Xantphos or DPEPhos were also not
effective. In contrast, reactions using bidentate ligands
such as DPPF, DPPE, DPPP, BINAP and DPPBz oc-
curred to full conversion after 10 h at 130 °C. It was found
that the reaction using DPPBz as the ligand afforded the
desired product in higher yield than those using other
ligands as determined by 19F NMR spectroscopy. The
reaction was sensitive to the base. Reactions using weak
base K3PO4 or Cs2CO3 led to lower yields. Using bases
such as NaOtBu or KOtBu led to much lower yield while
reaction with LiOtBu as the base gave comparable yield
under the same conditions. Next, the effect of the solvent
was further evaluated. No product was observed when the
reaction was conducted in polar, aprotic solvent such as
dimethylacetamide. Reactionsinlesspolarsolventssuchas
dioxane, diethoxy ethane or 1,2-dichloroethane occurred
slowly to afford the product in lower yields. Finally, to our
delight, the catalyst loading can reduce to 5.0 mol %
without significant loss of the yield. With the optimized
conditions now in hand, we investigated the scope of
the palladium-catalyzed CꢀF/CꢀH bond activation/
carbonꢀcarbon bond formation reaction of polyfluoroaryl
pyridines, and the results are summarized in Scheme 2. A
variety of 4-, 5- or 6-subsittuted benzoxazoles were sub-
jected to the reaction conditions to afford the desired
coupled products in good yields. It is worth noting that
the carbon-chloride bond of 5-chlorobenzoxazole re-
mained intact under these conditions, indicating that
the directing group favors the cleavage of the strong
CꢀF bond (Scheme 2, entry 3c). The presence of Cl in
the products is very useful for further synthetic manip-
ulations via numerous cross-coupling reactions. When
6-fluorobenzoxazole was used, the desired product 3j was
(10) For reviews on CꢀX/CꢀH activation, see: (a) Ackermann, L.;
Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (b)
Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.
2009, 48, 5094. (c) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev.
2007, 107, 174. (d) Campeau, L.-C.; Fagnou, K. Chem. Soc. Rev. 2007,
36, 1058. (e) Catellani, M.; Motti, E.; Della Ca, N. Acc. Chem. Res. 2008,
41, 1512. (f) Daugulis, O. Top. Curr. Chem. 2010, 292, 57.
(11) For selected examples on CꢀX/CꢀH activation, see: (a) Ye, M.;
Gao, G.-L.; Edmunds, A. J. F.; Worthington, P. A.; Morris, J. A.; Yu,
J.-Q. J. Am. Chem. Soc. 2011, 133, 19090. (b) Sun, C.-L.; Li, H.; Yu,
D.-G.; Yu, M.; Zhou, X.; Lu, X.-Y.; Huang, K.; Zheng, S.-F.; Li, B.-J.;
Shi, Z.-J. Nat. Chem. 2010, 2, 1044. (c) Liu, W.; Cao, H.; Zhang, H.;
Zhang, H.; Chung, K.-H.; He, C.; Wang, H.; Kwong, F.-Y.; Lei, A.
J. Am. Chem. Soc. 2010, 132, 16737. (e) Campeau, L.-C.; Rousseaux, S.;
Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020. (d) Kalyani, D.; Deprez,
N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330. (e)
Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046. (f)
Ackermann, L.; Althammer, A.; Fenner, S. Angew. Chem., Int. Ed. 2009,
48, 201. (g) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593. (h)
Hachiya, H.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 1737.
(i) Muto, K.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2012, 134, 169.
(j) Zanardi, A.; Novikov, M. A.; Martin, E.; BEnet-Buchholz, J.;
Grushin, V. V. J. Am. Chem. Soc. 2011, 133, 20901.
(12) Yu, D.-H.; Shen, Q.; Lu, L. J. Org. Chem. 2012, 77, 1798.
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