Hence, Pd-catalyzed directed C(sp2)ÀH bond cleavage/
C(sp2)ÀO bond formation sequence is a desirable ap-
proach. In 2004, Sanford reported oxime as a directing
group for ortho-acetoxylation of aromatic/aliphatic CÀH
bonds.9 Later, Yu disclosed a Pd-catalyzed ortho-hydro-
xylation of carboxylic acid salts at 115 °C (Scheme 1B).10
Apart from Pd catalysis, the Rao and Lei groups recently
showed that Ru and Cu complexes could be applied in the
hydroxylation of benzoate esters and electron-deficient
arenes, respectively.11,12 These establishments potentially
provide a synthetic method to access an ortho-acylphenol
moiety. However, additional steps are necessary to retrieve
the phenol or obtain the ketone moiety (Scheme 1B).
Therefore, it would be attractive to access ortho-
acylphenols if the ketone group could be directly employed
as the directing group for direct C(sp2)ÀH bond oxygenation.
bond-forming strategy,14 there have been very limited exam-
ples on CÀX bond formation. Until very recently, Liu15 and
Glorius16 reported ketone-directed CÀN and CÀBr bond
formation by employing Pd and Rh catalysts, respectively.
Pal reported the hydroxylation of benzophenone under
UV photoactivation conditions, leading to a mixture of
regioisomers.17 Yet, there has been no report on ketone-
directed arene oxidation (CÀO bond formation) to date.
Presumably the weaker coordinating ability (with respect
to amides, oximes, carboxylic salts/esters, and 2-phenyl-
pyridine)18 likely gives lower reactivity at the initial ortho-
directed electrophilic palladation, and consequently more
forcing conditions are needed, in which these conditions
would lead to substrate decomposition or undesired pro-
duct formation. Inspired by the need for efficient synthesis
of ortho-acylphenol motifs from arylketones, we started to
embark on this challenge by using a Pd-catalyzed arene
oxygenation approach. In continuing our research pro-
gram on Pd-catalyzed ortho-acylaniline synthesis19 and
direct CÀH acetoxylation,20 herein, we report our investi-
gation on the ketone-directed ortho-oxygenation of aro-
matic ketones. This protocol presents a straightforward
access of ortho-acylphenol frameworks and also allows
enolizable ketones to react smoothly. In particular, halo
groups are found to be compatible under these mild reac-
tion conditions (80 °C).
Scheme 1. Synthetic Pathways for ortho-Acylphenol Motifs
We initially started our investigation by using benzo-
phenone as the model substrate (Table 1). Commonly used
oxidants were examined (entries 1À4). A more electrophi-
lic oxidant, PhI(OTFA)2, was found to be significantly
better than PhI(OAc)2 (entry 3 vs 4). However, there was
no essential difference between Pd(OAc)2 and Pd(OTFA)2
when they were used as the precatalysts (entry 4 vs 12). A
screening of solvents revealed that DCE was the solvent of
choice (entries 4À7). Also, 5 mol % Pd was found to be the
lowest level of catalyst loading to provide a good yield
(entries 8À10). Indeed, the initial product formed from this
reaction was the 2-trifluoroacetoxylbenzophenone. Upon
aqueous workup, the hydrolyzed phenolic product 1a was
obtained.
Ketone-directed CÀH bond functionalization has been
established since Murai’s initial work on Ru-catalyzed
olefin coupling.13 Apart from the significant develop-
ment of the ketone-directed CÀH bond cleavage/CÀC
With our optimized reaction conditions in hand, we next
tested the substrate scope of this oxgyenation reaction
(Table 2). The aromatic ketones proceeded smoothly to
give the corresponding product in good yields. Fluoro,
chloro, and bromo groups were compatible under these
reaction conditions (entries 3, 9À10). This halo group
tolerance is versatile for further modification of ortho-
acylphenol using traditional cross-coupling technology.21
Apart from the symmetrical diarylketones, we also probed
the hydroxylation regioselectivity of the unsymmetrical
(9) (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2004, 126, 9542. (b) Neufeldt, S. R.; Sanford, M. S. Org. Lett. 2010, 12,
532.
(10) Zhang, Y. H.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 14654.
(11) Yang, Y.; Lin, Y.; Rao, Y. Org. Lett. 2012, 14, 2874.
(12) In addition to Pd catalysis, the Cu complex was found to be
applicable for electron-deficient arene hydroxylation. For the most
recent reference, see: Liu, Q.; Wu, P.; Yang, Y.; Zeng, Z.; Liu, J.; Yi,
H.; Lei, A. Angew. Chem., Int. Ed. 2012, 51, 4666.
(13) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Nature 1993, 366, 529.
(14) For recent selected references, see: (a) Patureau, F. W.; Besset,
T.; Kuhl, N.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2154.
(b) Muralirajan, K.; Parthasarathy, K.; Cheng, C.-H. Angew. Chem.,
Int. Ed. 2011, 50, 4169. (c) Patureau, F. W.; Besset, T.; Glorius, F. Angew.
Chem., Int. Ed. 2011, 50, 1064. (d) Gandeepan, P.; Parthasarathy, K.;
Cheng, C.-H. J. Am. Chem. Soc. 2010, 132, 8569. (e) Kakiuchi, F.;
Matsuura, Y.; Kan, S.; Chatani, N. J. Am. Chem. Soc. 2005, 127, 5936.
(f) Satoh, T.; Miura, M.; Nomura, M. J. Organomet. Chem. 2002, 653,
161. (g) Terao, Y.; Kametani, Y.; Wakui, H.; Satoh, T.; Miura, M.;
Nomura, M. Tetrahedron 2001, 57, 5967.
(17) Basu, M.; Sarkar, S.; Pande, S.; Jana, S.; Sinha, A. K.; Sarkar, S.;
Pradhan, M.; Pal, A.; Pal, T. Chem. Commun. 2009, 7191.
(18) Hartwig, J. F. Organotransition Metal Chemistry: from Bonding
to Catalysis; University Science Books: Mill Valley, 2009.
(19) (a) Wu, Y.; Li, B.; Mao, F.; Li, X.; Kwong, F. Y. Org. Lett. 2011,
13, 3258. (b) Wu, Y.; Choy, P. Y.; Mao, F.; Kwong, F. Y. Chem.
Commun. 2013, 49, 689.
(20) Choy, P. Y.; Lau, C. P.; Kwong, F. Y. J. Org. Chem. 2011, 76, 80.
(21) de Meijere, A.; Diederich, F., Eds. Metal-Catalyzed Cross-
Coupling Reaction, 2nd ed., Vols. 1À2; Wiley-VCH: Weinheim, 2004.
(15) Xiao, B.; Gong, T.-J.; Xu, J.; Liu, Z.-J.; Liu, L. J. Am. Chem.
Soc. 2011, 133, 1466.
€
(16) Schroder, N.; Wencel-Delord, J.; Glorius, F. J. Am. Chem. Soc.
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