Pd(II)-Catalyzed Hydroxyl-Directed C-H Olefination
A R T I C L E S
Figure 2. Remote C-H activation directed by common functional groups.
Moreover, we have sought to achieve reactivity through
relatively remote coordination, rather than via five-membered
cyclometalation.8a,19 Despite the realization of these goals with
phenylacetic acids (I),20 3-phenylpropionic acids (II),8h and
phenethylamines (III),8f Pd(II)-catalyzed C-H activation of
alcohols (IV) has not been reported to date.21,22 Herein, we
report an example of hydroxyl-directed C-H olefination (Figure
2) promoted by monoprotected amino acid ligands.
Figure 1. Comparison of Mizoroki-Heck chemistry (left) with arene C-H
olefination (right).
vantageous, as they often leave behind undesired chemical
“footprints”. Converting a directing group to the requisite
functionality for a given synthetic need could require several
extra steps or be impossible altogether. Moreover, many
directing groups only effect C-H activation of proximate bonds
via five-membered palladacycles, which restricts the range of
carbon skeletons that can be accessed and constrains further
potential synthetic elaboration.
Inspired by the power of other substrate-directable reactions
in organic synthesis,15 including catalytic, hydroxyl-directed
epoxidation reactions,16,17 we envisioned that the directing group
limitations in the area of C-H activation could be largely
alleviated by using a range of simple, commonly encountered
functional groups to direct C-H insertion, and by developing
tactics to activate remote C-H bonds (those located 5-6 bonds
away from the directing atom).18 Taken together, these advance-
ments will not only enable functionalization of C-H bonds in
multiple locations of a given molecule using available adjacent
functional groups but also allow chemists to plan synthetic
sequences in which the directing group is indeed the precise
functional group needed for the following steps.
2. Results
2.1. Initial Studies and Reaction Optimization. At the outset,
we were aware of several potential difficulties that we could
encounter in using alcohols to direct C-H palladation. First,
σ-chelation of alcohols with Pd(II) is known to be weak, and
prior to our experimental work, we questioned whether the
palladium alkoxide (Pd-OR) species would be electrophilic
enough for C-H activation. Second, Pd(II) is known to oxidize
primary and secondary alcohols23 and decompose tertiary
alcohols.21 Despite these concerns, we set forth to develop this
chemistry, beginning our investigation by undertaking a rigor-
ous, systematic evaluation of viable reaction conditions.
In light of the facile oxidation of primary and secondary
alcohols by Pd(II), tertiary alcohol 1 was selected as the
screening substrate. Our first approach was to promote in situ
formation of a [Pd(II)-OR] species using strong bases such as
t-BuOLi in accordance with a literature report.24 However,
attempts to perform C-H olefination failed to give any of the
desired product in the presence of t-BuOLi, t-BuONa, and
CH3ONa. Subsequently, we hypothesized that we could exploit
another coordination mode between Pd(II) and the alcohol, with
the latter serving as a neutral ligand (Figure 3).24 Through
extensive screening of solvents and bases, we found that the
combination of nonpolar aromatic solvents, such as toluene and
R,R,R-trifluorotoluene, and weaker bases, such as Li2CO3, was
promising. However, under these conditions we observed
concomitant, undesired Pd(II)-catalyzed olefination of the arene
solvent. This finding later prompted us to examine C6F6 as a
potential solvent, which we hypothesized would be similarly
To implement this strategy, we have focused on developing
C-H activation reactions with three major classes of syntheti-
cally useful substrates: carboxylic acids, amines, and alcohols.
(12) For examples of arene-olefin coupling reactions using metals other
than Pd, see: (a) Lewis, L. N.; Smith, J. F. J. Am. Chem. Soc. 1986,
108, 2728. (b) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.;
Kamatani, A.; Sonoda, M.; Chatani, N. Nature 1993, 366, 529. (c)
Matsubara, T.; Koga, N.; Musaev, D. G.; Morokuma, K. J. Am. Chem.
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Taube, H.; Yoshida, H. J. Am. Chem. Soc. 2000, 122, 7414. (f) Jun,
C.-H.; Hong, J.-B.; Kim, Y.-H.; Chung, K.-Y. Angew. Chem., Int. Ed.
2000, 39, 3440. (g) Weissman, H.; Song, X.; Milstein, D. J. Am. Chem.
Soc. 2001, 123, 337. (h) Thalji, R. K.; Ellman, J. A.; Bergman, R. G.
J. Am. Chem. Soc. 2004, 126, 7192. (i) Luedtke, A. T.; Goldberg,
K. I. Angew. Chem., Int. Ed. 2008, 47, 7694.
(13) (a) Trost, B. M.; Godleski, S. A.; Genet, J. P. J. Am. Chem. Soc. 1978,
100, 3930. (b) Cushing, T. D.; Sanz-Cervera, J. F.; Williams, R. M.
J. Am. Chem. Soc. 1993, 115, 9323. (c) Baran, P. S.; Corey, E. J.
J. Am. Chem. Soc. 2002, 124, 7904. (d) Garg, N. K.; Caspi, D. D.;
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Hatley, R.; Gaunt, M. J. Angew. Chem., Int. Ed. 2008, 47, 3004. (f)
Bowie, A. L., Jr.; Trauner, D. J. Org. Chem. 2009, 74, 1581.
(14) For recent reviews concerning Pd-catalyzed directed C-H activation
reactions, see: (a) Daugulis, O.; Zaitzev, V. G.; Shabashov, D.; Pham,
Q.-N.; Lazareva, A. Synlett 2006, 3382. (b) Campeau, L.-C.; Stuart,
D. R.; Fagnou, K. Aldrichim. Acta 2007, 40, 35. (c) Chen, X.; Engle,
K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094.
(d) Lyons, T. W.; Sanford, M. S. Chem. ReV. 2010, 110, 1147. (e)
Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O.
Chem.sEur. J. DOI: 10.1002/chem.200902374.
(19) For COOH-directed C-H activation via five-membered metallacycles,
see ref 8a and the following: (a) Giri, R.; Maugel, N.; Li, J.-J.; Wang,
D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am. Chem. Soc.
2007, 129, 3510. (b) Chiong, H. A.; Pham, Q.-N.; Daugulis, O. J. Am.
Chem. Soc. 2007, 129, 9879.
(20) Wang, D.-H.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130,
17676.
(21) For phenol-directed intramolecular C-H arylation via Pd(0) catalysis,
see: (a) Hennings, D. D.; Iwasa, S.; Rawal, V. H. J. Org. Chem. 1997,
62, 2. (b) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew.
Chem., Int. Ed. 1997, 36, 1740.
(22) For pioneering efforts on benzylic hydroxyl-directed arylation of
biphenyls via Pd(0) catalysis, see: Terao, Y.; Wakui, H.; Satoh, T.;
Miura, M.; Nomura, M. J. Am. Chem. Soc. 2001, 123, 10407.
Substantial R-C-C cleavage of benzylic alcohols was observed
therein. .
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(16) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974.
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H. J. Am. Chem. Soc. 2007, 129, 286.
(23) (a) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725.
(b) Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Am. Chem. Soc.
2001, 123, 7475.
(18) For the definition of remote C-H functionalization, see: Breslow, R.
Acc. Chem. Res. 1980, 13, 170.
(24) Alsters, P. L.; Boersma, J.; Smeets, W. J. J.; Spek, A. L.; van Koten,
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