DOI: 10.1002/anie.201103327
CÀH Activation
Remarkably High Reactivity of Pd(OAc) /Pyridine Catalysts:
2
À
Nondirected C H Oxygenation of Arenes**
Marion H. Emmert, Amanda K. Cook, Yushu J. Xie, and Melanie S. Sanford*
Over the past eight years there has been tremendous progress
derivatives. Remarkably, these catalysts can be formed in situ
II/IV
in the development of Pd -catalyzed ligand-directed CÀH
from Pd(OAc) and the simple ligand pyridine (pyr). Fur-
2
oxidation reactions to form CÀO, CÀN, CÀS, CÀhalogen, and
thermore, their catalytic activities and site selectivities can be
dramatically modulated through variation of the palladium/
pyridine ratio.
[1]
CÀC bonds. In marked contrast, analogous CÀH oxidation
reactions of substrates that do not contain directing groups
[
2–7]
0/II
remain challenging.
The lack of a directing group typically
Inspired by recent reports of Pd -catalyzed CÀH func-
[
8–10]
renders these transformations (as exemplified by CÀH oxy-
tionalizations,
our initial explorations focused on pyridine
II/IV
genation) kinetically slow, particularly with electron-deficient
as a ligand for the Pd -catalyzed CÀH acetoxylation of
[
3d,6,7c]
arene substrates.
genation of simple arenes is also plagued by low turnover
The palladium-catalyzed CÀH oxy-
benzene with [PhI(OAc) ]. As shown in Figure 1, the Pd-
2
(OAc) -catalyzed transformation proceeded to completion
2
[
3–6]
numbers
leads to catalyst decomposition through precipitation of
and competing biaryl formation, which often
after 24 hours at 1008C. However, in marked contrast,
[(pyr) Pd(OAc) ] (generated in situ from 1 equiv of Pd(OAc)
2
2
2
[
5]
palladium black. Furthermore, with substituted aromatic
substrates, the site selectivity is typically low and difficult to
control. As part of a program aimed at developing efficient,
selective, and robust catalysts for nondirected CÀH function-
and 2 equiv of pyr) performed very poorly, providing less than
20% yield under the same reaction conditions (Figure 1).
[
7]
alization reactions, we sought to identify supporting ligands
II/IV
that would address these limitations and promote the Pd
-
catalyzed CÀH acetoxylation of arenes.
The vast majority of palladium-catalyzed arene CÀH
oxygenations utilize simple palladium salts (e.g., Pd(OAc) or
2
[
3–5]
PdCl ),
and literature studies have provided conflicting
2
data about the influence of added ligands on these reactions.
Several reports have shown that most common ligands (e.g.,
2
,2’-bipyridine, 1,10-phenanthroline, pyridine, triphenylphos-
phine oxide, etc.) inhibit the palladium-catalyzed CÀH
[
3b,d]
acetoxylation of arenes.
In contrast, in a few related
2
systems bidentate sp N-donor ligands (e.g., 2,2’-bipyridine
Figure 1. Influence of pyridine on the Pd(OAc) -catalyzed acetoxylation
2
and/or 1,10-phenanthroline) were shown to provide modest
&
of benzene. Pd(OAc) /pyr 1:1 ( ); Pd(OAc) (&); Pd(OAc) /pyr 1:2 (x).
2
2
2
[
4c,d,6]
enhancement of catalytic activity.
However, these latter
reactions exhibited low turnover numbers (typically < 10);
furthermore, the origin of the observed effects was not
explored in detail. Herein we describe the use of careful
mechanistic analysis to identify new, efficient, and general
palladium catalysts for the CÀH acetoxylation of benzene
We hypothesized that the low reactivity of [(pyr) Pd-
2
(OAc) ] might be due to the lack of open coordination sites at
2
the palladium center. Therefore, we next explored the use of a
palladium/pyridine ratio of 1:1 to generate a coordinatively
unsaturated pyridine-ligated palladium species such as
[9–11]
[
(pyr)Pd(OAc) ] in situ.
The combination of 2 mol% of
2
[*] Dr. M. H. Emmert, A. K. Cook, Y. J. Xie, Prof. M. S. Sanford
Pd(OAc) and 2 mol% of pyridine (1:1 ratio of [Pd] to [pyr];
2
Department of Chemistry, University of Michigan
catalyst loading relative to oxidant) clearly provided a
dramatic rate enhancement, with the reaction proceeding to
930 N. University Ave, Ann Arbor, MI 48109 (USA)
E-mail: mssanfor@umich.edu
[
12,13]
[
**] We thank the NSF for support of this work through the Center for
Enabling New Technologies through Catalysis (CENTC), and
Professors Karen Goldberg, Bill Jones, Mike Heinekey, Elon Ison,
and Jim Mayer for valuable discussions. M.H.E. thanks the
Deutsche Forschungsgemeinschaft for a postdoctoral fellowship.
A.K.C. thanks the Rackham Graduate School for a predoctoral
fellowship. Y.J.X. thanks CENTC for a summer undergraduate
fellowship. We also thank J. Brannon Gary and Dr. Dipannita Kalyani
for editorial assistance.
completion in less than 3 hours (Figure 1).
A systematic
study of the initial reaction rate (approximated by the yield of
PhOAc after 2 h) as a function of the palladium/pyridine ratio
is shown in Figure 2. A large dependence was observed, with
the fastest initial rates at palladium/pyridine ratios between
1
:0.5 and 1:1.3. Further experimentation (see the Supporting
Information for details) revealed that a palladium/pyridine
[
14]
ratio of 1:0.9 is optimal.
We next sought to probe the longevity of the palladium/
pyridine catalysts. Importantly, literature reports suggest that
Angew. Chem. Int. Ed. 2011, 50, 9409 –9412
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9409