Catalytic and highly regioselective cross-coupling of aromatic C-H substrates

Article abstract of DOI:10.1021/ja074395z

This communication describes a new Pd-catalyzed reaction for the highly chemo- and regioselective oxidative cross-coupling of aromatic C-H bonds. This transformation is proposed to proceed via two discrete C-H activation steps whose selectivities are pred

Full text of DOI:10.1021/ja074395z

Published on Web 09/11/2007
Catalytic and Highly Regioselective Cross-Coupling of Aromatic C-H Substrates
Kami L. Hull and Melanie S. Sanford*
Department of Chemistry, UniVersity of Michigan, 930 North UniVersity AVenue, Ann Arbor, Michigan 48109
Received June 16, 2007; E-mail: mssanfor@umich.edu
Table 1. Scope and Selectivity of Bzq/Arene Cross-Coupling
Aryl-aryl bonds are a key structural feature of diverse natural
products, medicinal agents, and organic materials. Currently, the
vast majority of biaryl linkages are constructed via the metal-
mediated cross-coupling of two prefunctionalized arene building
blocks.1 However, a far more efficient approach to these bonds
would involve direct oxidative coupling of two arene C-H sub-
strates. Recent work has shown that PdII salts can catalyze the
oxidative dimerization (homocoupling) of benzene,2 thiophene,3 and
arylpyridine derivatives4 under mild conditions. In contrast, very
few reports have described the more synthetically useful catalytic
oxidative cross-coupling of arenes.5,6 Such reactions are particularly
challenging because both the chemo- and regioselectivity of arene
C-H activation and C-C coupling must be well-controlled to avoid
formation of intractable mixtures of regioisomeric homo- and
heterocoupled biaryls.
In order to develop selective arene C-H cross-coupling reactions,
we sought to exploit ligand-directed C-H activation at PdII. It is
well-known that the stoichiometric cyclopalladation of diverse
substrates L∼CAr-H (A, eq 1) is facile and highly regioselective.7
Furthermore, the mono-cyclometalated PdII products are typically
unreactive toward a second ligand-directed C-H activation event
under Pd0/II conditions,4,8 which should limit competitive homo-
coupling of L∼CAr-H (eq 1, path a). As such, we hypothesized
that the desired cross-coupling between L∼CAr-H and a simple
arene (Ar-H) would be possible if the cyclopalladated complex
could participate in a second, nondirected C-H activation reaction
with Ar-H (eq 1, path b). We demonstrate herein the application
of this strategy to the Pd-catalyzed oxidatiVe cross-coupling of
diVerse L∼CAr-H and Ar-H substrates. This noVel transformation
proceeds with extremely high chemoselectiVity for cross-coupling;
further, the two discrete C-H actiVation steps can both proceed
with excellent (and in some cases tunable) leVels of regiocontrol.
conditions were examined with benzoquinone (BQ) as the stoichio-
metric oxidant; however, despite the utility of BQ as an oxidant in
other PdII/0 reactions,9 only a single turnover to form 2 was observed.
We next explored AgI salts, which are known to be effective
oxidants in the Pd-catalyzed oxidative dimerization of thiophenes.3
We were pleased to discover that the use of 2 equiv of Ag2CO3 in
the presence of 0.5 equiv of BQ, 98 equiv of C6H6, and 10 mol %
of Pd(OAc)2 afforded 2 catalytically in 74% yield. The addition of
4 equiv of DMSO further enhanced the yield to 89%, possibly by
slowing catalyst decomposition/Pd0 aggregation.10 Importantly,
under these optimized conditions, none of the homocoupled
products (Ph-Ph or bzq-bzq) were observed (eq 3).
The scope of this reaction with respect to the arene coupling
partner was next explored. Initial studies revealed that p-xylene
(which is electronically similar to C6H6 but has significantly more
sterically hindered arene C-H bonds) exhibited low reactivity under
our conditions (Table 1, entry 1). This observation was surprising
because p-xylene was reported to be a good substrate for other PdII-
catalyzed oxidative cross-couplings.5 This result suggested that steric
factors might be uniquely critical for controlling reactivity (and
also potentially selectivity) during the C-H activation of Ar-H
in our system. To probe this possibility, we examined a series of
1,2-disubstituted arenes, in which the two different aromatic C-H
bonds are electronically similar but have very different steric
environments. In all cases, oxidative coupling proceeded in good
yield and with high (g10:1) selectivity for coupling at the less
hindered 4-position of Ar-H (entries 2-5).11
Our initial studies focused on stoichiometric reactions between
cyclopalladated benzo[h]quinoline (Bzq) complex 1 and C6H6.
Heating 1 to 150 °C in C6H6 did not afford any of the cross-coupled
product 2, indicating that this complex does not directly effect arene
C-H activation. However, gratifyingly, the addition of 2 equiv of
benzoquinone (an additive previously shown to promote C-H
activation reactions at PdII centers)9 to a C6H6 solution of 1 at
130 °C produced 2 in 77% yield along with a black/silver precipitate
believed to be Pd0 aggregates (eq 2).
With this encouraging result in hand, we turned our efforts to
rendering this reaction catalytic in Pd. A variety of catalytic
9
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10.1021/ja074395z CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Figure 1. Cross-coupling products with other directing groups.
Figure 3. Preliminary proposed mechanism.
oxidation of the Pd0 to PdII by Ag2CO3. The nature of the second
C-H activation event is particularly intriguing because the
electronic and steric effects are very different from those previously
observed at PdII centers. These effects are not consistent with either
an electrophilic C-H activation mechanism (which should result
in dramatically faster reaction rates with electron rich arenes)7,14
or a C-H deprotonation mechanism (which should show preference
for activation of the most acidic CAr-H bonds next to electron-
withdrawing F/NO2 substituents).15
In summary, this communication describes a new Pd-catalyzed
reaction for the highly chemo- and regioselective oxidative cross-
coupling of aromatic C-H bonds. This transformation is proposed
to proceed via two discrete C-H activation steps whose selectivities
are predominantly controlled by proximity to a ligand (first C-H
activation) or by the steric environment around the arene C-H bond
(second C-H activation). Ongoing work seeks to exploit this
mechanistic manifold for other synthetically useful cross-coupling
reactions as well as to further probe the mechanism of these new
transformations.
Figure 2. Effect of benzoquinone structure on selectivity.
A series of 1,3-di- and 1,2,3-trisubstituted arenes were also in-
vestigated (entries 6-10). Again, high selectivity was obtained for
coupling at the less hindered 5-position, which can be particularly
challenging to functionalize selectively using traditional organic
reactions. The only substrate that afforded >5% of the 4-regioi-
somer was 1-methyl-3-methoxybenzene (entry 7, 2.5:1 isomer ratio).
The minor product resulted from coupling adjacent to the OMe
group, presumably due to the relatively small size of this substituent.
Even with nitrobenzene and anisole, coupling at the p- and m-posi-
tions was significantly favored over the o-position (entries 11 and
12). Notably, similar steric-based selectivity has been reported for
Ir- and Rh-catalyzed C-H activation/borylation;11 however, to our
knowledge, the observed selectivities are unprecedented in arene
C-H activation at PdII.
With data on steric effects in hand, we next probed the influence
of electronic factors on the C-H activation of Ar-H. The reaction
of Bzq was conducted with a mixture of 40 equiv of 1,3-dimethyl-
2-nitrobenzene and 40 equiv of 1,3-dimethyl-2-methoxybenzene,
which contain sterically identical arene C-H bonds. Remarkably,
this reaction afforded a 1:1.4 ratio of 10/12, showing that the relative
rates of C-H activation are barely affected by large electronic
perturbations of the aromatic ring.
Acknowledgment. We thank the Beckman, Dreyfus, and Sloan
Foundations as well as Abbott, Amgen, AstraZeneca, BMS,
Boehringer Ingelheim, Eli Lilly, GSK, and Merck for support.
K.L.H. thanks Novartis and Eli Lilly for fellowship support.
Supporting Information Available: Experimental details and
spectroscopic and analytical data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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These transformations could also be applied to a variety of other
L∼C-H coupling partners. Under identical conditions to the Bzq
reactions, 2-arylpyridine, 1-arylpyrazole, and 2-arylpyrimidine
derivatives afforded biaryl products in modest to good yields (Figure
1). 8-Methylquinoline was also an effective substrate and reacted
to form a new sp3-sp2 C-C bond.
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regioselectivity of arene C-H activation. To test this hypothesis,
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methylation of the BQ led to a dramatic decrease in coupling at
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at the m- and p-positions (Figure 2).13 Mechanistically, this result
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arene C-H activation.12 In addition, these data proVide promising
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