Analysis of the concerted metalation-deprotonation mechanism in palladium-catalyzed direct arylation across a broad range of aromatic substrates

Article abstract of DOI:10.1021/ja802533u

The concerted metalation-deprotonation mechanism predicts relative reactivity and regioselectivity for a diverse set of arenes spanning the entire spectrum of known palladium-catalyzed direct arylation coupling partners. An analysis following an active st

Full text of DOI:10.1021/ja802533u

Published on Web 07/29/2008
Analysis of the Concerted Metalation-Deprotonation Mechanism in
Palladium-Catalyzed Direct Arylation Across a Broad Range of Aromatic
Substrates
Serge I. Gorelsky,* David Lapointe, and Keith Fagnou*
Center for Catalysis Research and InnoVation, UniVersity of Ottawa, Department of Chemistry, 10 Marie Curie,
Ottawa, Ontario, Canada K1N 6N5
Received April 7, 2008; E-mail: sgorelsk@uottawa.ca; keith.fagnou@uottawa.ca
Palladium-catalyzed direct arylation is emerging as a valuable
and efficient alternative to traditional metal-catalyzed cross-
couplings in the construction of biaryl compounds (eq 1).1–3 To
predict substrate suitability and regioselectivity, however, will
require a more complete understanding of the underlying physical
parameters governing reactivity and selectivity across the
activation-strain analysis was performed (Scheme 1).14 The
broadest range of substrates possible. With palladium, several
reaction pathways have been proposed including oxidative C-H
insertion,4 electrophilic aromatic substitution (SEAr),5 Heck-like,6
anionic cross-coupling, and concerted metalation-deprotonation
(CMD).7 Two of these mechanisms have received the most
support: SEAr with electron-rich, π-nucleophilic heteroarenes and
CMD with simple and electron-deficient benzenes. Herein we
demonstrate that the CMD pathway not only predicts the
reactivity and regioselectivity observed with some simple and
electron-deficient benzenes but also does so for a diverse set of
arenes spanning the entire spectrum of known direct arylation
coupling partners, including those that have been proposed to
react via SEAr (Figure 1).
energetic cost (distortion energy, Edist) associated with distortion
of the catalyst and arene from ground state I and II to TS geometries
III and IV, as well as the energetic gain arising from bringing III
and IV together to form TS V (electronic interaction energy, Eint),
was determined. As could be anticipated, π-electron-rich arenes 4
to 10 benefit from the largest negative Eint values. This gain is offset,
however, by large Edist penalties. On the other hand, electron-
deficient arenes 11 and 3 do not benefit from large Eint values, but
the TS remains accessible due to favorably low Edist arising from
a more facile arene distortion. Thiazole N-oxides 1 and 2 represent
special cases (as also observed experimentally) since they benefit
from both a small Edist penalty and a large Eint gain. Reaction with
benzene 12 is not favored by either value, resulting in the highest
∆E‡ of all the arenes evaluated.
The mechanism for reaction with arenes 1 to 148 was evaluated
by density functional theory (DFT) with the B3LYP9 exchange-
correlation functional (Figure 1). In each case, a relevant transition
state (TS) corresponding to the CMD pathway was located (the
TS for arene 8 is included in Figure 2). This pathway corresponds
to the lowest energy pathway and predicts regioselectivity for all
arenes, regardless of their electronic properties.10 Furthermore, the
calculated relative reactivity of substituted indolizines 8, 9, and 10
under the CMD pathway correlates well with the minimal impact
of these substituents on experimental outcomes.5c Evaluation of
the CMD TS as a potential deprotonation step in an SEAr
mechanism was performed by searching for relevant stationary
points corresponding to Wheland intermediates. Intermediate
complexes were identified with arenes 1 and 8 (Figure 2); however,
these species are best described as η1- and η2-C-Pd coordination
complexes, not Wheland intermediates. Very little charge is present
on the aromatic ring (-0.005 au for 1-RC and +0.145 au for 8-RC),
and retention of aromaticity is observed for all substrates at the
CMD TS.11
Figure 1. Free energy of activation (∆G‡298K, kcal mol-1) for direct
arylation via the CMD pathway involving an acetate ligand. Red bonds
indicate the experimentally observed sites of arylation.
Experimentally, 3-fluorobenzothiophene 14 reacts preferentially
over the more nucleophilic benzothiophene 13 in a competition
reaction (eq 2). While this outcome is incompatible with SEAr
reactivity,12,13 it conforms with calculated CMD values (Figure 1).
A kinetic isotope effect of 2.1 is obtained for a reaction run in the
presence of 10 and 1,3- d2-10.11
To cast light on how arenes such as 11 and 8 with such disparate
physical properties might follow the same CMD pathway, an
Figure 2. Structures corresponding to minima on the CMD reaction for 1
and 8 leading to the CMD TS (shown only for 8).
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10848 J. AM. CHEM. SOC. 2008, 130, 10848–10849
10.1021/ja802533u CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Activation-Strain Analysis
Acknowledgment. We thank NSERC, the Research Corpora-
tion, the Sloan Foundation, the ACS (PRF AC), Merck Frosst,
Merck Inc, Amgen, Eli Lilly, Astra Zeneca, and Boehringer
Ingelheim for financial support. We thank Prof. Tom K. Woo
computing facilities use funded by the CFI and the ORF.
Supporting Information Available: Experimental procedures and
computational details. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Table 1. Distortion/Interaction Analysis (kcal mol-1) for the Lowest
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interactions. The accessible electron density of arene defines the
CAr-Pd covalent interaction15 and can be quantified by the Pd-CAr
bond order16 at the TS (Table 1). The factors contributing to Edist
are a focus of ongoing study. Previously, a correlation between
C-H acidity and reactivity with electron-deficient arenes such as
12 has been noted.2e A closer examination of C-H bond elongation
(∆dC-H) at the CMD TSs reveals that the largest ∆dC-H values
are, in fact, not associated with the most acidic arenes (Figure 3).
This indicates that simple Bro¨nsted acidity may be a paralleling
trend in some cases but not a governing influence.
These studies indicate that the involvement of the CMD
mechanism, as described or as a related variant, may be much more
broadly implicated than previously imagined in palladium-catalyzed
direct arylation. Further critical mechanistic evaluation of this
pathway should lead to a better understanding of the necessary
substrate/catalyst parameters leading to successful coupling and
facilitate the establishment of predictive rules for use with pal-
ladium-catalyzed direct arylation in biaryl synthesis.
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