High-yielding palladium-catalyzed intramolecular alkane arylation: Reaction development and mechanistic studies

Article abstract of DOI:10.1021/ja076588s

Palladium-catalyzed alkane arylation reactions with aryl halides are described for the preparation of 2,2-dialkyl-dihydrobenzofuran substrates. These reactions occur in excellent yield and very high selectivity for the formation of one sole product arising from a reaction at nearby methyl groups. Mechanistic and computational studies point to the involvement of a concerted, inner-sphere palladation-deprotonation pathway that is enabled by the presence of three-center agostic interactions at the transition state. This mechanism accurately predicts the experimentally observed kinetic isotope effect as well as the site selectivity and should be useful in the design of new reactions and catalysts. Copyright

Full text of DOI:10.1021/ja076588s

Published on Web 11/07/2007
High-Yielding Palladium-Catalyzed Intramolecular Alkane Arylation: Reaction
Development and Mechanistic Studies
Marc Lafrance, Serge I. Gorelsky, and Keith Fagnou*
Center for Catalysis Research and InnoVation, UniVersity of Ottawa, Department of Chemistry, 10 Marie Curie,
Ottawa, Ontario, Canada K1N 6N5
Received August 31, 2007; E-mail: keith.fagnou@uottawa.ca
Scheme 1. Palladium-Catalyzed Alkane Arylationa
Catalytic hydrocarbon functionalization has undergone rapid
growth over the past decade, especially through the application of
transition-metal catalysis.1 In the context of C-C bond formation,
reactions occurring at sp2 C-H bonds are more prevalent and
widespread than those at sp3 C-H bonds.1-3 Transformations at
sp2 C-H bonds benefit from catalyst interactions with the
π-electrons that enable catalyst-substrate binding and C-H bond
cleavage via electrophilic aromatic metalation,4 concerted metala-
tion-deprotonation5 or other pathways.6 Since this type of interac-
tion cannot occur with unactivated sp3 centers, they must rely on
other, less clearly defined, substrate-catalyst interactions.7 Fur-
thermore, while the growing mechanistic understanding of reactions
at sp2 bonds can inspire methodological development, the relative
lack of similar insight for C-C bond forming processes at
corresponding sp3 C-H bonds makes a rational approach to this
class of reaction challenging.7,8
Herein, we describe the development of Pd-catalyzed alkylation
reactions of aryl bromides and chlorides including rare examples
of sp3 C-H bond cleavage/functionalization occurring in near
quantitative yield. These reactions provide a novel and comple-
mentary route to medicinally important 2,2-dialkyldihydrobenzo-
furans.9 Mechanistic studies point to the involvement of a concerted,
inner-sphere palladation-deprotonation pathway enabled by the
presence of three-center agostic interactions at the transition state.
This mechanism accurately predicts the preference for reaction at
methyl groups over other secondary sp3 C-H bonds at the same
proximity, a feature which has also been observed in other classes
of alkane functionalization.10
a Conditions: Pd(OAc)2 (3 mol %), PCy3‚HBF4 (6 mol %), the base
Following a similar strategy to that previously employed in the
development of benzene arylation reactions,11 a variety of bases
were evaluated in the presence and absence of catalytic quantities
of carboxylic acid additives. These studies led to the finding that
the reaction of 1 in the presence of Pd(OAc)2 (3 mol %) and PCy3‚
HBF4 (6 mol %) in conjunction with Cs2CO3 (1.1 equiv) and 2,2-
dimethylpropionic acid (pivalic acid, 30 mol %) in mesitylene at
135 °C results in complete and clean conversion to 2 which can be
isolated in 97% yield. The superior reactivity associated with the
combined use of an insoluble carbonate base and a catalytic quantity
of soluble carboxylate base (in this case via deprotonation of the
pivalic acid in situ) is illustrated by the lower conversions and yields
that are obtained when either component is used as the stoichio-
metric base alone (entry 6 vs entries 1 and 2). Additional examples
are included in Scheme 1. When different aliphatic groups are
present that may undergo reaction, high selectivity is observed for
reaction at a methyl substituent over a secondary carbon atom as
illustrated by the clean formation of 9, 10, 11, and 13. Trifluo-
romethyl substituents are inert under the reaction conditions
enabling the preparation of CF3 substituted dihydrobenzofuran
compounds such as 12 which would be difficult to prepare via the
more commonly employed cationic cyclization routes to this class
of molecule.12 Ring closure at a methyl group may still compete
with reaction at an aromatic substituent so long as a six-membered
ring closure is not accessible as illustrated in the formation of 13
(1.1 equiv) and 2,2-dimethylpropionic acid (30 mol % if added) and the
aryl halide were heated to 135 °C in mesitylene 10 to 15 h (overnight).
b Determined by GC-MS. c Isolated yield. d Isolated yield using the
conditions from entry 6 with 5 mol % catalyst. e Performed at 150 °C.
f Isolated with 4-6% of the hydrodebromination byproduct.
and 14. The preferential reaction at the aromatic ring over the
methyl substituent in the formation of 14 illustrates the greater ease
with which the reaction at sp2 positions can occur. The diminished
yield of 13 is due to a competitive reaction at the aromatic ring to
close the seven-membered ring.13 An aryl chloride may also be
employed as in the formation of 2. In this case, a slightly lower
yield is observed compared to the aryl bromide (77% versus 97%)
as a consequence of incomplete conversion.
To further understand the important reaction parameters leading
to high yield and selectivity, the mechanism of C-H bond cleavage
was examined by density functional theory (DFT) calculations.13
Both PdII and PdIV pathways were explored. The PdIV pathway
involving an oxidative insertion into the methyl C-H bond was
ruled out based on the high energy of the PdIV alkyl-hydride
intermediate (Figure S1, ∆G298K ) 47.7 kcal/mol) calculated at the
B3LYP/DZVP level of theory, and because re-optimization of this
intermediate at the B3LYP/TZVP level fails to locate the corre-
sponding energy minimum. On the other hand, a transition state
(TS) corresponding to a concerted palladation-deprotonation
pathway (Figure 1) was found to have a ∆Gq298K of 29.4 kcal/mol
9
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J. AM. CHEM. SOC. 2007, 129, 14570-14571
10.1021/ja076588s CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
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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Acknowledgment. We thank NSERC, the Research Corpora-
tion, the Ontario government, Merck Frosst, Boehringer Ingelheim,
Astra Zeneca, KCT and Merck Inc. for additional support. We thank
Professor Tom K. Woo for use of the computing facilities funded
by the Canada Foundation for Innovation and the Ontario Research
Fund.
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