Exclusive 5-exo-dig hydroarylation of o-alkynyl biaryls proceeding via C-H activation pathway

Article abstract of DOI:10.1021/ja8006534

The first example of the palladium-catalyzed exclusive 5-exo-dig hydroarylation of o-alkynyl biaryls has been demonstrated. In contrast to the reported earlier carbocyclizations proceeding via the Friedel-Crafts mechanism, this hydroarylation efficiently proceeds with electron-neutral and electron-deficient arenes, producing fluorene frameworks with defined stereochemistry of the double bond. On the basis of the high reactivity of electron-deficient arenes toward cyclization, high values of inter- and intramolecular kinetic isotope effects, and the exclusive cis-selectivity of cyclization, a mechanism involving a C-H activation motif has been proposed for this transformation. Copyright

Full text of DOI:10.1021/ja8006534

Published on Web 03/22/2008
Exclusive 5-exo-dig Hydroarylation of o-Alkynyl Biaryls
Proceeding via C-H Activation Pathway
Natalia Chernyak and Vladimir Gevorgyan*
Department of Chemistry, UniVersity of Illinois at Chicago, Chicago, Illinois 60607
Received January 26, 2008; E-mail: vlad@uic.edu
Table 1. Pd-Catalyzed Hydroarylation of o-Alkynyl Biarylsa
Intramolecular palladium-catalyzed hydroarylation of alkynes
was first reported by Fujiwara in 2000.1a–c Shortly after, other
transition-metal-2,3 and Lewis acid-catalyzed4 versions of this
transformation emerged, and the method quickly became a
powerful tool for the construction of carbo- and heterocycles.
This transformation is most efficient with electron-rich aromatic
rings, hence, not surprisingly, a Friedel–Crafts-type electrophilic
aromatic substitution path has been generally accepted as the
most probable mechanism for this reaction.3,5 Thus, one of the
representative examples reported by Fürstner3b shows that
o-alkynyl biaryls possessing an electron-rich aryl ring in the
presence of transition metals undergo a facile intramolecular
hydroarylation reaction. Reaction proceeds via electrophilic
activation of the triple bond followed by exclusive or predomi-
nant 6-endo-dig6 carbocyclization, leading to the phenanthrene
frameworks (eq 1). Herein, we wish to report the first example
of the Pd-catalyzed exclusive 5-exo-dig hydroarylation of
electron-neutral and electron-deficient o-alkynyl biaryls pro-
ceeding via a C-H activation path (eq 2).
We turned our attention to the palladium-catalyzed intramo-
lecular hydroarylation of alkynes, which proceeds under ligand-
free acidic conditions and produces the 6-endo-dig cyclization
products.1,2 Although a C-H activation motif was initially
proposed,1 an electrophilic aromatic substitution path has been
suggested later as the most probable path for this transformation.3,5
We hypothesized that switching from acidic to neutral reaction
conditions may affect the reaction mechanism. To this end,
cyclization of o-alkynyl biaryls 1 in the presence of a palladium
catalyst/phosphine ligand combination has been investigated.
We were pleased to find that 2-(phenylethynyl)biphenyl (1a)
in the presence of the Pd(OAc)2/dppf system in toluene at 120
°C underwent smooth 5-exo-dig carbocyclization to produce
fluorene 2a in 70% GC yield! Moreover, switching to bulkier
1,1′-bis(diisopropylphosphino)ferrocene allowed us to obtain 2a
in nearly quantitative yield (Table 1, entry 1).
With these conditions in hand, the generality of the cyclization
has been studied. It was found that a variety of o-alkynyl biaryls
bearing electron-neutral, and even more surprisingly electron-
deficient aryl rings, underwent highly effective 5-exo-dig
carbocyclization to give 9-benzylidene-9H-fluorene derivatives
2a-2j in good to excellent yields (Table 1). Various groups,
such as F, NO2, CO2Me, and OMe, were perfectly tolerated
a Reaction conditions: 0.5 mmol of 1, 0.025 mmol of Pd(OAc)2,
0.035 mmol of 1,1′-bis(diisopropylphosphino)ferrocene,
1 mL of
toluene, 120 °C. b Isolated yields.
under these reaction conditions. Importantly, in contrast to the
previously reported intramolecular hydroarylation of alkynes,1–5
o-alkynyl biaryls, possessing electron-deficient substituents (R2
) F, CF3, CO2Me), underwent substantially faster cyclization
compared to that for the o-alkynyl biaryls bearing electron-
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10.1021/ja8006534 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
213 with alternative geometry of the double bond apparently,
via a cis-cyclization path (Table 1, Scheme 2).
Scheme 1. Kinetic Isotope Effect Studies
In conclusion, we have demonstrated the first example of the
palladium-catalyzed exclusive 5-exo-dig hydroarylation. This
method allows for efficient cyclization of a variety of o-alkynyl
biaryls possessing electron-neutral and electron-deficient aryl
rings into the corresponding fluorenes. On the basis of the high
efficiency of the cyclization of substrates bearing electron-
deficient aryl rings, the observed high values of kinetic isotope
effects, as well as on the exclusive cis-selectivity of cyclization,
a mechanism involving the C-H activation motif has been
proposed for this transformation.
Acknowledgment. The financial support of the National
Institutes of Health (GM-64444) and the National Science
Foundation (Grant CHE-0710749) is gratefully acknowledged.
Scheme 2. Proposed Mechanism
Note Added after ASAP Publication. Errors in the Supporting
Information have been corrected on April 5, 2008.
Supporting Information Available: Experimental data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
References
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Scheme 3. Electrophilic Path for Cyclization of 1
neutral aryl rings. Substrates with electron-deficient groups at
the alkyne moiety (R1) reacted slightly faster, though no
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been observed (Table 1, entries 5, 7, 8, and 11). Remarkably,
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selectivity, providing geometrically pure fluorenes 2a-r (Table
1).7
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In order to better understand this transformation, we per-
formed kinetic isotope effect studies. Experiment demonstrated
that this cyclization exhibits significant intermolecular (kH/kD
) 2.6) and intramolecular (kH/kD ) 3.5) hydrogen/deuterium
kinetic isotope effect (Scheme 1).8 These data are in a range of
the isotope effects observed for the reactions proceeding via
the Pd-catalyzed aromatic C-H activation pathways.9,10 Ac-
cordingly, we envision that this reaction proceeds via ortho-
palladation of intermediate 1 to give 8 (Scheme 2), which, upon
migratory insertion to a triple bond, gives vinylpalladium species
9. Protiodepalladation of 9 produces 2 and regenerates the
catalyst. An alternative path may involve palladium hydride
species 10, which, via consecutive carbopalladation of the triple
bond and reductive elimination, would furnish the reaction
product. However, on the basis of the substantial loss of
deuterium observed in the cyclization of 4,11 this pathway was
considered to be less likely. Possible involvement of the
Friedel–Crafts mechanism (Scheme 3) was ruled out based on
the higher propensity of the electron-deficient alkynes toward
this hydroarylation reaction, as well as on the high values of
the kinetic isotope effects (Scheme 1).12 The stereochemistry
of the obtained products 2 also contradicts with the electrophilic
pathway. Indeed, based on the literature reports,1–5 Friedel-
–Crafts cyclization of 1 is expected to proceed in the trans-
fashion to produce (Z)-fluorene 2′ (Scheme 3). In contrast, the
Pd-catalyzed hydroarylation, described herein, produces fluorene
(7) It was assumed that the geometry of all geometrically pure products was
the same as that for 2e,f, the geometry of which was confirmed by NOESY
experiments. See Supporting Information for details.
(8) See Supporting Information for details.
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(11) Cyclization of 4 produced 5 in 85% yield with 60% deuterium incorporated
at the vinylic position.
(12) The inverse kinetic isotope effect (kH/kD ) 0.64) was reported for the
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(13) Careful analysis of the reaction at the early stages indicated that the obtained
stereoisomers of fluorenes 2 are the kinetic products of this cyclization.
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