Base-mediated intermolecular sp2 C-H bond arylation via benzyne intermediates

Article abstract of DOI:10.1021/ja200184b

A transition-metal-free method for arylation of heterocycle and arene carbon-hydrogen bonds by aryl chlorides and fluorides has been developed. The reactions proceed via aryne intermediates and are highly regioselective with respect to the C-H bond coupling component.

Full text of DOI:10.1021/ja200184b

COMMUNICATION
pubs.acs.org/JACS
Base-Mediated Intermolecular sp2 C-H Bond Arylation via Benzyne
Intermediates
Thanh Truong and Olafs Daugulis*
Department of Chemistry, University of Houston, Houston, Texas 77204-5003, United States
S Supporting Information
b
Benzyne can be generated from silyl aryl triflates under mild
conditions.7b However, these starting materials are quite expen-
ABSTRACT: A transition-metal-free method for arylation
of heterocycle and arene carbon-hydrogen bonds by aryl
chlorides and fluorides has been developed. The reactions
proceed via aryne intermediates and are highly regioselec-
tive with respect to the C-H bond coupling component.
sive, and only a few of them are commercially available. Conse-
quently, we decided to use readily accessible and cheap aryl
chloride benzyne sources. Use of hindered 2,2,6,6-tetramethyl-
piperidides (TMPs) should retard the reaction of benzyne with
base.10 The relative reactivity of the base and aryl anion with
benzyne can be modulated by employing a solvent in which the
amide base is sparingly soluble. A brief optimization of the
reaction conditions showed that the best results were obtained
by employing a mixed pentane/THF solvent system. In pentane,
the arylations are slow because of low base solubility. Compe-
titive addition of TMPLi to benzyne decreases the arylation
yields in THF.
egioselective formation of aryl-aryl bonds has attracted
R
substantial interest because of the prevalence of sp2-sp2
bonds in pharmaceuticals, natural products, and dyes.1 In recent
years, classical methods for creating aryl-aryl bonds have been
supplanted by direct arylation methodology in which the car-
bon-hydrogen bond is used as a functional group.2 A majority of
the C-H bond arylation examples include palladium-, rhodium-,
or ruthenium-catalyzed functionalization of five-membered-ring
heterocycles and directing-group-containing arenes.3 Copper-
catalyzed deprotonative arylation of heterocycles and electron-
deficient arenes results in the functionalization of the most acidic
sp2 C-H bonds.4 Several recent reports have described the
arylation of arenes and electron-deficient heterocycles by aryl
halides, which presumably proceed by radical-type mechanisms
without transition metal involvement.5 The latter methods avoid
heavy-metal contamination of the products, simplifying the
purification for pharmaceutical applications.6 Additionally, these
methods are among the simplest synthetic routes to biaryls.
However, arylations of simple arenes such as anisole afford
isomer mixtures, and the arene coupling component is often
employed in large excess (up to 100 equiv) as a solvent. We report
here a method for transition-metal-free intermolecular sp2 C-H
bond arylation via benzyne intermediates that is highly regioselec-
tive with respect to the arene coupling component and does not
require a large excess of any of the coupling components.
The arylation scope with respect to aryl halides is presented in
Table 1. Benzothiophene is arylated by aryl halides at the most
acidic position. Arylation by 2-chloroanisole and 2-chlorobenzo-
trifluoride (entries 1 and 2) affords the meta-substituted pro-
ducts in good yields. When benzothiophene is arylated using
either 2- or 3-chloro-N,N-dimethylaniline, the meta-substituted
product is obtained (entries 3 and 4). This regioselectivity
pattern may be advantageous if o-chloroarene is more available
than the corresponding meta isomer. Substitutions by a benzyne
mechanism often produce the same isomer when 2- and 3-ha-
loarene starting materials are used.11 The regioselectivity is explained
in terms of the energy required to distort the aryne into two
possible transition states and ground-state polarization of the
aryne by electron-withdrawing substituents.11c 3,5-Dimethoxy-
chlorobenzene is reactive, and the arylation product is obtained
in good yield (entry 5). 2,3,4,5-Tetrasubstituted chloroarenes
can be employed, and benzothiophene is arylated by 9-chlorophe-
nanthrene (entry 6). When 3-chloro-4-methoxytoluene is used, the
arylation occurs meta to the methoxy substituent (entry 7).
Fluoroarene starting materials can be employed, and the reaction
tolerates an ester group (entry 8). If 4-substituted chloroarenes are
used, a nearly 1/1 isomer mixture is obtained, as expected (entry 9).11
The arylation scope with respect to heterocycles and arenes is
shown in Table 2. In most cases, use of TMPLi as the base affords
slightly higher yields than either lithium dicyclohexylamide or
diisopropylamide (entries 1-4 and 6). When fluorobenzene is used
instead of chlorobenzene, nearly identical yields are obtained in
the reactions with benzothiophene (entry 1). Furan derivatives,
such as benzofuran and 2-butylfuran, are arylated in good yields
(entries 2 and 3). N-Methylbenzimidazole and benzothiazole are
reactive (entries 4 and 5). Thiophene, indole, and pyrrole
We have recently reported a transition-metal-free, base-
mediated intramolecular C-arylation of phenols with aryl halides.
In the presence of t-BuOK in dioxane at 140 °C, the cyclization of
3-(2-halobenzyloxy)phenols affords 6H-benzo[c]chromenes in
high yields.7a The reaction proceeds by an initial formation of a
benzyne intermediate followed by an aromatic sp2 C-H func-
tionalization to form the carbon-carbon bond. To expand the
synthetic utility of the reaction, we decided to investigate inter-
molecular carbon-carbon bond formation proceeding via ben-
zyne intermediates. The reaction would occur by a simulta-
neous generation of benzyne and the aryl anion8 followed by
biaryl formation.9 Early examples of chloroarene phenylation by
phenyllithium were reported by Huisgen more than 50 years
ago.9a More recent examples of aryne arylations have been
described by Hart, Schlosser, Meyers, Aubert, and Mamane.9
Received: January 7, 2011
Published: March 08, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja200184b J. Am. Chem. Soc. 2011, 133, 4243–4245
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COMMUNICATION
Table 1. Arylation Scope with Respect to Aryl Halidesa
Table 2. Arylation Scope with Respect to Heterocycles and
Arenesa
a Conditions: aryl halide (1.6-2.5 equiv), benzothiophene (1 equiv),
0.5 mmol scale. Yields are isolated yields. See the Supporting Informa-
tion for details. b tert-Butyl-3-bromobenzoate was used. c Isomer mix-
ture; meta/para ratio = 1/1.2.
a Conditions: chlorobenzene (1.3-2 equiv), arene or heterocycle
(1 equiv), 0.5 mmol scale. Yields are isolated yields. See the
Supporting Information for details. b Lithium dicyclohexylamide
was used as the base. c PhF was used instead of PhCl. d LiN(iPr)2
was used as the base. e Phenylpyrrole (2 equiv) and PhCl (1 equiv)
were used.
derivatives afford the arylation products in excellent yields
(entries 6-8). The arylation is not limited to five-mem-
bered-ring heterocycles. Pyridine and pyridazine derivatives are
arylated in reasonable yields (entries 9 and 10). Arenes such as
1,3-dimethoxybenzene and 3-methoxybenzotrifluoride are reac-
tive (entries 11 and 12).
We performed a sequential one-pot diarylation of N-methyli-
midazole. The heterocycle mixture with chlorobenzene was
treated with LDA in THF at room temperature, and this was
followed by quenching with MeOH and evaporation. Following
the addition of 2-chloroanisole and TMPLi in THF, a single
isomer of the diarylation product was obtained in50% yield (eq 1).
In conclusion, we have developed a transition-metal-free
method for base-promoted arylation of heterocycles and arenes
by aryl chlorides and fluorides. The reactions proceed via aryne
intermediates at mild temperatures and allow for highly regiose-
lective arylation of the arene and heterocycle C-H bonds.
Functionalization occurs at the most acidic carbon-hydrogen
bond.
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’ ASSOCIATED CONTENT
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Supporting Information. Experimental procedures and
b
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
olafs@uh.edu
’ ACKNOWLEDGMENT
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We thank the Welch Foundation (Grant E-1571), the National
Institute of General Medical Sciences (Grant R01GM077635), the
Alfred P. Sloan Foundation, and the Camille and Henry Dreyfus
Foundation for supporting this research.
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