Transition-metal-free alkynylation of aryl chlorides

Article abstract of DOI:10.1021/ol2014736

Two sets of conditions have been developed for a base-mediated, transition-metal-free alkynylation of aryl chlorides that proceeds via benzyne intermediates. The first set of conditions involves the use of TMPLi base in a pentane/THF mixture at 25 °C. The

Full text of DOI:10.1021/ol2014736

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4172–4175
Transition-Metal-Free Alkynylation of
Aryl Chlorides
Thanh Truong and Olafs Daugulis*
Department of Chemistry, University of Houston, Houston, Texas 77204-5003,
United States
olafs@uh.edu
Received May 31, 2011
ABSTRACT
Two sets of conditions have been developed for a base-mediated, transition-metal-free alkynylation of aryl chlorides that proceeds via benzyne
intermediates. The first set of conditions involves the use of TMPLi base in a pentane/THF mixture at 25 °C. The second set involves use of a metal
alkoxide base in dioxane at elevated temperature. Reasonable functional group tolerance has been observed. Fluoro, trifluoromethyl, silyl, cyano,
and alcohol functionalities are compatible with the reaction conditions.
Transition-metal-catalyzed formation of carbonÀ
carbon bonds has become an indispensable tool in organic
synthesis.1 Specifically, the Sonogashira reaction, palla-
dium- and copper-cocatalyzed formation of sp2Àsp car-
bonÀcarbon bonds between aryl halides and terminal
alkynes, is one of the most important methods for the
synthesis of substituted acetylenes.2 However, trace resi-
dues of transition metals are often difficult to remove from
final products that are used for pharmaceutical appli-
cations.3 Consequently, it is advantageous to develop
transition-metal-free cross-coupling reactions.4 Several
examples of such sp2Àsp carbonÀcarbon bond formation
reactions have been described in the literature.5 In most
cases, however, either photochemical activation, pre-
formed Grignard reagents, or activated aryl halides are
required.
A few examples of benzyne reactions with alkynes have
been reported. A mechanistically distinct publication de-
scribes an ene reaction of arynes with alkynes affording
allenes.6 The arynes are generated from 2-(trimethylsilyl-
)aryl triflates, and only alkynes possessing propargylic
hydrogen substituents are reactive. Benzyne cycloaddi-
tions with alkynes have also been reported.7 In an early
mechanistic work, Roberts has investigated benzyne reac-
tivity with a variety of nucleophiles such as fluorenyl,
anilide, acetophenone enolate, and phenylacetylide.8 Cop-
per- and other transition-metal-catalyzed reactions of
alkynes with arynes have been described.9 However, a
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r
10.1021/ol2014736
Published on Web 07/25/2011
2011 American Chemical Society

Table 1. Alkynylation Scope with Respect to Aryl Chloridesa
a Method A: aryl halide (1.5À2.5 equiv), phenylacetylene (1 equiv), TMPLi (3À4 equiv), pentane/THF, 25 °C. Method B: aryl halide (2.6À3 equiv),
phenylacetylene (1 equiv), tBuONa or tBuOK (7 equiv), dioxane, 106À135 °C. Yields are isolated yields of a pure major isomer unless otherwise noted,
and reactions were run on a 0.5 mmol scale. See Supporting Information for details. b 1:1 ratio of PhCl and alkyne. c Isomer mixture; m/p ratio 1/1.2.
general procedure for aryl chloride alkynylation that pro-
ceeds via a benzyne mechanism has not been developed.
We have recently reported a direct transition-metal-free,
base-mediated intermolecular arylation of heterocycles
and arenes by aryl halides.10 By employing hindered
lithium amidebases inpentane/THF mixtures, thiophenes,
furans, imidazoles, indoles, pyrroles, pyrazines, pyridines,
and methoxybenzene derivatives can be arylated by aryl
chlorides and fluorides. The reactions proceed via benzyne
intermediates and are highly regioselective with respect to
an arene coupling component. In this report, we expand
the methodology to base-mediated alkynylation of aryl
chlorides that can be thought of as a transition-metal-free
Sonogashira coupling.
pentane/THF mixture. Use of hindered LiTMP retards the
reaction of benzyne with a base. The relative reactivity of
the base and alkynyl anion with benzyne is modulated by
employing a solvent where the amide base is sparingly
soluble. This set of conditions is based on an earlier report
for heterocycle arylation by aryl halides.10 The second set
of conditions involves heating a reaction mixture in diox-
ane in the presence of an alkoxide base and is based on a
previously published intramolecular arylation of phenol
derivatives proceeding via benzyne intermediates.12 For
most of the examples, both sets of conditions afford
comparable yields.
The reaction scope with respect to aryl chlorides is
presented in Table 1. Arylation of phenylacetylene by 2-
and 3-chloroanisole affords 3-methoxydiphenylacetylene
(entries 2 and 3). Both of the isomeric aryl chlorides form
Two sets of reaction conditions were developed for
the aryl chloride alkynylation. The first one employs a
lithium 2,2,6,6-tetramethylpiperidide (LiTMP) base11 in a
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Org. Lett., Vol. 13, No. 16, 2011
4173

3-methoxybenzyne.13 The following regioselective nucleophile
addition to benzyne is explained in terms of ground-state
polarization of the aryne by electron-withdrawing substitu-
ents and the energy that is required to distort the aryne into
two possible transition states.14 3-Chlorodimethylaniline and
3-chlorobenzotrifluoride are reactive, and products are ob-
tained in good yields (entries 4 and 6). For the latter substrate,
both reaction conditions afford good yields. Interestingly, by
employing the tBuONa base, it is possible to selectively
substitute chloride in 3-fluorochlorobenzene (entry 5). For
this substrate, use of the TMPLi base was not successful. In
several cases, isomer mixtures are obtained. For 2-chlorocu-
mene (entry 8), a 12/1 isomer mixture was obtained with the
3-isomer as a major product. The alkynylation of 1- and
2-chloronaphthalenes affords product as 5.4/1 and 11.6/1
isomer mixtures, with the 2-isomer of the product pre-
dominating (entries 9 and 10). The reported yields are
those of a pure major isomer after purification by HPLC.
3,5-Dimethoxychlorobenzene, 3-chloro-4-methoxytoluene,
and 9-chlorophenanthrene are reactive, and products are
obtained in good yields (entries 11À13). If 4-chloro-tert-
butylbenzene is used, a nearly 1/1 mixture of alkynylation
product isomers is obtained (entry 14).
Table 2. Alkynylation Scope with Respect to Alkynesa
The reaction scope with respect to alkynes is presented in
Table 2. Sodium acetylide can be used under both reaction
conditions to form disubstitution products (entry 1). Sub-
stituted phenylacetylenes are reactive (entries 2À3). Cyano
group is tolerated (entry 4). 3-Ethynylthiophene affords the
product in good yield (entry 5). Many aliphatic alkynes can
be used as coupling partners. t-Butylacetylene, cyclohexy-
lacetylene, and 3-methyl-1-hexyne are reactive and cou-
plings proceed in good yields (entries 6À8). However, for
alkynes possessing propargylic hydrogens, careful tempera-
ture optimization is required to prevent base-mediated
conversion to allene and method B could not be used due
to high reaction temperature. Primary alkylacetylenes suffer
extensive isomerization to allenes and acceptable yields
could not be obtained. Tertiary and hindered secondary
hydroxyl groups are tolerated (entries 9 and 10). Silyl group-
containing alkynes are arylated in good yields and cleavage
of the silyl substituent is not observed if TMPLi base is
employed (entries 11 and 12).
Preliminary mechanistic investigations were performed.
Thus, 3-chloroanisole and 4-methoxyphenylacetylene
were heated in dioxane at 110 °C in the presence of 6 equiv
of tBuOK and 6.5 equiv of tBuOD (Scheme 1). The H/D
exchange conditions were chosen to mimic conditions B.
Workup and isolation afforded the coupling product in
31% yield. Unreacted 3-chloroanisole was recovered in
25% yield. Analysis by 1H NMR showed extensive
incorporation of the deuterium label adjacent to methoxy
and chloro substituents arising from the metalationÀ
deuteration sequence in recovered chloroarene and the
coupling product. Similar results were obtained in the
reaction of 2-chloroanisole with 4-methoxyacetylene. In-
terestingly, t-BuOK is able to ortho-metalate nonactivated
a Method A: PhCl (1.8À2 equiv), alkyne (1 equiv), TMPLi (3.2À4.4
equiv), pentane/THF, THF, or diethyl ether solvent, 25 °C. Method B: chlor-
obenzene (3.0 equiv), alkyne (1.0 equiv), tBuOK (7 equiv), dioxane, 106 °C.
Yields are isolated yields, and reactions were run on a 0.5 mmol scale. See Sup-
porting Information for details. b PhCl (4 equiv), TMPLi (5.6 equiv). c PhCl
(5 equiv), tBuOK (8 equiv). d Reaction at À55 °C. e Reaction at À63 °C.
methoxyarenes as evidenced by deuteration of the p-meth-
oxyphenyl group.
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Org. Lett., Vol. 13, No. 16, 2011

Collum and co-workers have measured the rate constants
for benzyne formation from substituted aryllithiums and
concluded that haloanisoles are especially reactive toward
LiX elimination.15d
Scheme 1. Deuteration Experiments
Scheme 2. MetalationÀBenzyne Formation Sequence
Deuterium incorporation at 2- and 4-positions of recov-
ered 3-chloroanisole is noteworthy. Deuterium incorpora-
tion in recovered 3-chloroanisole can be explained by the
intermediacy of three isomers of the arylpotassium species:
A, B, and C (Scheme 2). ortho-Aryne cannot be formed
from C. Compound A can form only 3-methoxybenzyne D
that regioselectively14 reacts with an alkyne anion to form
the observed product F. On the other hand, arylpotassium
B could form 4-methoxybenzyne E that would react to
afford two product isomers F and G in nearly equal
amounts. Since compound G is not observed, and the
deuteration experiment suggests that B is present in the
reaction mixture, it must be concluded that aryne forma-
tion from A is more facile than aryne formation from B.15
In conclusion, two sets of conditions for base-mediated,
transition-metal-free alkynylation of aryl chlorides have
been developed. The first set of conditions involves the use
of the hindered TMPLi base in a pentane/THF mixture at
room temperature. The second set involves use of a metal
alkoxide base in dioxane at elevated temperature. The
methodtolerates functional groupssuchasfluoro, trifluor-
omethyl, silyl, and cyano. Tertiary and secondary alcohols
are also compatible with the reaction conditions.
Acknowledgment. We thank the Welch Foundation
(Grant No. E-1571), NIGMS (Grant No. R01GM077635),
A. P. Sloan Foundation, and Camille and Henry Dreyfus
Foundation for supporting this research.
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Ott, N.; Anneser, E. Chem. Ber. 1960, 93, 412. (c) Ramirez, A.; Candler,
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Supporting Information Available. Experimental pro-
cedures and characterization data for new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 16, 2011
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