Copper-catalyzed decarboxylative cross-coupling of alkynyl carboxylic acids with aryl halides

Article abstract of DOI:10.1039/c0cc03772a

The copper-catalyzed decarboxylative reactions of alkynyl carboxylic acids with aryl halides were performed under relatively mild reaction conditions. Benzofurans could be further prepared smoothly by a one-pot domino protocol on the basis of decarboxylative cross-coupling of 2-iodophenol.

Full text of DOI:10.1039/c0cc03772a

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Copper-catalyzed decarboxylative cross-coupling of alkynyl carboxylic
acids with aryl halidesw
Dongbing Zhao, Chao Gao, Xiaoyu Su, Yunqing He, Jingsong You* and Ying Xue*
Received 10th September 2010, Accepted 11th October 2010
DOI: 10.1039/c0cc03772a
The copper-catalyzed decarboxylative reactions of alkynyl
carboxylic acids with aryl halides were performed under
relatively mild reaction conditions. Benzofurans could be
further prepared smoothly by a one-pot domino protocol on the
basis of decarboxylative cross-coupling of 2-iodophenol.
At the turn of this century, the economic attractiveness and
good functional tolerance of copper-catalytic systems led to
remarkable progress in the development of copper-catalyzed
coupling reactions.9 However, in contrast to well-established
palladium-catalyzed decarboxylative coupling reactions, the
copper-only-mediated systems are less developed.10 To the best
of our knowledge, there is no example describing the copper-
catalyzed decarboxylative coupling to form C(sp)(aryl)C(sp2)
bonds so far. As part of our ongoing research into the
development of highly efficient, versatile copper-catalyzed
cross-coupling reactions,11 we herein disclose the first
copper-catalyzed decarboxylative cross-coupling of alkynyl
carboxylic acids with aryl halides in the presence of
inexpensive and commercially available CuI and 1,10-
phenanthroline (phen).
The alkyne moiety is prevalent in molecular materials,
pharmaceuticals, and natural products.1 During the past
decades, the Sonogashira coupling has become one of the
most versatile and powerful methods for the preparation of
arylalkynes and conjugated enynes.2,3 Recently, the scope of
the reaction has been extended from organic halides to various
pseudohalides.4 Despite remarkable advances in this type of
transformation, from an academic standpoint, further
development of reliable alternatives for the straightforward
synthesis of internal arylalkynes, especially starting from other
readily available sources rather than terminal alkynes, is still a
subject of importance in this area.
Our initial investigation aimed at the coupling of readily
available phenylpropiolic acid with p-chloroiodobenzene in
1,2-dimethoxyethane (DME) using copper(I) iodide as the
catalyst. As Cs2CO3 was used as the base, initial reaction
screening led to disappointing results in the absence of
ligand. We subsequently screened a variety of ligands,
solvents, and bases (Table S1). The best results were
obtained in DMF at 130 1C for 24 h by using Cs2CO3 as
base in the presence of CuI (10 mol%) and phen (10 mol%).
With optimized conditions now in hand, we explored the
scope of this process with respect to a wide array of aryl halide
structure as summarized in Table 1. Gratifyingly, no matter
whether the aryl iodides were electron-rich, electron-poor, or
sterically bulky, all of them afforded good to excellent yields
(Table 1). The high yields observed in the reaction of
4-chlorophenyl iodide or 4-bromophenyl iodide implied that
there was good chemoselectivity between aryl iodide and
bromide or chloride (Table 1, 3h–3j). The heteroaryl iodide
was also coupled with phenylpropiolic acid in a good yield
(Table 1, 3t). Moreover, high-yielding decarboxylative coupling
was possible with aryl bromide bearing an electron-withdrawing
group or heteroaryl bromide, although the reaction has not yet
been investigated in detail (Table 1, 3w and 3x). It is important
to stress that the reaction conditions were compatible with the
presence of functional groups such as hydroxymethyl, ketone,
amino, ester and nitro groups, which may then be subject to
further synthetic transformations (Table 1, 3k–s). When t-butyl-
3,5-diiodobenzene was treated with phenylpropiolic acid, a two-
fold decarboxylative coupling took place to afford the
conjugated alkyne in 92% yield (Table 1, 3v), which indicated
that the current copper-catalysis may have a broad potential for
constructing extended p-electron systems. Importantly, when
aryl iodide bore the carboxyl group, phenylpropiolic acid
preferably underwent the decarboxylation rather than
arenecarboxylic acid (Table 1, 3u).
Carboxylic acids are conveniently available, easy to store,
and simple to handle, and carboxylate groups may function as
the leaving group in cross-coupling, in which only carbon
dioxide is produced as byproduct. Recently, Pd-catalyzed
decarboxylative coupling reactions have provided attractive
protocols for regioselective C–C or C–heteroatom bond
formation.5 Alkynyl carboxylic acid represents a promising
alternative to terminal alkyne owing to higher reactivity,
simplicity and ready availability from inexpensive aldehyde.6
In particular, the use of alkynyl carboxylic acid as the coupling
partner may efficiently suppress the formation of dimerization
product diynes that frequently occurs in the Sonogashira
reactions.7 Recently, pioneering work has established that
the Pd-catalyzed decarboxylative couplings of alkynyl
carboxylic acids with aryl halides,8a–c arylboronic acids8d or
benzyl halides8e afford internal alkynes. This strategy provides
a potential alternative to achieve internal alkyne from
aldehyde.6 It would be useful for total synthesis of natural
products containing internal alkyne frameworks. However,
these palladium-mediated methods still suffer from some
limitations. Firstly, tetrabutylammonium fluoride (TBAF)
(2–6 equiv.), stoichiometric silver salt, and/or lithium iodide
(2–3 equiv.) as additives are required to improve yields.
Secondly, highly expensive, air- and/or moisture-sensitive
bulky phosphines are frequently encountered in the reactions.
Key Laboratory of Green Chemistry and Technology of Ministry
of Education, College of Chemistry, and State Key Laboratory
of Biotherapy, West China Medical School, Sichuan University,
29 Wangjiang Road, Chengdu 610064, P.R. China.
E-mail: jsyou@scu.edu.cn; Fax: (+86) 28-85412203
w Electronic supplementary information (ESI) available: Detailed
experimental procedures, analytical data. See DOI: 10.1039/c0cc03772a
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 9049–9051 9049

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Table 1 Copper-catalyzed decarboxylative coupling of phenylpropiolic
acid with a variety of aryl halidesa
Table
2
Copper-catalyzed decarboxylative coupling of alkynyl
carboxylic acids with aryl iodidesa
Entry Ar
R
Product
Yieldb
91%
1
2
4-MeC6H4
4-ClC6H4
4-NH2C6H4 4-MeC6H4
82%
90%c
92%
3
4
4-ClC6H4
4-ClC6H4
2-MeOC6H4
4-MeOC6H4
5
4-ClC6H4
1-naphthyl
90%
6
7
4-ClC6H4
2-thienyl
87%
85%
4-MeC6H4
n-Pent
8
9
1-naphthyl
4-ClC6H4
n-Bu
88%c
n-Pent
87%
10
4-NH2C6H4 n-Bu
84%c
a
Conditions: aryl iodide (0.25 mmol), alkynyl carboxylic acid (0.35
mmol), CuI (10 mol%), phen (10 mol%), Cs2CO3 (0.375 mmol), DMF
b
c
(1 mL), 24 h, 130 1C. Yield of isolated product. CuI (20 mol%).
a
Conditions: aryl halide (0.25 mmol), phenylpropiolic acid (0.35 mmol),
CuI (10 mol%), phen (10 mol%), Cs2CO3 (0.375 mmol), DMF (1 mL),
Benzofuran-containing molecules are frequently found in a
variety of biologically active compounds. Although these
bioactive properties have motivated the development of
efficient methods for creating the benzofuran framework,
exploring improved routes is still a very active and prolific
field of research. Herein, we utilized our protocol to prepare
substituted benzofurans directly from 2-iodophenol by a
sequential one-pot reaction. For example, 2-iodophenol
underwent the domino reactions involving decarboxylative
coupling and subsequent intramolecular hydroalkoxylation
to provide the benzofuran derivatives in good yields
(Scheme 1).
b
c
24 h, 130 1C. Isolated yield given in parentheses. CuI (20 mol%). CuI
(20 mol%), phenylpropiolic acid (0.70 mmol).
To expand the scope of our methodology, we used this
catalytic system in the decarboxylative couplings of other
alkynyl carboxylic acids with aryl iodides (Table 2). Overall,
we were pleased with the generality of our methodology. As
shown in Table 2, various alkynyl carboxylic acids proceeded
smoothly to afford the desired arylated alkynes in good to
excellent yields. A variety of aromatic alkynyl carboxylic acids
could be efficiently converted into the corresponding coupling
products, which demonstrated that electronic and steric effects
of substituents could be neglected nearly (Table 2, entries 1–5).
Heteroaryl alkynyl carboxylic acid was reactive (Table 2, entry
6). Worthy of note was that aliphatic alkynyl carboxylic acids
could be effectively coupled with aryl iodides to furnish the
desired products in good to excellent yields (Table 2, entries
7–10).
Although more detailed investigations of the reaction
mechanism are currently underway, we have addressed the
competition between decarboxylation and oxidative addition
with the DFT calculations of the corresponding reaction
mechanisms (Fig. S1). Computational investigation suggests
that the oxidant addition should occur at first on copper(I) to
generate the copper(III) intermediate, which subsequently
reacts with alkynyl carboxylic acid to produce the coupling
c
9050 Chem. Commun., 2010, 46, 9049–9051
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2 For reviews of Sonogashira reactions, see: (a) R. Chinchilla and
C. Najera, Chem. Rev., 2007, 107, 874; (b) H. Doucet and
J.-C. Hierso, Angew. Chem., Int. Ed., 2007, 46, 834; (c) H. Plenio,
Angew. Chem., Int. Ed., 2008, 47, 6954.
3 For selected examples of new catalytic systems, see:
lez-Arellano, A. Abad, A. Corma, H. Garca,
nchez, Angew. Chem., Int. Ed., 2007, 46,
(a) C. Gonza
´
M. Iglesias and F. Sa
Scheme 1 Synthesis of benzofurans from 2-iodophenol.
´
1536; (b) F. Monnier, F. Turtaut, L. Duroure and M. Taillefer,
Org. Lett., 2008, 10, 3203; (c) O. Vechorkin, D. Barmaz, V. Proust
and X. Hu, J. Am. Chem. Soc., 2009, 131, 12078; (d) E. Zuidema
and C. Bolm, Chem.–Eur. J., 2010, 16, 4181.
4 For selected examples of Sonogashira reactions with
pseudohalides, see: (a) S. Silva, B. Sylla, F. Suzenet,
product through decarboxylation and reductive elimination.
Notably, the preferential oxidative addition established herein
is opposite to the previously reported copper-catalyzed
decarboxylative coupling of potassium polyfluorobenzoates,
in which the oxidative addition occurred on copper(I) after the
decarboxylation.10
A. Tatibouet, A. P. Rauter and P. Rollin, Org. Lett., 2008, 10,
¨
853; (b) G. Fabrizi, A. Goggiamani, A. Sferrazza and S. Cacchi,
Angew. Chem., Int. Ed., 2010, 49, 4067.
In conclusion, we have developed for the first time the
copper-catalyzed decarboxylative reactions that allow the
cross-coupling of alkynyl carboxylic acids with aryl halides.
The process is not only simple and convenient in terms of the
reaction conditions and purification, but is also tolerant of a
variety of functional groups, which constitutes a practical
route to give unsymmetric internal arylalkynes. Although
aryl bromides or iodides rather than chlorides are required in
this copper-catalyzed system, the scope, experimental ease, and
reliability of a system are often much more important factors
in terms of practical application. In addition, benzofurans are
prepared smoothly by treatment of 2-iodophenol with alkynyl
carboxylic acids under relatively mild reaction conditions. We
believe that these simple procedures outlined here will find
wide applications in various fields of synthetic chemistry.
This work was supported by grants from the National NSF
of China (Nos 21025205, 21021001, 20972102, 20702035,
20772086, and 20773089) and PCSIRT (No IRT0846). We
thank the Centre of Testing & Analysis, Sichuan University for
NMR measurements.
5 For examples of the decarboxylative coupling reactions, see:
(a) L. J. Gooben, G. Deng and L. M. Levy, Science, 2006, 313,
662; (b) H.-P. Bi, L. Zhao, Y.-M. Liang and C.-J. Li, Angew.
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Y. Ariyarathna, K. Chattopadhyay and J. A. Tunge, J. Am. Chem.
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6 J. P. Das, U. K. Roy and S. Roy, Organometallics, 2005, 24, 6136.
7 For a review, see: P. Siemsen, R. C. Livingston and F. Diederich,
Angew. Chem., Int. Ed., 2000, 39, 2632.
8 (a) J. Moon, M. Jeong, H. Nam, J. Ju, J. H. Moon, H. M. Jung and
S. Lee, Org. Lett., 2008, 10, 945; (b) H. Kim and P. H. Lee, Adv.
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J.-H. Li, J. Org. Chem., 2010, 75, 5259.
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Chem. Rev., 2008, 108, 3054; (c) F. Monnier and M. Taillefer,
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10 Only one example for the copper-only system has been described so
far, and see: R. Shang, Y. Fu, Y. Wang, Q. Xu, H.-Z. Yu and
L. Liu, Angew. Chem., Int. Ed., 2009, 48, 9350.
11 For selected examples, see: (a) D. Zhao, W. Wang, F. Yang, J. Lan,
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J. You, Angew. Chem., Int. Ed., 2009, 48, 8729; (c) P. Xi, F. Yang,
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Notes and references
1 (a) L. Brandsma, Synthesis of Acetylenes, Allenes and Cumulenes:
Methods and Techniques, Elsevier, Oxford, 2004; (b) F. Diederich,
P. Stang and R. R. Tykwinski, Acetylene Chemistry: Chemistry,
Biology, and Material Science, Wiley-VCH, Weinheim, 2005.
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 9049–9051 9051