Cu(I)-catalyzed carboxylative coupling of terminal alkynes, allylic chlorides, and CO2

Article abstract of DOI:10.1021/ol102172v

A highly selective synthesis of a variety of functionalized allylic 2-alkynoates was realized via the carboxylative coupling of terminal alkynes, allylic chlorides, and CO₂ catalyzed by the N-heterocyclic carbene copper(I) complex (IPr)CuCl. The catalyst can be easily recovered without any loss in activity and product selectivity.

Full text of DOI:10.1021/ol102172v

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4748-4751
Cu(I)-Catalyzed Carboxylative Coupling
of Terminal Alkynes, Allylic Chlorides,
and CO2
Wen-Zhen Zhang,* Wen-Jie Li, Xiao Zhang, Hui Zhou, and Xiao-Bing Lu*
State Key Laboratory of Fine Chemicals, Dalian UniVersity of Technology,
Dalian, 116012, China
zhangwz@dlut.edu.cn; lxb-1999@163.com
Received July 19, 2010
ABSTRACT
A highly selective synthesis of a variety of functionalized allylic 2-alkynoates was realized via the carboxylative coupling of terminal alkynes,
allylic chlorides, and CO2 catalyzed by the N-heterocyclic carbene copper(I) complex (IPr)CuCl. The catalyst can be easily recovered without
any loss in activity and product selectivity.
Catalytic transformations of carbon dioxide (CO2) have
gained considerable attention due to its potential use as an
attractive, abundant, and inexpensive C1 source and its main
contribution to global warming.1 Significant efforts have been
devoted toward developing convenient approaches to convert
CO2 into carboxylic acid and derivatives.2-6 CO2 usually
serves as a cycloaddition partner of unsaturated com-
pounds1c,7 and more importantly as an electrophile in the
carboxylation of nucleophilic organometallic reagents.8
Although the direct carboxylation of highly reactive org-
anolithium and Grignard reagents with CO2 can be easily
carried out, transition-metal-catalyzed carboxylation of less
reactive carbon nucleophiles such as organoboron and
organozinc reagents represents a more practical method to
access carboxylic acids bearing various functional groups.3,4
(1) (a) Arakawa, H.; Aresta, M.; Armor, J. N.; Barteau, M. A.; Beckman,
E. J.; Bell, A. T.; Bercaw, J. E.; Creutz, C.; Dinjus, E.; Dixon, D. A.; Domen,
K.; DuBois, D. L.; Eckert, J.; Fujita, E.; Gibson, D. H.; Goddard, W. A.;
Goodman, D. W.; Keller, J.; Kubas, G. J.; Kung, H. H.; Lyons, J. E.; Manzer,
L. E.; Marks, T. J.; Morokuma, K.; Nicholas, K. M.; Periana, R.; Que, L.;
Rostrup-Nielson, J.; Sachtler, W. M. H.; Schmidt, L. D.; Sen, A.; Somorjai,
G. A.; Stair, P. C.; Stults, B. R.; Tumas, W. Chem. ReV. 2001, 101, 953.
(b) Louie, J. Curr. Org. Chem. 2005, 9, 605. (c) Mori, M. Eur. J. Org.
Chem. 2007, 4981. (d) Sakakura, T.; Choi, J.-C.; Yasuda, H. Chem. ReV.
2007, 107, 2365. (e) Aresta, M.; Dibenedetto, A. Dalton Trans. 2007, 2975.
(2) (a) Shi, M.; Nicholas, K. M. J. Am. Chem. Soc. 1997, 119, 5057.
(5) (a) Greco, G. E.; Gleason, B. L.; Lowery, T. A.; Kier, M. J.;
Hollander, L. B.; Gibbs, S. A.; Worthy, A. D. Org. Lett. 2007, 9, 3817. (b)
Williams, C. M.; Johnson, J. B.; Rovis, T. J. Am. Chem. Soc. 2008, 130,
14936. (c) Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2008, 130, 15254.
(d) Tanaka, R.; Yamashita, M.; Nozaki, K. J. Am. Chem. Soc. 2009, 131,
14168. (e) Correa, A.; Martin, R. J. Am. Chem. Soc. 2009, 131, 15974.
(6) (a) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. J. Am. Chem.
Soc. 2006, 128, 11040. (b) Yoshida, H.; Morishita, T.; Ohshita, J. Org.
Lett. 2008, 10, 3845. (c) Riduan, S. N.; Zhang, Y.; Ying, J. Y. Angew.
Chem,. Int. Ed. 2009, 48, 3322. (d) Chen, G.; Fu, C.; Ma, S. Org. Lett.
2009, 11, 2900.
(b) Franks, R. J.; Nicholas, K. M. Organometallics 2000, 19, 1458
.
(7) (a) Louie, J.; Gibby, J. E.; Farnworth, M. V.; Tekavec, T. N. J. Am.
Chem. Soc. 2002, 124, 15188. (b) Takimoto, M.; Nakamura, Y.; Kimura,
K.; Mori, M. J. Am. Chem. Soc. 2004, 126, 5956. (c) Aoki, M.; Izumi, S.;
Kaneko, M.; Ukai, K.; Takaya, J.; Iwasawa, N. Org. Lett. 2007, 9, 1251.
(d) Lu, X.-B.; Liang, B.; Zhang, Y.-J.; Tian, Y.-Z.; Wang, Y.-M.; Bai, C.-
X.; Wang, H.; Zhang, R. J. Am. Chem. Soc. 2004, 126, 3732. (e) Zhou, H.;
Zhang, W.-Z.; Liu, C.-H.; Qu, J.-P.; Lu, X.-B. J. Org. Chem. 2008, 73,
8039. (f) Ren, W.-M.; Liu, Z.-W.; Wen, Y.-Q.; Zhang, R.; Lu, X.-B. J. Am.
Chem. Soc. 2009, 131, 11509.
(3) For carboxylation of organoboronic esters, see: (a) Ukai, K.; Aoki,
M.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2006, 128, 8706. (b) Takaya,
J.; Tadami, S.; Ukai, K.; Iwasawa, N. Org. Lett. 2008, 10, 2697. (c) Ohishi,
T.; Nishiura, M.; Hou, Z. Angew. Chem., Int. Ed. 2008, 47, 5792
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(4) For carboxylation of organozinc reagents, see: (a) Yeung, C. S.;
Dong, V. M. J. Am. Chem. Soc. 2008, 130, 7826. (b) Ochiai, H.; Jang, M.;
Hirano, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2008, 10, 2681. (c)
Kobayashi, K.; Kondo, Y. Org. Lett. 2009, 11, 2035
.
10.1021/ol102172v  2010 American Chemical Society
Published on Web 10/07/2010

With respect to the mechanism of transition-metal-
catalyzed carboxylation, active species II bearing a new
metal-carbon bond is generally thought to be first formed
through metalation of a relatively active C-H bond9 or
transmetalation of a less reactive carbon nucleophile with
transition-metal catalyst I. The insertion of CO2 to the
metal-carbon bond affords transition-metal carboxylate III.
Next, transmetalation of III with alkali metal compounds
regenerates catalyst I and simultaneously forms carboxylate
IV (Scheme 1, A). The acidification of the resulting
alkyl 2-alkynoates at 100 °C.11 However, when allylic or
benzyl 2-alkynoates, which are versatile synthetic intermedi-
ates,12 were targeted, this methodology suffered from major
formation of direct coupling or dialkyl carbonate byproduct.13
On the basis of the possible mechanistic aspects of carboxyl-
ative coupling shown in Scheme 1, we envisioned that, using
less reactive allylic chlorides together with wise choice of
catalyst, the allylic 2-alkynoates, which were generally prepared
by condensation of alkynecarboxylic acid and allylic alcohol,
could be directly synthesized using CO2 as a carboxylative
agent. Herein we report a convenient route for highly selective
synthesis of allylic 2-alkynoates from the carboxylative coupling
of terminal alkynes, allylic chlorides, and CO2 catalyzed by the
N-heterocyclic carbene (NHC) copper(I) complex.14 Further-
more, the copper(I) catalyst can be readily recovered, without
any loss in activity and product selectivity.15
Scheme 1
.
Transition-Metal-Catalyzed Carboxylation and
Carboxylative Coupling Reaction
Initially, the carboxylative coupling reaction of phenyl-
acetylene (1a), cinnamyl chloride (2a), and CO2 was chosen
as a model reaction to identify an effective catalytic system
and optimize the reaction conditions (Table 1). The reaction
did not occur in the absence of any catalyst (entry 1). When
copper(I) salt alone or in combination with N ligands such as
2,2′-bipyridine (bpy) and N,N,N′,N′-tetramethylethylenediamine
(TMEDA) was used as catalyst, a modest yield of carboxylative
coupling product 4a accompanied with a considerable amount
of direct coupling product 3a was obtained (entries 2-6).16
In this carboxylative coupling reaction, the active species
II in Scheme 1 should be copper(I) acetylide generated by
the reaction of terminal alkyne, K2CO3, and copper(I)
catalyst, which is also proposed commonly as an intermediate
in a copper-cocatalyzed Sonogashira reaction.17 Hou and co-
workers reported that N-heterocyclic carbene copper(I)
complexes are excellent catalysts for carboxylation of
organoboronic esters, wherein CO2 can easily insert into an
sp2-hybridized carbon-copper(NHC) bond.3c Inspired by this
insight, we envisioned that CO2 could also insert into the
sp-hybridized carbon-copper(NHC) bond when an N-
carboxylate IV releases carboxylic acid. Given that an alkyl
halide was introduced to the above reaction system, it is
possible to produce carboxylic acid ester from the coupling
between the transition-metal carboxylate III and alkyl halide
(Scheme 1, B).10 As a result, it would provide a convenient
route for synthesizing carboxylic acid ester directly from the
carboxylative coupling of the carbon nucleophile, alkyl
halide, and CO2. However, the easily formed byproduct from
the cross-coupling between the active species II and alkyl
halide (Scheme 1, C) results in poor selectivity for the
carboxylative coupling product. Therefore, highly selective
synthesis of carboxylic acid ester by the carboxylative
coupling shown in Scheme 1 (B) is a promising challenge.
Compared with much-studied carboxylation reactions to
prepare carboxylic acid, the carboxylative coupling for
directly affording carboxylic acid ester has been rarely
reported. In 2000, Franks and Nicholas reported palladium-
catalyzed carboxylative coupling of allylstannanes, allyl
halides, and CO2 at 5.0 MPa CO2 pressure to produce allyl
ester, but the substrate scope is very limited.2b Inoue and
co-workers disclosed the copper-catalyzed carboxylative
coupling of terminal alkynes and alkyl bromides to synthesize
(11) (a) Fukue, Y.; Oi, S.; Inoue, Y. J. Chem. Soc., Chem. Commun.
1994, 2091. (b) Oi, S.; Fukue, Y.; Nemoto, K.; Inoue, Y. Macromolecules
1996, 29, 2694.
(12) (a) Ma, S.; Lu, X. J. Org. Chem. 1993, 58, 1245. (b) Zhang, Q.;
Lu, X.; Han, X. J. Org. Chem. 2001, 66, 7676. (c) Rayabarapu, D. K.;
Tunge, J. A. J. Am. Chem. Soc. 2005, 127, 13510. (d) Yin, G.; Liu, G.
Angew. Chem., Int. Ed. 2008, 47, 5442. (e) Pi, S.-F.; Tang, B.-X.; Li, J.-
H.; Liu, Y.-L.; Liang, Y. Org. Lett. 2009, 11, 2309. (f) Lee, Y. T.; Kang,
Y. K.; Chung, Y. K. J. Org. Chem. 2009, 74, 7922.
(13) Reaction of phenylacetylene, cinnamyl bromide, and CO2 under
the conditions of reference 11a gave 89% yield of direct coupling product
and 6% yield of dicinnamyl carbonate, but no carboxylative coupling product
was detected.
(14) For reviews on N-heterocyclic carbene complexes, see: (a)
Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290. (b) Crabtree,
R. H. Coord. Chem. ReV. 2007, 251, 595. (c) Hahn, F. E.; Jahnke, M. C.
Angew. Chem., Int. Ed. 2008, 47, 3122. (d) D´ıez-Gonza´lez, S.; Marion, N.;
Nolan, S. P. Chem. ReV. 2009, 109, 3612.
(15) For recovery of the homogeneous catalysts, see: (a) Cole-Hamilton,
D. J. Science 2003, 299, 1702. (b) Kingsbury, J. S.; Harrity, J. P. A.;
Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791.
(16) For coupling of terminal alkynes with allylic and benzyl halides,
see: (a) Grushin, V. V.; Alper, H. J. Org. Chem. 1992, 57, 2188. (b) Larsen,
C. H.; Anderson, K. W.; Tundel, R. E.; Buchwald, S. L. Synlett 2006, 2941.
(c) Bieber, L. W.; da Silva, M. F. Tetrahedron Lett. 2007, 48, 7088. (d)
Davies, K. A.; Abel, R. C.; Wulff, J. E. J. Org. Chem. 2009, 74, 3997.
(17) For reviews, see: (a) Chinchilla, R.; Najera, C. Chem. ReV. 2007,
107, 874. (b) Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2007, 46,
834.
(8) Correa, A.; Martin, R. Angew. Chem., Int. Ed. 2009, 48, 6201.
(9) (a) Boogaerts, I. F.; Nolan, S. P. J. Am. Chem. Soc. 2010, 132, 8858.
(b) Vechorkin, O.; Hirt, N.; Hu, X. Org. Lett. 2010, 12, 3567.
(10) For copper-catalyzed C-O(carboxylate) coupling of carboxylic
acids and organic halides, see: (a) Yamamoto, T. Synth. Commun. 1979, 9,
219. (b) Yamamoto, T.; Kurata, Y. Can. J. Chem. 1983, 61, 86. (c) Thasana,
N.; Worayuthakarn, R.; Kradanrat, P.; Hohn, E.; Young, L.; Ruchirawat,
S. J. Org. Chem. 2007, 72, 9379. (d) Sun, C.; Fang, Y.; Li, S.; Zhang, Y.;
Zhao, Q.; Zhu, S.; Li, C. Org. Lett. 2009, 11, 4084.
Org. Lett., Vol. 12, No. 21, 2010
4749

The CO2 pressure has a promising effect on reaction rate
and product selectivity (entry 11). Relatively high CO2
pressure (1.5 MPa) is beneficial to suppressing the formation
of direct coupling byproduct 3a and signficantly improving
the reaction rate. Further screening of reaction parameters
(see Supporting Information) established the optimum condi-
tions: CO2 (1.5 MPa), (IPr)CuCl (10 mol %), K2CO3 (2
equiv), DMF, 60 °C, 24 h.
Table 1. Copper-Catalyzed Carboxylative Coupling of
Phenylacetylene, Cinnamyl Chloride, and CO2
a
Under the optimized reaction conditions, the scope of
carboxylative coupling of terminal alkynes, allylic chlorides,
and CO2 was investigated. Carboxylative coupling reaction
of a variety of aryl- and alkyl-substituted terminal alkynes
with cinnamyl chloride proceeded smoothly to afford the
corresponding cinnamyl 2-alkynoates in good yield and
excellent selectivity (Table 2). As expected, the catalyst
yield (%)b
entry
catalyst
3a
4a
1c
2
3
4
5
-
-
-
CuCl
CuBr
10
35
28
23
12
3
<1
<1
17
8
46
47
24
52
68
51
91
74
-
CuI
CuCl + bpy
CuCl + TMEDA
(IMes)CuCl
(IPr)CuCl
(IPr)CuCl
(IPr)CuCl
(IPr)CuCl
6
7
Table 2. (IPr)CuCl-Catalyzed Carboxylative Coupling of
a
8d
9e
10f
11g
Terminal Alkynes, Cinnamyl Chloride, and CO2
26
a Reaction conditions: 1a (2 mmol), 2a (3 mmol), K2CO3 (4 mmol), Cu
catalyst (10 mol %), 20 mL of DMF. b Isolated yield. c In the absence of
catalyst. d 92% catalyst was recovered after reaction. e 5 mol % catalyst.
f In the absence of CO2. g 0.2 MPa CO2.
heterocyclic carbene copper(I) complex was used as catalyst
in this carboxylative coupling reaction. We delightedly found
that the copper(I) complex (IPr)CuCl (Scheme 2) could
function as a highly active catalyst for this reaction to
Scheme 2. N-Heterocyclic Carbene Copper(I) Complexes
selectively afford the carboxylative coupling product 4a
(entry 8). Notably, the catalyst (IPr)CuCl was easily recov-
ered in 92% yield by column chromatography after the
reaction. It is noteworthy that no carboxylative coupling
product 4a was obtained in the absence of CO2 (entry 10).
a Reaction conditions: 1 (2 mmol), 2a (3 mmol), 20 mL of DMF.
b Isolated yield, <1% yield of direct coupling byproduct was obtained.
Also, a carboxylative coupling reaction using 13C-labeled
13
CO2 gave product
C -labeled (E)-cinnamyl phenyl-
carbonyl
propiolate (4a′) in high yield (see Supporting Information).
These results suggest that the CO2 unit in 4a orginates from
free CO2 rather than K2CO3. The presence of CO2 resulting
in the enhanced conversion of reactants suggests that the
coupling reaction of cinnamyl chloride with copper(I)
acetylide species is slower than that with the copper(I)
carboxylate intermediate, indicating the fast insertion of CO2
to the sp-hybridized carbon-copper(NHC) bond.
(IPr)CuCl could be recovered without any loss in activity
and product selectivity. This catalytic system exhibited good
tolerance toward a wide range of functional groups including
ether, cyclopropane, cyano, and ester (entries 4, 9, 12, 14,
and 15). It should be emphasized that no self-coupling
product was detected in the system of 1m, indicating that
the chloride group in 1m showed no reactivity at the reaction
conditions (entry 13). However, the reaction concerning
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Org. Lett., Vol. 12, No. 21, 2010

heteroaryl-substituted alkyne 1g gave the corresponding
product 4g in modest yield and relatively low catalyst
recovery (entry 7).
Various allylic chlorides could undergo a carboxylative
coupling reaction with phenylacetylene and CO2 to selec-
tively afford the corresponding allylic phenylpropiolates in
good yield (Table 3, entries 2-5). Propargylic chlorides were
also found to be suitable substrates (entries 6-8).18 Anastas
and co-workers reported that silver-catalyzed reaction of
phenylacetylene, CO2, and 3-bromo-1-phenyl-1-propyne af-
forded arylnaphthalene lactones.19 On the contrary, in our
reaction conditions, propargylic phenylpropiolates were
predominantly obtained. This catalytic system also proved
applicable for a carboxylative coupling reaction concerning
benzyl chlorides and R-chloro carbonyl compounds (entries
9-13). Likewise, the catalyst (IPr)CuCl could be recovered
in high yield (72-93%) through simple chromatography after
the reaction (Table 3).
Table 3. (IPr)CuCl-Catalyzed Carboxylative Coupling of 1a
with Allylic Chlorides and Other Chloride Compoundsa
In summary, we have developed an effective method for
selectively synthesizing functionalized allylic 2-alkynoates
by the carboxylative coupling of terminal alkynes, allylic
chlorides, and CO2. N-Heterocyclic carbene copper(I) com-
plex (IPr)CuCl proved to be a highly selective and active
catalyst for this reaction. Also, the catalyst (IPr)CuCl can
be easily recovered in high yield by simple chromatography.
Further exploration of highly active catalyst systems for
carboxylative coupling and mechanistic study on CO2 as a
carboxylation reagent are in progress in our laboratory.
Acknowledgment. This work is supported by National
Natural Science Foundation of China (Grant 20802007) and
National Basic Research Program of China (973Program:
2009CB825300). X.-B. Lu gratefully acknowledges the
Outstanding Young Scientist Foundation of NSFC (Grant
20625414).
Supporting Information Available: Experimental pro-
cedure and characterization of products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL102172V
a Reaction conditions: 1a (2 mmol), 2 (3 mmol), 20 mL of DMF.
b Isolated yield, <1% yield of direct coupling byproduct were obtained.
(18) When propargylic chlorides were used as substrates, no allene
byproduct was detected in our reaction conditions.
(19) Eghbali, N.; Eddy, J.; Anastas, P. T. J. Org. Chem. 2008, 73, 6932.
Org. Lett., Vol. 12, No. 21, 2010
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