Copper-catalyzed decarboxylative cross-coupling of propiolic acids and terminal alkynes

Article abstract of DOI:10.1016/j.tetlet.2009.12.138

A copper-catalyzed decarboxylative cross-coupling reaction of propiolic acids with terminal alkynes is developed leading to unsymmetric 1,3-conjugated diynes under mild conditions. This method provides a novel decarboxylative cross-coupling for sp-sp bond formation. Compared to organic halides, only carbon dioxide is produced as by-products in this approach.

Full text of DOI:10.1016/j.tetlet.2009.12.138

Tetrahedron Letters 51 (2010) 1287–1290
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Tetrahedron Letters
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Copper-catalyzed decarboxylative cross-coupling of propiolic acids
and terminal alkynes
b
b
c
b,
Miao Yu a, , Delin Pan , Wei Jia , Wei Chen , Ning Jiao
*
*
a Department of Radiology, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing 100853, China
b State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, China
c Chinese PLA Postgraduate Medical School, No. 28, Fuxing Road, Beijing 100853, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A copper-catalyzed decarboxylative cross-coupling reaction of propiolic acids with terminal alkynes is
developed leading to unsymmetric 1,3-conjugated diynes under mild conditions. This method provides
a novel decarboxylative cross-coupling for sp-sp bond formation. Compared to organic halides, only car-
bon dioxide is produced as by-products in this approach.
Received 2 October 2009
Revised 22 December 2009
Accepted 24 December 2009
Available online 7 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Diynes are important structural motifs in a great number of
natural products as well as building blocks in organic synthesis.1
The compounds containing 1,3-conjugated diynes fragment show
an interesting array of biological activities.2 For example, Norcap-
illene is isolated from Yin Chen Hao (Artemisia capillaris) (Fig. 1),
which is well-known in traditional Chinese medicine.3 Thiarub-
rine A, isolated from Aspilia Africana (Fig. 1), has been shown to
exhibit a wide spectrum of potent antiviral, antifungal, and anti-
bacterial activities.4 19-(2-Furyl)nonadeca 5,7-diynoic acid
(Fig. 1), isolated from Polyalthia, shows antiplasmodial activity.5
And falcarindiol (Fig. 1), isolated from Panax ginseng, is antistaph-
ylococcal acetylene.6 Therefore, efficient construction of conju-
gated diynes, especially unsymmetrical diynes, has attracted
great attention.1,7
Oxidative homocoupling reaction of terminal alkynes was first
reported by Glaser8 in 1869 (a, Scheme 1). To date this coupling
reaction and related modified methods9 are still widely applied
in the construction of symmetric diynes.7 Cadiot–Chodkiewicz
coupling, which is Cu-catalyzed coupling between a haloalkyne
and a terminal alkyne, has been reported to be a useful route to
diynes for over five decades,10 and is currently the major method
for constructing unsymmetric conjugated diynes.11 (b, Scheme 1)
A variety of organometallic acetylides, such as alkynylcoppers,12
alkynylsilanes,11f alkynylmagnesiums,13 and alkynylzincs14 repre-
sent interesting alternatives to the terminal alkynes utilized in
Cadiot–Chodkiewicz coupling. Co13a and Pd15 are also used to
catalyze this cross-coupling reaction. Several new processes have
been introduced to the construction of unsymmetrical conjugated
diynes. Lei et al. reported a method directly coupling two different
terminal alkynes with high loading of one alkyne partner.16 Negishi
et al. developed an efficient tandem protocol, utilizing terminal al-
kynes and ICH@CHCl as the substrates7b,17 (c, Scheme 1). However,
halogenated substrates or alkynyl metal reagents were required
and halid by-products were produced in these methods. There is
still space for improvement in the synthesis of unsymmetric conju-
gated diynes.
Carboxylic acids have shown great potential in catalytic trans-
formations. The protodecarboxylation of carboxylic acids is long
established in organic synthesis.18,19 They can also be considered
to be valid candidates for the replacement of organometallic com-
pounds, or direct C–H bond activation in numerous cross-coupling
reactions18b,20 and Heck reactions.19v We hypothesized that propi-
olic acids could be used as the alkyne candidates, instead of alkynyl
metal reagents in the construction of unsymmetric conjugated diy-
nes (Scheme 1). Carboxylic acids are among the most common
functionalities in organic molecules. They are largely available, sta-
ble, and easy to handle and store. The decarboxylative cross-
coupling reaction of aryl-carboxylates and
a-oxocarboxylates has
been used in biaryls and aryl ketones synthesis.19,21 Propiolic acids
were also employed for the palladium-catalyzed decarboxylative
CH3
H3C
S
S
Norcapillene
Thiarubrine A
CO2H
OH
9
O
Falcarinol
19-(2-furyl)nonadeca-5,7-diynoic acid
* Corresponding authors. Tel./fax: +86 10 8280 5297.
E-mail addresses: yum301fsk@163.com (M. Yu), jiaoning@bjmu.edu.cn (N. Jiao).
Figure 1. Examples of conjugated diynes in natural products.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.138

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M. Yu et al. / Tetrahedron Letters 51 (2010) 1287–1290
gand instead of TMEDA (Table 1, entry 2). Then we examined the
[Cu]
(a)
R
R
H (M)
R
R
oxidant
efficiency of various ligands (entries 1–4). 1,10-Phenanthroline
proved most efficient for this coupling reaction (Table 1, entry 3).
The organic base Et3N showed the best activity compared to other
inorganic base such as KOAc and K3PO4 (Table 1, entries 5–7). On
the contrary, the reaction gave low yield in the absence of base
(10%, Table 1, entry 8). Further investigations showed that the
most effective catalyst is CuI (Table 1, entry 11). DMF proved to
be a particularly suitable solvent for this transformation (Table 1,
cf. entries 3 with 12 and 13). It is noteworthy that only a trace of
3a was obtained when the reaction was carried out under N2 (Table
1, entry 14). After a great deal of screening on different parameters,
we concluded that the reaction proceeded most efficiently under
these conditions: CuI (10 mol %), 1,10- phenanthroline (10 mol %),
Et3N (2.0 equiv), reacted at 120 °C in DMF under air (Table 1, entry
11).
Glaser Coupling
[Cu], N2
- HBr or MBr
(b)
H(M) +
X
+
I
R
R'
Br
R'
Cadiot-Chodkiewicz Coupling
X
1. BuLi
R
(c)
(d)
R
R
R''
Negishi's Protocol
2. Base
[Cu], air
- CO2, - H2O
R1
CO2H
+
R1
R2
H
R2
This work
Scheme 1. Methods for synthesis of conjugated diynes.
Under the optimal reaction conditions, different propiolic acids
and terminal alkynes were surveyed, respectively. The results are
summarized in Table 2. Substituted arylpropiolic acid with substit-
uents at the para or meta positions of the aryl group could react
with terminal alkynes smoothly (Table 2, entries 2, 3, and 6–13).
The reaction of 3-(2-furfuryl)-propiolic acid 1d gave a lower yield
than other reactions (Table 2, entry 4). It is noteworthy that 4-sty-
rylpropiolic acid 1e reacted successfully with 2a giving the desired
product 3e in 47% yield (Table 2, entry 5). Notably, halogen-substi-
tuted phenylacetylenes are also tolerable to this kind of transfor-
mation (Table 2, entries 9, and 11). Moreover, heterocycle
substituted alkyne 2h reacted smoothly with arylpropiolic acid 1f
producing the desired 1, 3-conjuated diynes 3j in 46% yield (Table
2, entry 12). Even alkynes with an alkenyl group or an alkyl group
coupling reaction with aryl halides by Lee et al.19h,o To the best of
our knowledge, decarboxylative cross-coupling has so far only
been reported for sp3–sp3, sp2–sp2, sp2–sp3, sp–sp2, and sp–sp3
bond formation.22 Herein, we report a Cu-catalyzed decarboxyla-
tive sp–sp cross-coupling of propiolic acids with terminal alkynes
under air leading to unsymmetric conjugated diynes.
Initially, we investigated the copper-catalyzed reaction of phe-
nyl-propiolic acid 1a and 4-methoxy phenylacetylene 2a (Table 1).
When the reaction was catalyzed by CuBr (10 mol %) in the pres-
ence of TMEDA (10 mol %) under air, only a trace amount of ex-
pected product 3a was obtained (Table 1, entry 1). Interestingly,
3a was produced in 10% yield when 2,20-bypyridine was used as li-
Table 1
Cu-catalyzed decarboxylative coupling reaction of phenyl-propiolic acid and 4-methoxyphenylacetylene.a,b
Ph
CO2H
[Cu]; ligand
+
bace, solvent, 120 oC
MeO
MeO
2a
3a
1a
N
N
Me2N
NMe2
N
N
N
N
L1
L3
L4
L2
Entry
[Cu]
Ligand
Base
Solvent
Yieldc (%)
1
2
3
4
5
6
7
8
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuCl
Cu(OAc)2
CuI
L1
L2
L3
L4
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
L3
K2CO3
K2CO3
K2CO3
K2CO3
KOAc
K3PO4
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMA
DMF
DMF
Trace
10
45
43
42
34
48
10
34
35
51
42
39
Trace
Trace
–
9
K2CO3
K2CO3
Et3N
K2CO3
K2CO3
K2CO3
K2CO3
10
11
12
13
14d
15e
CuBr
CuBr
CuBr
CuI
a
The reaction was carried out with 1a (0.6 mmol), 2a (0.5 mmol, 1.0 equiv), copper-catalyzer (0.05 mmol), ligand (0.05 mmol), base, and solvent (3 mL) heated to 120 °C
under air for 20 h.
b
The product of homocoupling of 1a and 2a were observed in all the reactions.
Isolated yield.
The reaction was carried out under N2.
0.01 mmol of CuI and 0.01 mmol of L3 was used.
c
d
e

M. Yu et al. / Tetrahedron Letters 51 (2010) 1287–1290
1289
Table 2
Cu-catalyzed decarboxylative coupling reaction of propiolic acids and terminal alkynesa
CuI (10 mol%)
1,10-phenanthroline (10 mol%)
R1
CO2H
R2
R1
R2
+
Et3N(2.0 eq.)
DMF, under air
120 oC
1
2
3
R1
R2
Entry
1
2
3
Yieldb (%)
1
2
1a
1b
2a
2a
3a
3b
51
53
OMe
Me
Me
OMe
OMe
3
1c
2a
3c
54
O
4
5
1d
1e
2a
2a
3d
3e
33
47
OMe
OMe
Ph
6
7
8
9
1f
1f
1f
1f
2b
2c
2d
2e
3b
3a
3f
51
46
46
47
MeO
Me
MeO
MeO
MeO
MeO
Et
F
3g
10
1f
2f
3h
49
Me
11
12
1f
1f
2g
2h
MeO
MeO
MeO
Cl
3i
3j
40
46
S
13
1g
2c
3k
57
MeO
14
15
1f
1f
2i
2j
MeO
MeO
3l
36
32
3m
a
The reaction was carried out with 1 (0.3 mmol), 2 (0.25 mmol), CuI (0.025 mmol), 1,10-phenanthroline (0.025 mmol), Et3N (0.5 mmol), and DMF (1.5 mL) heated to 120 °C
under air for 20 h.
b
Isolated yield.
reacted successfully with arylpropiolic acid, but the yields were
lower than other reactions (Table 2, entries 14 and 15).
Research Program of China (973 Program) (Grant No.
2009CB825300), and Ph.D. Programs Foundation of Ministry of
Education of China (No. 20070001808) are greatly appreciated.
In conclusion, we have developed a copper-catalyzed decarb-
oxylative cross-coupling reaction of propiolic acids with terminal
alkynes under air, leading to 1,3-conjugated unsymmetric diynes.
This method provides a novel decarboxylative cross-coupling for
sp–sp bond formation. Compared to organic halides, only carbon
dioxide is produced as by-products in this approach. The reaction
is carried out at mild conditions, avoiding the use of haloalkynes
and alkynyl metal reagents. Further study on the application of this
method in organic synthesis is ongoing in our laboratory.
Supplementary data
Supplementary data (experimental details and NMR spectra)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.12.138.
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Financial support from Peking University, National Science
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