Palladium and copper catalyzed Sonogashira decarboxylative coupling of aryl iodides and alkynyl carboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2016.06.073

A mild procedure of palladium and copper catalyzed decarboxylative cross-coupling reaction of aryl halides and alkynyl carboxylic acids has been developed. Low molecular weight acids, to introduce small building blocks, were specifically used. This method

Full text of DOI:10.1016/j.tetlet.2016.06.073

Tetrahedron Letters 57 (2016) 3358–3362
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Tetrahedron Letters
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Palladium and copper catalyzed Sonogashira decarboxylative
coupling of aryl iodides and alkynyl carboxylic acids
⇑
⇑
Carine Maaliki, Yoan Chevalier, Emilie Thiery , Jérôme Thibonnet
Université François-Rabelais, ISP-UMR 1282, UFR Sciences et Techniques, Parc Grandmont, 37000 Tours, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild procedure of palladium and copper catalyzed decarboxylative cross-coupling reaction of aryl
halides and alkynyl carboxylic acids has been developed. Low molecular weight acids, to introduce small
building blocks, were specifically used. This methodology is easy to implement and uses common reac-
tants and catalysts.
Received 9 May 2016
Revised 15 June 2016
Accepted 16 June 2016
Available online 17 June 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Copper
Decarboxylative coupling
Alkynyl carboxylic acids
Aryl halides
Introduction
homocoupling reaction for the formation of corresponding diynes.
Lee and co-workers extended palladium-catalyzed DCC reactions
The Sonogashira cross-coupling reaction is the most useful tool
for the formation of the C(sp2)–C(sp) bond1 and it is used as a key
step in total synthesis.2 This reaction proceeds via palladium cat-
alyzed coupling between aryl halides and terminal alkynes in the
presence of copper salts as co-catalysts. One limitation of this cou-
pling is the alkyne source, in particular the use of volatile terminal
alkynes. The decarboxylative Sonogashira reaction between aryl
halides and alkynyl carboxylic acids has emerged as an alternative
to the Sonogashira reaction,3 and terminal alkynes are replaced by
the corresponding alkynyl carboxylic acids that are easily available
and stable for handling and storage. Lee and co-workers reported
the first decarboxylative coupling of alkynyl carboxylic acids and
aryl halides in 2008:4 unsymmetrically substituted diaryl alkynes
were synthetised from propiolic acid via the consecutive reactions
of the Sonogashira reaction and the decarboxylative coupling
(DCC) reaction using palladium salts in the presence of a phosphine
ligand and a base to catalyze the two couplings. This methodology
has been developed for the preparation of unsymmetrical diaryl
alkynes, one pot5 or in continuous flow reaction systems,6 and also
for the preparation of symmetrical diaryl alkynes from aryl bro-
mides7 or aryl chlorides.8 In 2011, Kim and co-workers described
Sonogashira – homocoupling sequence from propiolic acid.9 After
the coupling between propiolic acid and aryl iodides under
Sonogashira conditions, addition of silver carbonate provided a
between phenylpropiolic acid or oct-2-ynoic acid with aryl halides
in the presence of a phosphine ligand and tetrabutylammonium
fluoride as the base at 90 °C.10 Coupling between aryl chlorides
and various alkynyl carboxylic acids has been catalyzed by
cyclopalladated ferrocenylimine in the presence of phosphine
ligand.11 The use of palladium nanoparticles as catalysts combined
with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) provided ligand-
free decarboxylative coupling.12 Development of this methodology
achieved a palladium-free DCC reaction with copper (I) as the cat-
alyst. Using this approach, Xue and co-workers reported the cou-
pling between aryl halides and alkynyl carboxylic acids catalyzed
by copper iodide in the presence of 1,10-phenathroline as the
ligand, cesium carbonate as the base, and N,N-dimethylformamide
as solvent at 130 °C.13 Another example was reported by Mao and
co–workers. The reaction was performed by copper iodide in the
presence of triphenylphosphine as the ligand, potassium carbonate
as the base, and dimethylsulfoxide or water as the solvent at
100 °C.14 Muthusubramanian and co-workers also developed a
DCC reaction followed by cyclization in order to form heterocy-
cles.15 This strategy was used with aryl alkynyl carboxylic acids
and substituted 2-iodotrifluoroacetanilide in the presence of cop-
per (I)/L-proline as the catalytic system. Moreover, a decarboxyla-
tive coupling reaction was developed with various substrates
such as benzyl halides,16 1,1,1-trifluoro-2-iodoethane,17 boronic
acids,18 or arene diazoniums19 instead of classical aryl halides.
Stereospecific decarboxylative coupling of benzyl esters of
⇑
Corresponding authors.
http://dx.doi.org/10.1016/j.tetlet.2016.06.073
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

C. Maaliki et al. / Tetrahedron Letters 57 (2016) 3358–3362
3359
propiolic acids has recently been reported.20 Mainly aryl alkynyl
carboxylic acids are used, though some methodologies have been
extended to alkyl alkynyl carboxylic acids.10,11,13,14b,21
We focused on using alkynyl carboxylic acids, in particular the
alkynyl alkyl acids, in the decarboxylative Sonogashira reaction.
But-2-ynoic acid and pent-2-ynoic acid were of particular interest
since they allow the introduction of propyne and butyne that are
more difficult to handle under the usual Sonogashira cross-cou-
pling conditions. We present here a new methodology for the
alkynylation of aryl halides under microwave conditions.
19–22) were then tested. Triethylamine and N,N-dimethylfor-
mamide (DMF) were the most efficient base and solvent respec-
tively (entry 7). In order to obtain a total conversion, the reaction
was performed under conventional heating or under microwave
irradiation (entries 23–27). Conversion was only 60% at 50 °C for
one day (entry 23). Heating at 100 °C under microwave irradiation
led to degradation of the product (entry 24).
However, similar conversion was achieved by conventional
heating at 50 °C for 1 day and under at 50 °C under microwave irra-
diation for 2 h (entries 23 and 27). Finally, the amount of acid 2a
was increased to 3 equiv to obtain total conversion at 50 °C MW
for 2 h (entry 29) or at room temperature for 2 days (entry 30).
The time saved obtained under microwave irradiation encouraged
us to develop this reaction under these conditions.
Various available aryl halides and alkyl alkynyl carboxylic acids
were used to investigate the scope of the decarboxylative Sono-
gashira reaction and the results are summarized in Table 2. First
the reaction was developed with but-2-ynoic acid 1a and ortho-,
meta-, or para-substituted aryl iodides 2 (entries 1, 2, 4, and 5).
The corresponding decarboxylative coupling product was isolated
in modest to good yields. With pent-2-ynoic acid 1b (entries 6–
11), hex-2-ynoic acid 1c (entries 13–16), hept-2-ynoic 1d (entries
17 and 18), or 5-hydroxy-5-phenylpent-2-ynoic acid 1e (entries
19 and 20), only 2 equiv of these acids were required to obtain total
conversion. Coupling of these acids with various aryl iodides pro-
vided the expected product in good yields. In the case of o-iodoani-
line 2d (entries 5, 10, 14), some amidation of the amine group (5–
10%) was observed in the crude but this by-product was easily
Results and discussion
In order to optimize the reaction protocol, we examined a range
of palladium and copper catalysts, ligands, bases, and solvents,
using the coupling of but-2-ynoic acid 1a with 1-iodo-4-methoxy-
benzene 2a as the test reaction (Table 1). It should be noted that
the conversion must be complete as the starting material 2a and
product 3aa cannot be separated by chromatography on silica
gel. The reaction was performed initially at room temperature to
determine the most appropriate catalysts and reagents (entries
1–22). A range of palladium catalysts (entries 1–6), copper cata-
lysts (entries 8–11) and ligands (12–14) were examined. The use
of palladium and copper seemed to be essential to carry out the
coupling reaction (entries 1 and 8). The use of palladium (II) acet-
ate, copper iodide, and triphenylphosphine as the catalytic system
provided the most effective reaction (entries 6 and 7). Various
organic and inorganic bases (entries 15–18) and solvents (entries
Table 1
Optimization of reaction conditions
[Pd] (5 mol%), [Cu] (10 mol%)
L (10 mol%), Base (2 equiv.)
+
MeO
Me
Me
CO2H
MeO
2a (1 equiv.)
I
Solvant, time, T°C
3aa
1a (1.2-3 equiv.)
Entry
[Pd]
[Cu]
Ligand
Alkyne (equiv)
Base
Solvent
Temp (°C)
Time (h)
Conv.a (%)
1
2
3
4
5
6
7
8
—
CuI
CuI
CuI
CuI
CuI
CuI
CuI
—
(CF3SO3)2Cu
CuSO4.5H2O
CuBr
CuI
CuI
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
—
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
48
16
16
16
16
16
48
48
48
48
48
72
72
72
0
PdCl2(PPh3)2
PdCl2(MeCN)2
Pd(Ph3)4
Pd2dba3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
15
15
20
36
50
85
0
9
4
10
11
12
13
14
10
37
0
0
14
Phenanthroline
CuI
L
-Proline
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2
i-Pr2NH
K2CO3
DBU
—
DMF
DMF
DMF
DMF
i-PrOH
H2O
rt
rt
rt
rt
rt
rt
rt
rt
48
48
48
48
48
48
48
48
24
0.5
0.5
1
11
29
5
0
0
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
0
THF
14
52
60
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
50 °C
b
MW 100 °C
MW 50 °C
MW 50 °C
MW 50 °C
MW 50 °C
MW 50 °C
rt
—
38
55
65
85
100
100
2
2
2
48
3
3
a
Determined by 1H NMR; only decarboxylative coupling products were observed.
Degradation of the product was observed.
b

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C. Maaliki et al. / Tetrahedron Letters 57 (2016) 3358–3362
Table 2
Decarboxylative cross-coupling between alkynyl acids 1 and aryl halides 2
R2
R2
Pd(OAc)2 (5 mol%), CuI (10 mol%)
PPh3 (10 mol%), Et3N (2-3 equiv.)
R1
CO2H
(2-3 equiv.)
Alkynyl carboxylic acids
+
X
R1
DMF, 2 h, 50°C MW
3
1
2
(1 equiv.)
Entry
1
Aryl halides
Product
Yielda (%)
41
Me
Me
Me
Me
CO2H
CO2H
CO2H
CO2H
MeO
O2N
O2N
I
MeO
O2N
O2N
Me
1a
1a
1a
1a
2a
2b
3aa
3ab
3ab
I
Me
Me
2
3
99
58
Br
2’b
I
Me
4
5
86
O2N
O2N
2c
3ac
Me
CO2H
Me
I
1a
44b
NH2
3ad
NH2
2d
Et
Et
Et
CO2H
CO2H
CO2H
MeO
I
I
MeO
O2N
O2N
Et
1b
1b
1b
1b
6
7
8
85
99
69
2a
2b
3ba
O2N
Et
3bb
3bb
Et
O2N
O2N
Br
2’b
Et
CO2H
I
Et
9
83
79
66
O2N
2c
3bc
Et
Et
Et
CO2H
CO2H
CO2H
Et
Et
I
1b
1b
1b
10
11
NH2
NH2
2d
3bd
I
CH2OH
2e
CH2OH
3be
I
Et
12
13
68
75
N
2f
N
3bf
n-Pr
n-Pr
CO2H
CO2H
MeO
n-Pr
MeO
I
1c
1c
3ca
2a
n-Pr
I
14
15
71
70
NH2
NH2
2d
3cd
n-Pr
CO2H
n-Pr
I
1c
CH2OH
CH2OH
3ce
2e

C. Maaliki et al. / Tetrahedron Letters 57 (2016) 3358–3362
3361
Table 2 (continued)
Entry
Alkynyl carboxylic acids
Aryl halides
Product
Yielda (%)
n-Pr
n-Bu
n-Bu
CO2H
CO2H
CO2H
Me
n-Pr
Me
2g
I
1c
1d
1d
16
17
67
83
3cg
3da
MeO
n-Bu
MeO
2a
I
I
n-Bu
I
18
19
97
68
O2N
O2N
3dc
2c
OH
MeO
MeO
Ph
Ph
Ph
CO2H
HO
HO
2a
1e
1e
3ea
OH
O2N
O2N
O2N
I
I
Ph
CO2H
CO2H
20
21
74
43
2b
3eb
3fb
Me3Si
O2N
SiMe3
1f
2b
a
Isolated yield.
Degradation of the product after 24 h.
b
CYCLE A
CYCLE B
Cu
L
oxydative addition
R
Ar Pd I
CO2
L
A2
B2
ArI
2
decarboxylation
NEt3, L
Pd(OAc)2
PdL2
A1
trans metallation
R
CO2Cu
B1
Ar
R
3
CuI
NEt3H,I
L
reductive elimination
Ar Pd
L
R
A3
R
CO2H, NEt3
1
Scheme 1. Plausible mechanism of decarboxylative Sonogashira reaction.
eliminated during the purification. Aryl bromide 20b was used in
DCC reaction with acids 1a, 1b, instead of aryl iodide 2b (entries
3 and 8): the coupling products 3ab and 3bb were obtained in
lower yields. No conversion was achieved with aryl chlorides.
The use of 2-iodopyridine 2f in the coupling with 2-pentynoic acid
1b yielded 68% of the product although the conversion was not
total (conv = 72%, entry 13). The coupling of 3-(trimethylsilyl)pro-
piolic acid 1f and aryl iodide 2b did not lead to total conversion
(conv = 57%) but in this case the coupling product 3fb could be iso-
lated in 43% yield (entry 22).
We therefore proposed a mechanism based on two catalytic cycles:
one for the C–C bond coupling involved the palladium salts (Cycle
A), the other one for the decarboxylation of alkynyl carboxylic acid
catalyzed by copper salts (Cycle B). In the presence of base and
copper (I), alkynyl carboxylic acid 1 led to the formation of copper
carboxylate B1 which was subjected to decarboxylation.14b,22 The
alkynyl copper B2 formed is
a well-known intermediate in
Sonogashira reaction.1 Palladium salts allowed the formation of
C–C bond via a classic mechanism: first an oxidative addition lead-
ing to intermediate A2 followed by a trans-metallation with alky-
nyl copper B2 which resulted in complex A3. Eventually, a
reductive elimination provided the expected compound 3 and
regenerated palladium (0) A1.
On the basis of our results and of the literature, the mechanism
reaction shown in Scheme 1 was proposed. The requirement of pal-
ladium and copper salts suggests that each has a distinct function.

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C. Maaliki et al. / Tetrahedron Letters 57 (2016) 3358–3362
3. Park, K.; Lee, S. RCS Adv. 2013, 3, 14165–14182.
Conclusion
4. Moon, J.; Jeong, M.; Nam, H.; Ju, J.; Moon, J. H.; Jung, H. M.; Lee, S. Org. Lett.
2008, 10, 945–948.
5. Tartaggia, S.; De Lucchi, O.; Gossen, L. J. Eur. J. Org. Chem. 2012, 1431–1438.
6. (a) Lee, H. J.; Park, K.; Bae, G.; Choe, J.; Song, K. H.; Lee, S. Tetrahedron Lett. 2011,
52, 5064–5067; (b) Park, K.; Bae, G.; Moon, J.; Choe, J.; Song, K. H.; Lee, S. J. Org.
Chem. 2010, 75, 6244–6251.
7. Park, K.; Bae, G.; Park, A.; Kim, Y.; Choe, J.; Song, K. H.; Lee, S. Tetrahedron Lett.
2011, 52, 576–580.
8. Li, X.; Yang, F.; Wu, Y. RCS Adv. 2014, 4, 13738–13741.
9. Park, J.; Park, E.; Kim, A.; Park, S.-A.; Lee, Y.; Chi, K.-W.; Jung, Y. H.; Kim, I. S. J.
Org. Chem. 2011, 76, 2214–2219.
10. Moon, J.; Jang, M.; Lee, S. J. Org. Chem. 2009, 74, 1403–1406.
11. Li, X.; Yang, F.; Wu, Y. J. Org. Chem. 2013, 78, 4543–4550.
12. Pyo, A.; Kim, J. D.; Choi, H. C.; Lee, S. J. Organomet. Chem. 2013, 724, 271–274.
13. Zhao, D.; Gao, C.; Su, X.; He, Y.; You, J.; Xue, Y. Chem. Commun. 2010, 9049–
9051.
To conclude, we have developed an efficient method for the
Sonogashira decarboxylative cross-coupling reaction between aryl
halides and alkynyl carboxylic acids. This reaction is easy to imple-
ment and uses common reactants and catalysts. It can be per-
formed either at room temperature or under microwave
conditions, the latter requiring shorter reaction times. A range of
aryl alkynyl compounds and aryl halides were prepared in modest
to good yields.
Acknowledgements
14. (a) Qu, X.; Li, T.; Sun, P.; Zhu, Y.; Yang, H.; Mao, J. Org. Biol. Mol. Chem. 2011, 9,
6938–6942; (b) Li, T.; Sun, P.; Yang, H.; Zhu, Y.; Yan, H.; Lu, L.; Mao, J.
Tetrahedron 2012, 68, 6413–6419.
Johnson Matthey Company is thanked for the generous gift of
palladium metal salts.
15. Ponpandian, T.; Muthusubramanian, S. Tetrahedron Lett. 2012, 53, 4248–4252.
16. Zhang, W.-W.; Zhang, X.-G.; Li, J.-H. J. Org. Chem. 2010, 75, 5259–5264.
17. Hwang, J.; Park, K.; Choe, J.; Min, H.; Song, K. H.; Lee, S. J. Org. Chem. 2014, 79,
3267–3271.
Supplementary data
18. (a) Feng, C.; Loh, T.-P. Chem. Commun. 2010, 4779–4781; (b) Shi, L.; Jia, W.; Li,
X.; Jioa, N. Tetrahedron Lett. 2013, 54, 1951–1955.
19. Jadhav, V. G.; Sarode, S. A.; Nagarkar, J. M. Tetrahedron Lett. 2015, 56, 1771–
1774.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.06.
073.
20. (a) Mendis, S. N.; Tunge, J. A. Org. Lett. 2015, 17, 5164–5167; (b) Tomita, R.;
Koike, T.; Akita, M. Angew. Chem., Int. Ed. 2015, 54, 12923–12927.
21. Caporale, A.; Tartaggia, S.; Castellin, A.; De Lucchi, O. Beilstein J. Org. Chem.
2014, 10, 384–393.
References and notes
1. Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874–922.
2. Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442–
22. Jia, W.; Jiao, N. Org. Lett. 2010, 12, 2000–2003.
4489.