Pd-catalyzed carbonylative reactions of aryl iodides and alkynyl carboxylic acids via decarboxylative couplings

Article abstract of DOI:10.1021/ol102993y

Alkynyl carboxylic acids reacted with aryl iodides under a CO atmosphere in the presence of a palladium catalyst to produce α,β-alkynyl aryl ketones in good yields. The maximum turnover number was 16 800. The desired carbonylative coupling was formed from phenyl propiolic acid without any formation of a noncarbonylative coupling product in the absence of CuI. However, the reaction with alkyl-substituted alkynyl carboxylic acids required CuI as a cocatalyst for high yield.(Figure Presented)

Full text of DOI:10.1021/ol102993y

ORGANIC
LETTERS
2011
Vol. 13, No. 5
944–947
Pd-Catalyzed Carbonylative Reactions of
Aryl Iodides and Alkynyl Carboxylic Acids
via Decarboxylative Couplings
Ahbyeol Park, Kyungho Park, Yong Kim, and Sunwoo Lee*
Department of Chemistry, Institute of Basic Science, Chonnam National University,
Gwangju, 500-757, Republic of Korea
sunwoo@chonnam.ac.kr
Received December 10, 2010
ABSTRACT
Alkynyl carboxylic acids reacted with aryl iodides under a CO atmosphere in the presence of a palladium catalyst to produce R,β-alkynyl aryl
ketones in good yields. The maximum turnover number was 16 800. The desired carbonylative coupling was formed from phenyl propiolic acid
without any formation of a noncarbonylative coupling product in the absence of CuI. However, the reaction with alkyl-substituted alkynyl
carboxylic acids required CuI as a cocatalyst for high yield.
The palladium-catalyzed carbonylation of aryl halides
togivecarboxylicacidderivatives hasbeenwidelyusedasa
valuable tool in organic synthesis.1 These reactions share
the incorporation of carbon monoxide into aryl halides in
the presence of a variety of nucleophiles. Since Heck first
reported palladium-catalyzed aminocarbonylation and
alkoxycarbonylation in 1974,2 a number of related reaction
methods have been developed. As a nucleophile, amines,
alcohols, hydrogen, aryl metal reagents, and alkynes have
been employed in the palladium-catalyzed carbonylation.
However, the carbonylativeSonogashira reaction, which is
the carbonylative three-component cross coupling of aryl
halides with a terminal alkyne, has received little attention
even though its product, which is an R,β-alkynyl ketone, is
a crucial moiety in many biologically active molecules,3
natural products,4 and pharmaceutical materials.5
A traditional route to synthesize the R,β-alkynyl ketone
involves the coupling reaction of alkynyl organometallic
reagentsand acid chlorides.6 However, these methodshave
the drawback of needing tobe handledindry solvent under
an inert atmosphere.7
To solve this problem, the palladium-catalyzed coupling
reactions of aryl halides and alkyne source in the presence
of carbon monoxide have been used as an alternative
(3) (a) Savarin, C. G.; Murry, J. A.; Dormer, P. G. Org. Lett. 2002, 4,
2071–2974. (b) Karpov, A. S.; Muller, T. J. Org. Lett. 2003, 5, 3451–
3454.
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J. Am. Chem. Soc. 2004, 126, 13942–13944.
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Gevorgyan, V. J. Org. Chem. 2002, 67, 95–98.
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45–56. (b) Logue, M. W.; Teng, K. J. Org. Chem. 1982, 47, 2549–2553.
(7) (a) Tohda, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1977,
777–778. (b) Alonso, D. A.; Najera, C.; Pacheco, M. C. J. Org. Chem.
2004, 69, 1615–1619. (c) Cox, R. J.; Ritson, D. J.; Dane, T. A.; Berge, J.;
Charmant, J. P. H.; Kantacha, A. Chem. Commun. 2005, 1037–1039.
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ylation, Direct Synthesis of Carbonyl Compounds; Plenum: New York,
1991. (b) Beller, M. In Applied Homogeneous Catalysis with Organome-
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3327–3331.
r
10.1021/ol102993y
Published on Web 01/28/2011
2011 American Chemical Society

approach. However, they also suffer two disadvantages:
the metalated alkynes such as alkynylstannanes8 or
alkynylsilanes9 have a waste problem due to the metal salts,
and the terminal alkyne requires a high reaction tempera-
ture and high carbon monoxide pressure.10 An alternative
pathway for the synthesis of R,β-alkynyl ketone is the
palladium-catalyzed carbonylative coupling reaction of
terminal alkynes with aryl iodides. Since Mori reported
the carbonylative Sonogashira coupling reaction under
mild conditions,11 a variety of reaction methods have been
developed, including copper-free, water solvent, ionic
liquids, microflow, and recyclable catalytic systems.12 In
addition, a copper-catalyzed, palladium-freecarbonylative
Sonogashira coupling reaction has also been reported.13
However, they suffer the following drawbacks: long reac-
tion time, high catalytic loading, high carbon monoxide
pressure, and the formation of noncarbonylative Sonoga-
shira product as a byproduct.
Due to their environmental friendliness as a leaving
group, carboxylic acids have recently been considered
candidates for the coupling partner in the transition metal-
catalyzed coupling reactions.14 Since we first reported the
palladium-catalyzed decarboxylative coupling of the alky-
nyl carboxylic acid,15 several other groups have employed
the alkynyl carboxylic acid as the coupling substrate in a
variety of coupling reactions.16
Table 1. Optimization of the Bases and the Solvents for the
Carbonylationa
yield (%)b
entry
base
DBU
solvent
conv (%)b
3aa
4aa
1
DMSO
DMSO
Toluene
CH3CN
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Xylene
DMSO
DMF
100
100
52
23
68
3
5
0
22
98
8
2c
3
DBU
DBU
23
6
4
DBU
5
5
Et3N
54
0
1
6
Pyridine
PhN(Et)2
(n-Pr)3N
N(i-Pr)2Et
Na2CO3
K2CO3
Cs2CO3
Et3N
0
7
0
0
0
8
2
0
0
9
10
0
0
0
10
11
12
13
14
15
16
17
0
0
0
0
0
59
59
99
68
70
0
42
52
46
49
52
0
4
5
Et3N
44
2
Et3N
Et3N
Dioxane
H2O
3
Et3N
0
Palladium-catalyzed decarboxylative carbonylations
have been reported.17 However, in the absence of any report
on the use of alkynyl carboxylic acid in the carbonylation
a Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), Pd (0.015
mmol), dppb (0.03 mmol), base (1.5 mmol), DMSO (1.0 mL), CO
(5 atm) at 80 °C for 3 h. b Yield was determined by GC. c In the presence
of CuI (0.03 mmol).
(8) (a) Goure, W. F.; Wright, M. E.; Davis, P. D.; Labadie, S. S.;
Stille, J. K. J. Am. Chem. Soc. 1984, 106, 6417–6422. (b) Grisp, G. T.;
Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1984, 106, 7500–7506.
(9) Arcadi, A.; Cacchi, S.; Marinelli, F.; Pace, P.; Sanzi, G. Synlett
1995, 823–824.
(10) Delaude, L.; Masdeu, A. M.; Alper, H. Synthesis 1994, 1149–
1151.
(11) Mohamed Ahmed, M. S.; Mori, A. Org. Lett. 2003, 5, 3057–
3060.
reaction, we investigated the decarboxylative carbonyla-
tion of alkynyl carboxylic acid and aryl iodide.
We studied the optimized conditions for the carbonyla-
tion of decarboxylative coupling with phenyl iodide and
phenyl propiolic acid as the substrate (Table 1).
(12) (a) Liang, B.; Dai, M.; Chen, J.; Yang, Z. J. Org. Chem. 2005, 70,
391–393. (b) Liang, B.; Huang, M.; You, Z.; Xiong, Z.; Lu, K.; Fathi, R.;
Chen, J.; Yang, Z. J. Org. Chem. 2005, 70, 6097–6100. (c) Fukuyama, T.;
Yamaura, R.; Ryu, I. Can. J. Chem. 2005, 83, 711–715. (d) Liu, J.; Peng,
X.; Sun, W.; Zhao, Y.; Xia, C. Org. Lett. 2008, 10, 3933–3936. (e) Liu, J.;
Chen, J.; Xia, C. J. Catal. 2008, 253, 50–56.
First, the reaction was carried out in the presence of
carbon monoxide according to our previously reported
optimization conditions for the decarboxylative coupling
of phenyl iodide and phenyl propiolic acid. Unfortunately,
the desired carbonylative product was obtained in only 5%
yield, and a noncarbonylative decarboxylative coupling
product was formed in 22% yield (entry 1). However,
following the addition of CuI as a cocatalyst, only non-
carbonylative coupling product 4aa was produced in 98%
yield (entry 2). Using toluene and acetonitrile instead of
DMSO solvent, toluene gave the desired product 3aa in
23% yield but acetonitrile showed only a 6% yield of
product (entries 3 and 4). In toluene solvent, a variety of
bases were tested. In the case of organic bases, only Et3N
afforded the desired carbonylative product 3aa in 54%
yield (entry 5), whereas the other tertiary amines did not
produce any coupling products (entries 6-9). Among the
tested inorganic bases, Cs2CO3 resulted in a 42% yield of
product (entry 12). In the presence of Et3N as a base, a
variety of solvents were tested. Although most solvents
(13) Tambade, P. J.; Patil, Y. P.; Nandurkar, N. S.; Bhanage, B. M.
Synlett 2008, 886–888.
(14) For some selected examples: (a) Goossen, L. J.; Deng, G.; Levy,
L. M. Science 2006, 313, 662–664. (b) Voutchkova, A.; Coplin, A.;
Leadbeater, N. E.; Crabtree, R. H. Chem. Commun. 2008, 6312–6314.
(c) Miyasaki, M.; Fukushima, A.; Satoh, T.; Hirano, K.; Miura, M.
Chem.;Eur. J. 2009, 15, 3674–3677. (d) Bilodeau, F.; Brochu, M.-C.;
Guimond, N.; Thesen, K. H.; Forgione, P. J. Org. Chem. 2010, 75, 1550–
1560. (e) Goossen, L. J.; Rodrıguez, N.; Lange, P. P.; Linder, C. Angew.
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Satoh, T.; Miura, M. Org. Lett. 2010, 12, 592–595. (g) Zhang, S.-L.; Fu,
Y.; Shang, R.; Guo, Q.-X.; Liu, L. J. Am. Chem. Soc. 2010, 132, 638–646.
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H. M.; Lee, S. Org. Lett. 2008, 10, 945–948. (b) Moon, J.; Jang, M.; Lee,
S. J. Org. Chem. 2009, 74, 1403–1406. (c) Park, K.; Bae, G.; Moon, J.;
Choe, J.; Song, K. H.; Lee, S. J. Org. Chem. 2010, 75, 6244–6251.
(16) (a) Kim, H.; Lee, P. H. Adv. Synth. Catal. 2009, 351, 2827–2932.
(b) Zhang, W.-W.; Zhang, X.-G.; Li, J.-H. J. Org. Chem. 2010, 75, 5259–
5264. (c) Feng, C.; Loh, T.-P. Chem. Commun. 2010, 46, 4779–4781. (d)
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Org. Lett., Vol. 13, No. 5, 2011
945

Table 2. Effects of Ligands, Temperature, Amount of Catalyst,
and Pressure of Carbon Monoxidea
Table 3. Carbonylation of Alkynyl Carboxylic Acids with Aryl
Iodidesa
yield (%)b
Pd
CO
temp conv
(%)b 3aa
entry (mol %)
ligand
Dppm
(atm) (°C)
4aa
1
5
5
5
80
80
46
60
43
50
23
38
82
33
25
86
89
91
87
84
6
5
5
4
5
0
0
5
0
0
0
0
2
5
Dppe
3
5
Dppbze
5
80
48
4
5
Xantphosf
5
80
69
5
5
-
-
-
-
-
-
-
-
5
80
99
6c
7d
8
5
5
80
40
5
5
80
44
1
5
80
99
9
1
10
10
10
10
100
100
100
100
100
100
91
10
11
12
0.5
0.05
0.005
87
a Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), Pd(PPh3)2Cl2
(0.015 - 0.003 mmol), ligand (0.03 mmol), Et3N (1.5 mmol), DMSO
(1.0 mL), CO (5-10 atm) at 80-100 °C for 3 h. b Yield was determined
by GC. c Pd(OAc)2 was employed. d Pd(dba)2 was employed. e 1,2-Bis-
(diphenylphosphino)benzene. f 4,5-Bis(diphenylphosphino)-9,9-dimethyl-
xanthene
showed similar product yields, DMSO afforded almost
equal amounts of 3aa and 4aa (entry 14). Water, which was
a good solvent in the case of terminal acetylene, did not
show any coupled product (entry 17). Toluene was the
most suitable solvent due to its high selectivity for the
carbonylation.
Next, we tested other conditions such as a variety of
ligands, palladium sources, carbon monoxide pressures,
reaction temperatures, and amounts of catalyst as shown
in Table 2.
In the presence of chelating phosphine ligands, the yield
was not improved (entries 1-4). Interestingly, Pd(PPh3)2-
Cl2 resulted in an 82% yield of 3aa and a 5% yield of 4aa in
the absence of any additional ligand (entry 5). However,
other palladium sources bearing nonphosphine ligands
such as Pd(OAc)2 and Pd(dba)2 produced low yields
(entries 6 and 7). With a decreasing palladium amount,
the product yield was increased to 86%; however, the yield
of byproduct was not decreased (entry 8). When the
carbon monoxide pressure and reaction temperature
were increased to 10 atm and 100 °C, respectively, only 3aa
was obtained without any 4aa being formed (entry 9).
Finally, 0.5 mol % of Pd(PPh3)2Cl2 afforded a 91%
yield of 3aa under 10 atm and 100 °C. When the
catalyst amount was decreased to 0.05 mol %, the
conversion was not completed (entry 11). At a catalyst
loading of 0.005 mol % catalyst, the turnover number
was 16 800 (entry 12).
a Reaction conditions: 1 (2.0 mmol), 2 (2.0 mmol), Pd(PPh3)2Cl2
(0.015 mmol), Et3N (10.0 mmol), solvent (5.0 mL), CO (10 atm) at
100 °C for 3 h. b Isolated yields. c The reaction was carried out in the
presence of 10 mol % CuI.
We intended to expand the scope of aryl iodide and
propiolic acid derivatives for the palladium-catalyzed car-
bonylation of decarboxylative coupling. The results are
summarized in Table 3. Iodobenzene afforded the desired
product in 89% isolated yield (entry 1), while ortho-, meta-
and para-iodotoluene produced the corresponding carbo-
nylative coupling products in 83%, 84%, and 65% yields,
respectively (entries 2-4). All iodoanisoles showed good
yields (entries 5-7). 1-Iodonaphthalene (1h) afforded the
desired product in 78% yield (entry 8).
946
Org. Lett., Vol. 13, No. 5, 2011

Scheme 1. Effect of CuI in the Carbonylation
Scheme 2. Proposed Mechanism
In the case of the phenyl propiolic acid 2a, the carbony-
lative product 4aa was dominant in the absence of CuI,
whereas the noncarbonylative coupling product 3aa was
also produced in a 44% yield in the presence of CuI. Our
results indicated that the rate of the transmetalation of
phenyl propiolic acid toward arylpalladium iodide com-
plex I was slower than that of the insertion of carbon
monoxide toward arylpalladium iodide complex I in the
absence of CuI, which preferentially supports the formation
of carbonylative coupling product 4aa (path A < path B).
However, in the presence of CuI, the yields of both
products were similar due to the similarity in their rates
(path A e path B). In the case of octynoic acid 2b, the
formation of the carbonylative product 4ab was predomi-
nant both with and without CuI, even though its yield was
low in the absence of CuI. We suggested two possible
pathways for the decarboxylation to form the alkynyl
acylpalladium complex III as shown in Scheme 2. One is
theinitial reactionwithalkynylcarboxylicacidand alkynyl
carboxylic acid, followed by decarboxylation (path D).
The other is the decarboxylation induced first by base and
thermal heating, followed by reaction with an acylpalla-
dium complex (path E). The mechanism of this reaction
has not been fully elucidated, and further mechanistic
studies are needed.
Aryl iodides bearing electron-withdrawing groups such
as trifluoromethyl, chloro, nitrile, methyl ester, and acetyl
afforded the corresponding carbonylative coupling pro-
ducts in 87%, 87%, 42%, 52%, and 78% yields, respec-
tively (entries 9-13). 2,4-Dimethyliodobenzene (1n)
resulted in a 58% yield (entry 14). Heteroaromatic aryl
iodides such as 2-iodothiophene and 3-iodopyridine
afforded the desired product in 53% and 63% yields,
respectively (entries 15 and 16). Although the alkyl-sub-
stituted alkynyl carboxylic acids such as 2b and 2c pro-
duced low yields, the yields were increased when the
reaction was carried out in the presence of 10 mol % CuI
(entries 17-22).
The aryl iodides showed similar reactivities in the car-
bonylation of decarboxylative coupling independent of the
substituted group’s electronic properties. However, in the
competition reaction, when equal amounts of 4-trifluoro-
methyliodobenzne and 4-iodoanisole were treated with
phenyl propiolic acid under carbonylation coupling con-
ditions, a 4-trifluoromethyliodobenzene-coupled product
was obtained as a major product (3ga/3ia = 18%/70%).18
In addition, when equal amounts of phenyl propiolic acid
(2a) and octynoic acid (2b) were reacted with iodobenzene
in the absence of CuI, more product was formed from phenyl
propiolic acid than from octynoic acid.19 The reactivity of
octynoic acid was less than that of phenyl propiolic acid in the
carbonylative decarboxylative coupling reaction.
In conclusion, we employed alkynyl carboxylic acid deri-
vatives as substrates in the palladium-catalyzed carbonyla-
tion of aryl iodide. The decarboxylation occurred even under
high carbon monoxide pressure. The desired carbonylative
coupling was formed from phenyl propiolic acid without any
formation of a noncarbonylative coupling product in the
absence of CuI. However, in the case of alkyl-substituted
alkynyl carboxylic acids, CuI was required as a cocatalyst to
ensure a high yield of the desired carbonylative product, as
this was formed in low yield in the absence of CuI.
A copper cocatalyst is known to accelerate the carbo-
nylative and noncarbonylative Sonogashira reactions of
terminal alkynes.11 We found that CuI afforded a non-
carbonylative coupling product dominantly as shown in
entry 2 ofTable 1. Basedonthisresult, we studied the effect
of CuI under our optimized conditions (Scheme 1).
Acknowledgment. This work was supported by a Na-
tional Research Foundation of Korea grant funded by the
Korean Government (2009-0077677)
Supporting Information Available. Reaction proce-
dures and spectral and analytical data for reaction pro-
ducts. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) See Supporting Information.
(19) 3aa (64%)/3ab (28%); see Supporting Information.
Org. Lett., Vol. 13, No. 5, 2011
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