Efficient copper-free PdCl2(PCy3)2- catalyzed sonogashira coupling of aryl chlorides with terminal alkynes

Article abstract of DOI:10.1021/jo0525175

Under copper-free conditions and with Cs₂CO₃ as a base, PdCl₂(PCy₃)₂ showed high catalytic activity for cross-coupling of electron-rich, elctron-neutral, and electron-deficient aryl chlorides with a variety of terminal alkynes in DMSO at 100-120 °C affording internal arylated alkynes in good to excellent yields.

Full text of DOI:10.1021/jo0525175

reported results focused on the development of copper-free
catalyst systems for aryl bromides and aryl iodides.3 The
examples of the efficient palladium catalyst systems for Sono-
gashira coupling of aryl chlorides are still few.4 The efficient
copper-free palladium catalyst system for Sonogashira coupling
of electron-rich, electron-neutral, and electron-poor aryl chlo-
rides was reported by Buchwald and co-workers with P(Cy)2Ar
as ligand.4b,f Other catalyst systems showed moderate or high
catalytic activity either in the use of activated aryl chlorides4e
Efficient Copper-Free PdCl2(PCy3)2-Catalyzed
Sonogashira Coupling of Aryl Chlorides with
Terminal Alkynes
Chenyi Yi and Ruimao Hua*
Department of Chemistry, Tsinghua UniVersity, InnoVatiVe
Catalysis Program, Key Laboratory of Organic Optoelectronics
& Molecular Engineering of Ministry of Education,
Beijing 100084, China
4a
or requiring CuI4c,d or ZnCl2 as cocatalyst. Therefore, the
purpose of our research work is to develop an effective, copper-
free, easily available palladium catalyst for Sonogashira coupling
of a wide variety of aryl chlorides. In this Note, we wish to
report our preliminary results.
ruimao@mail.tsinghua.edu.cn
ReceiVed December 6, 2005
We chose the cross-coupling of chlorobenzene (1a) with
phenyl acetylene as the model reaction to screen the catalyst
and optimize the reaction conditions. First, the catalytic activities
of some catalysts such as NiCl2(dppp), PdCl2(PPh3)2, PdCl2-
(PPhMe2)2, and PdCl2(PCy3)2 were tested in the presence of
Cs2CO3 at 120 °C in NMP (NMP ) N-methylpyrrolidone). As
shown in Table 1, NiCl2(dppp) and PdCl2(PPh3)2 showed no
catalytic activity at all and the starting materials were recovered
completely (entries 1 and 2), while PdCl2(PPhMe2)2 displayed
low catalytic activity to give 2a in 25% GC yield (entry 3).
Fortunately, PdCl2(PCy3)2, which has more basic and bulky
groups of PCy3, showed moderate catalytic activity (entry 4).
These results encouraged us to further optimize the reaction
conditions in the presence of PdCl2(PCy3)2 by using different
bases and solvents, as well as changing the reaction temperature.
As can be seen from Table 1, among the bases tested, Cs2CO3
was the best chosen. In addition, the use of p-xylene, 1,4-
dioxane, or DMF to replace NMP as solvent resulted in
decreasing the catalytic activity of PdCl2(PCy3)2 (entries 8-10).
However, in the case of DMSO used as solvent, even at a
relative low temperature (100 °C), PdCl2(PCy3)2 also showed
some catalytic activity, and at 120 °C, 2a could be obtained in
60% GC yield (entries 11 and 12). More importantly, increase
Under copper-free conditions and with Cs2CO3 as a base,
PdCl2(PCy3)2 showed high catalytic activity for cross-
coupling of electron-rich, electron-neutral, and electron-
deficient aryl chlorides with a variety of terminal alkynes in
DMSO at 100-120 °C affording internal arylated alkynes
in good to excellent yields.
Palladium/copper-catalyzed Sonogashira cross-coupling of
terminal alkynes with aryl halides has become a powerful
method for constructing carbon-carbon bonds leading to the
formation of internal arylated alkynes (eq 1).1 A number of
(3) Recent reports on copper-free Sonogashira reactions: (a) Bohm, V.
P. M.; Herrmann, W. A. Eur. J. Org. Chem. 2000, 6, 3679-3681. (b)
Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu, I. Org. Lett.
2002, 4, 1691-1694. (c) Alonso, D. A.; Najera, C.; Pacheco, M. C.
Tetrahedron Lett. 2002, 43, 9365-9368. (d) Leadbeater, N. E.; Tominack,
B. J. Tetrahedron Lett. 2003, 44, 8653-8656. (e) Soheili, A.; Albaneze-
Walker, J.; Murry, J. A.; Dormer, P. G.; Hughes, D. L. Org. Lett. 2003, 5,
4191-4194. (f) Mery, D.; Heuze, K.; Astruc, D. Chem. Commun. 2003,
1934-1935. (g) Heuze, K.; Mery, D.; Gause, D.; Astruc, D. Chem.
Commun. 2003, 2274-2275. (h) Park, S. B.; Alper, H. Chem. Commun.
2004, 1306-1307. (i) Park, S.; Kim, M.; Koo, D. H.; Chang, S. AdV. Synth.
Catal. 2004, 346, 1638-1640. (j) Urganonkar, S.; Verkade, J. G. J. Org.
Chem. 2004, 69, 5752-5755. (k) Cheng, J.; Sun, Y.; Wang, F.; Guo, M.;
Xu, J.-H.; Pan, Y.; Zhang, Z. J. Org. Chem. 2004, 69, 5428-5430. (l)
Arques, A.; Aunon, D.; Molina, P. Tetrahedron Lett. 2004, 45, 4337-4340.
(m) Djakovitch, L.; Rollet, P. Tetrahedron Lett. 2004, 45, 1367-1370. (n)
Djakovitch, L.; Rollet, P. AdV. Synth. Catal. 2004, 346, 1782-1792. (o)
Heuze, K.; Mery, D.; Gauss, D.; Blais, J. C.; Astruc, D. Eur. J. Chem.
2004, 10, 3936-3944. (p) Tyrrell, E.; Al-Saardi, A.; Millet, J. Synlett 2005,
487-488. (q) Liang, B.; Dai, M.; Chen, J.; Yang, Z. J. Org. Chem. 2005,
70, 391-393.
efficient catalyst systems have been developed for coupling of
aryl bromides or aryl iodides.2,3 In recent years, although the
Sonogashira reaction has been intensively investigated to extend
the application generality and simplify the catalyst systems, the
(1) Reviews, see: (a) Sonogashira, K. J. Organomet. Chem. 2002, 653,
46-49. (b) Negishi, E.; Anastasia, L. Chem. ReV. 2003, 103, 1979-2017.
(c) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005,
44, 4442-4489.
(2) Recent publications: (a) Elangovan, A.; Wang, Y.-H.; Ho, T.-I. Org.
Lett. 2003, 5, 1841-1844. (b) Datta, A.; Plenio, H. Chem. Commun. 2003,
1504-1505. (c) Hillerich, J.; Plenio, H. Chem. Commun. 2003, 3024-
3025. (d) Mas-Marza, E.; Segarra, A. M.; Claver, G.; Peris, E.; Fernandez,
E. Tetrahedron Lett. 2003, 44, 6595-6599. (e) Garcia, D.; Cuadro, A. M.;
Alvarez-Builla, J.; Vaquero, J. J. Org. Lett. 2004, 6, 4175-4178. (f) Wolf,
C.; Lerebours, R. Org. Biomol. Chem. 2004, 2, 2161-2164. (g) DeVasher,
R. B.; Moore, L. R.; Shaughnessy, K. H. J. Org. Chem. 2004, 69, 7919-
7927. (h) Bhattacharya, S.; Sengupta, S. Tetrahedron Lett. 2004, 45, 8733-
8736. (i) Feuerstein, M.; Doucet, H.; Santelli Tetrahedron Lett. 2005, 46,
1717-1720. (j) Kollhofer, A.; Plenio, H. AdV. Synth. Catal. 2005, 347,
1295-1300.
(4) (a) Eberhard. M. R.; Wang, Z.; Jensen, C. M. Chem. Commun. 2002,
818-819. (b) Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003,
42, 5993-5996. (c) Kollhofer, A.; Pullmann, T.; Plenio, H. Angew. Chem.,
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10.1021/jo0525175 CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/15/2006
J. Org. Chem. 2006, 71, 2535-2537
2535

TABLE 1. Palladium-Catalyzed Cross-Coupling of Chlorobenzene
with Phenyloacetylene under Different Conditionsa
TABLE 2. Palladium-Catalyzed Cross-Coupling of Aryl Chlorides
with Terminal Alkynesa
temp
(°C)
yield
(%)b
entry
catalyst
solvent
NMP
NMP
base
1
2
3
NiCl2(dppp)c
PdCl2(PPh3)2
PdCl2(PPhMe2)2 NMP
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Et3N
pyridine
Na3PO4
Cs2CO3
120
120
120
120
120
120
120
120
120
120
100
120
150
0
0
25
55
<5
<5
<5
<5
44
50
10
60
85 (81)
4
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
NMP
NMP
NMP
NMP
5d
6
7
8
9
10
11
12
13
p-xylene
1,4-dioxane Cs2CO3
DMF
DMSO
DMSO
DMSO
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
a Reactions were carried out with 0.66 mmol of 1a, 0.6 mmol of phenyl
acetylene, 0.7 mmol of base, and 0.02 mmol of catalyst in 0.8 mL of solvent
in a sealed tube for 12 h. b Yield according to GC based on the amount of
phenyl acetylene used. Number in parentheses is isolated yield. c DPPP )
1, 3-bis(diphenylphosphino)propane. d For 20 h.
of the reaction temperature could greatly accelerate the reaction
to give 2a in 85% GC yield (entry 13). Therefore, the catalysis
system of PdCl2(PCy3)2/Cs2CO3 in DMSO is considered as an
efficient catalyst system for Sonogashira cross-coupling of aryl
chlorides.
To assess the scope of the PdCl2(PCy3)2-catalyzed Sono-
gashira reaction, the cross-coupling reactions of 1a with several
terminal alkynes and the unactivated as well as activated aryl
chlorides with 1-heptyne have been investigated. The results
are concluded in Table 2. p-Tolylacetylene showed somewhat
low reactivity compared to phenyl acetylene: the cross-coupling
with 1a at 150 °C for 12 h afforded the corresponding product
phenyl-p-tolyl acetylene 2b in 77% GC yield (entry 1). Although
the cross-coupling of 1a with phenyl acetylene at 100 °C
proceeded slowly (heating for 12 h, 10%), the reactions of 1a
with aliphatic alkynes took place smoothly under this reaction
temperature to give the corresponding 1-alkyl-2-phenylacetylene
in excellent yields (Table 1, entry 11 vs Table 2, entries 2-4).
The electron-rich aryl chlorides 4-chlorotoluene (1b) and
4-chlorobenzyl alcohol (1c) reacted with 1-heptyne at 120 °C
to give the cross-coupling products 2f and 2g in near quantitative
yields (entries 5 and 6). As expected, under the same reaction
conditions, the electron-poor aryl chlorides underwent cross-
coupling reaction smoothly. For example, the reactions of methyl
3-chlorobenzoate (1d) and 4-chlorobenzophenone (1e) with
1-heptyne afforded the desired products in high yields (entries
7 and 8). These results also indicated that a variety of important
functional groups such as alcohol, ester, and ketone were
tolerated under the present conditions.
a Reactions were carried out with 0.66 mmol of aryl chloride, 0.6 mmol
of alkynes, 0.7 mmol of Cs2CO3, and 0.02 mmol of PdCl2(PCy3)2 in 0.8
mL of DMSO in a sealed tube for 12 h. b Yield according to GC based on
the amount of alkyne used. Numbers in parentheses are isolated yields.
c Aryl chlorde:alkyne ) 1:3 molar ratio.
It should be noted that under the same conditions, the reaction
of 1a with trimethylsilyl acetylene afforded diphenyl acetylene
(2a) as the major product (46% GC yield, based on the amount
of phenyl acetylene used). The corresponding Sonogashira
coupling product of 1-phenyl-2-(trimethylsilyl)acetylene was
determined in very low yield (<10%) (eq 2). These results
indicated that the present catalyst system also displayed the high
catalytic activity to catalyze the cross-coupling reaction of 1a
with 1-phenyl-2-(trimethylsilyl) acetylene via activation of
C-Si.5
When 1,4-dicholorobenzene was employed, the product
distribution could be controlled completely by the use of a
different ratio of the reactants. Therefore, 1-(4-chlorophenyl)-
1-heptyne (2j) and 1,4-bis(1-heptynyl)benzene (2k) were ob-
tained in good yields (entries 9 and 10).
In summary, we developed a practical and efficient PdCl2-
(PCy3)2-catalyzed sonogashira coupling of aryl chlorides with
(5) Examples of palladium-catalyzed Sonogashira-type coupling of aryl
halides with 1-aryl-2-(trimethylsilyl)acetylene have been reported, see:
Sorense, U. S.; Pombo-Villar, E. Tetrahedron 2005, 61, 2697-2703 and
references therein.
In addition, 1-chloronaphthalene (1g) showed reactivity
similar to that of phenyl acetylene at 120 °C, affording 2l in
92% GC yield (entry 11).
2536 J. Org. Chem., Vol. 71, No. 6, 2006

and GCMS analyses, removing the solvents and volatiles under
vacuum, the residue was then subjected to preparative TLC isolation
(silica, eluted with cyclohexane). 2a was obtained (85.5 mg, 0.48
mmol, 80%) as a white solid. The results of GC analysis of the
reaction mixture revealed that 2a was formed in 85% yield.
A larger scale reaction (3.3 mmol) of 1a or 1g with 1-heptyne
(3.0 mmol) afforded a similar isolated yield of 2e (93%) or 2l (87%)
as described in Table 2.
terminal alkynes. The advantages of this catalytic procedure
include (1) omission of a copper cocatalyst, (2) ready availability
and easily handling of catalyst, and (3) the high catalytic activity
for not only electron-poor aryl chlorides but also electron-rich
aryl chlorides under mild and convenient conditions.
Experimental Section
Typical experimental procedure for cross-coupling of chlo-
robenzene (1a) with phenyl acetylene to afford diphenyl
acetylene (2a) (Table 1, entry 13): A mixture of chlorobenzene
(1a) (75.0 mg, 0.66 mmol), phenyl acetylene (61.5 mg, 0.6 mmol),
Cs2CO3 (230.0 mg, 0.7 mmol), PdCl2(PCy3)2 (15.4 mg, 0.02 mmol),
and DMSO (0.8 mL) under nitrogen in a sealed tube was heated
with stirring at 120 °C for 12 h. After cooling, the reaction mixture
was diluted with CH2Cl2 to 1.5 mL and octadecane (45 mg, 0.18
mmol) was added as internal standard for GC analysis. After GC
Acknowledgment. This project (20573061) was supported
by the National Natural Science Foundation of China.
Supporting Information Available: General method, charac-
terization data, and charts of 1H, 13C NMR for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0525175
J. Org. Chem, Vol. 71, No. 6, 2006 2537