Copper-free sonogashira coupling reaction with PdCl2 in water under aerobic conditions

Article abstract of DOI:10.1021/jo048599z

(Chemical Equation Presented). A mild protocol for the copper-free Sonogashira coupling of aryl iodides with terminal acetylenes in water under aerobic conditions has been developed. The use of 1 mol % PdCl₂ in the presence of pyrrolidine allows the coupling reaction to proceed at room temperature or 50°C with good to excellent yields.

Full text of DOI:10.1021/jo048599z

terminal acetylenes are difficult to obtain. The use of
other cocatalysts such as zinc, tin, boron, aluminum,
Ag2O, and AgOTf have been developed to address this
issue,4 but additional steps are needed to make these
agents.
Recently, a palladium system modified by a bulky,
electron-rich phosphine ligand (such as PtBu3) has been
reported to display unusually high activity in the Sono-
gashira reaction of aryl bromides.5 In the meantime,
significant progress has been made in the Sonogashira
reaction to give diminished homocoupling.6 Many of the
reactions were carried out without copper salts,7 which
provides the opportunity to develop the Sonogashira
reaction under aerobic conditions, because the copper-
mediated oxidative homocoupling of acetylene is pre-
vented.3
Copper-Free Sonogashira Coupling
Reaction with PdCl2 in Water under
Aerobic Conditions
Bo Liang,† Mingji Dai,† Jiahua Chen,*,† and
Zhen Yang*,†,‡
Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education, College of Chemistry,
Beijing 100871, China, Laboratory of Chemical Genetics,
Shenzhen Graduate School of Peking University, The
University Town, Shenzhen 518055, China, and VivoQuest,
Inc., 711 Executive Boulevard, Valley Cottage,
New York 10989
zyang@chem.pku.edu.cn
Received August 11, 2004
In this paper, we present our contribution to the field
by developing a mild protocol for the copper-free Sono-
gashira coupling of aryl iodides with terminal acetylenes
in water under aerobic conditions.
In connection with our development of a chemical
genetic approach to analyzing biological systems by using
interfacing small molecule libraries,8 we needed to syn-
thesize a variety of phenyl acetylenes using the Sono-
gashira reaction. One of the complications with the
Sonogashira couplings is that the reaction need degassed
solvents, and have to be carried out under an inert
atmosphere.5 This is particularly inconvenient when the
reactions are carried out in multiple vessels for library
generation. Therefore, the development of a convenient
method is an important objective in this effort.
A mild protocol for the copper-free Sonogashira coupling of
aryl iodides with terminal acetylenes in water under aerobic
conditions has been developed. The use of 1 mol % PdCl2 in
the presence of pyrrolidine allows the coupling reaction to
proceed at room temperature or 50 °C with good to excellent
yields.
The Sonogashira reaction of terminal acetylenes with
aryl or vinyl halides provides a powerful tool for C-C
bond formation, which has been widely applied to diverse
areas such as natural product synthesis and material
science.1 Typical procedures for the Sonogashira coupling
utilize catalytic palladium with a metal cocatalyst and a
base.2 The most widely employed cocatalysts are copper
salts, which mediates homocoupling of terminal alkynes
when the copper acetylide is exposed to oxidative agents
or air.3 This side reaction is problematic when the
To realize this goal, we screened a variety of coupling
conditions and were pleased to find that the coupling
(4) For recent reviews on alkyne cross-coupling, see: (a) Sonogash-
ira, K. J. Organomet. Chem. 2002, 653, 46. (b) Tykwinski, R. R. Angew.
Chem., Int. Ed. 2003, 42, 1566. (c) Negishi, E.; Anastasia, L. Chem.
Rev. 2003, 103, 1979. (d) Mori, A.; Kawashima, J.; Shimada, T.; Suguro,
M.; Hirabayashi, K.; Nishihara, Y. Org. Lett. 2000, 2, 2935. (e) Liao,
Y.; Fathi, R.; Yang. Z. Org. Lett. 2003, 5, 909. For metal-free
Sonogashira-type coupling, see: (a) Leadbeater, N. E.; Marco, M.;
Tominack, B. J. Org. Lett. 2003, 5, 3919. (b) Cheng, J.; Sun, Y.; Wang,
F.; Guo, M.; Xu, J.; Pan, Y.; Zhang, Z. J. Org. Chem. 2004, 69, 5428.
(c) Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 5752.
(5) (a) Bo¨hm, V. P. W.; Herrmann, W. A. Eur. J. Org. Chem. 2000,
22, 3679. (b) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G.
C. Org. Lett. 2000, 2, 1729. (c) Eckhardt, M.; Fu, G. C. J. Am. Chem.
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(6) (a) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem.,
Int. Ed. 2000, 39, 2632. (b) Rossi, R.; Carpita, A.; Bigelli, C. Tetrahe-
dron Lett. 1985, 26, 523. (c) Liu, Q.; Burton, D. J. Tetrahedron Lett.
1997, 38, 4371. (d) Liao, Y.; Fathi, R.; Reitman, M.; Zhang, Y.; Yang,
Z. Tetrahedron Lett. 2001, 42, 1815. (e) Elangovan, A.; Wang, Y.-H.;
Ho, T.-I. Org. Lett. 2003, 5, 1841.
* To whom correspondence should be addressed. Tel: + (8610) 6275-
9105. Fax: + (8610) 6275-9105.
† Key Laboratory of Bioorganic Chemistry and Molecular Engineer-
ing of Ministry of Education, College of Chemistry, and Shenzhen
Graduate School of Peking University.
‡ VivoQuest, Inc.
(1) (a) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998; Chapter
5. (b) Brandsma, L.; Vasilevsky, S. F.; Verkruijsse, H. D. Application
of Transition Metal Catalysts in Organic Synthesis; Springer-Verlag:
Berlin, 1998; Chapter 10. (c) Rossi, R.; Carpita, A.; Bellina, F. Org.
Prepr. Proced. Int. 1995, 27, 127. (d) Sonogashira, K. In Comprehensive
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3, Chapter 2.4.
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K.; Gupta, S.; Yeleswarapu, K. R. Synlett 2002, 12, 1976-1982. (f)
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1975, 4467. (b) Nicolaou, K. C.; Ladduwahetty, T.; Taffer, I. M.; Zipkin,
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10.1021/jo048599z CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/24/2004
J. Org. Chem. 2005, 70, 391-393
391

TABLE 1. Sonogashira Reactions of Phenylacetylene
with Phenyl Iodides
TABLE 2. Sonogashira Reactions of Acetylenes with
Phenyl Iodides
reaction proceeded well using PdCl2 in water9 in the
presence of pyrrolidine under aerobic conditions. We then
studied the effect of various reaction parameters (pal-
ladium catalyst, base, temperature) on the outcome of
the coupling reaction with phenyl acetylene and phenyl
iodide as the substrates. It was found that among
the catalysts tested [PdCl2, PdI2, Pd(OAc)2, and PdCl2-
(PPh3)2], PdCl2 proved to be the most efficient. Among
the bases used [triethylamine, pyridine, pyrrolidine,
K2CO3, Na2CO3, NaHCO3, CsCO3, and CsOAc], pyrroli-
dine was the best choice. For the temperatures evaluated
[25, 50, and 80 °C], 50 °C gave the best result. Taken
together, good to excellent results were obtained when
the reactions were carried out with 1 mol % of PdCl2 in
water9 at 50 °C in the presence of pyrrolidine as base
under aerobic conditions. As shown in Table 1, the
optimized catalyst system is quite general and tolerant
of a range of functionalities. For the electron-deficient
phenyl iodides, the coupling reactions were carried out
at 25 °C, and the others needed a higher temperature.
using other Sonogashira reaction conditions (such as
PdCl2(PPH3)2/CuI/Et3N or Pd(PPH3)4/CuI/Et3N), and only
trace amounts of the desired product were obtained.
Although a number of Sonogashira reactions that were
carried out in aqueous media were reported previously
with CuI as a cocatalyst,10 the advantages of this copper-
free Sonogashira reaction are its insensitivity to air and
its production of only trace amounts of homocoupling
products of terminal acetylenes.
To evaluate the concentration effect of PdCl2 in the
Sonogashira reaction, we have tried the lifetime of
palladium catalyst with 0.1 mol % of Pd loading and used
phenyl iodide and phenyl acetylene as substrates to do
the coupling reaction. As a result, 93% coupling product
was obtained, and no Pd precipitation was observed after
24 h, which may indicate an effect of palladium concen-
tration on the rate of Pd cluster formation.11
To examine the scope for this coupling reaction, a
variety of terminal acetylenes were coupled with different
phenyl iodides, and good results were obtained (Table 2).
The coupling reaction of 2, 5-diiodo-1,4-dibromobenzene
with phenyl acetylene (entry 14 in Table 2) gave 2,5-
diphenylacetylene-1,4-dibromobenzene in 65% yield. It
is noteworthy that the same coupling reaction was tried
In conclusion, we have developed a mild copper-free
Sonogashira coupling of aryl iodides and terminal acetyl-
enes in water using pyrrolidine as base12 under aerobic
conditions. Current work in our laboratories is focused
(10) (a) Dibowski, H.; Schmidtchen, F. P. Angew. Chem., Int. Ed.
1998, 37, 476. (b) Radhakrishnan, U.; Stang, P. J. Org. Lett. 2001, 3,
859. (c) Lo´pez-Deber, M. P.; Castedo, L.; Granjia, J. R. Org. Lett. 2001,
3, 2823. (d) Nova´k, Z.; Szabo´, A.; Re´pa´si, J.; Kotschy, A. J Org. Chem.
2003, 68, 3327.
(11) De Vries, A. H. M.; Mulders, J. M. C. A.; Mommers, J. H. M.;
Henderickx, H. J. W.; De Vires, J. G. Org. Lett. 2003, 5, 3285.
(9) To run the chemical reaction in water, see: Li, C.-J. Chem. Rev.
1993, 93, 2023. Application of ligand-free palladium for the Heck and
Suzuki reactions in water, see: (a) Jeffery, T. In Advances in Metal-
Organic Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, CT,
1996; Vol. 5, p 153. (b) Leadbeater, N. E.; Marco, M. Org. Lett. 2002,
4, 2973.
392 J. Org. Chem., Vol. 70, No. 1, 2005

and the combined organic layer was dried with anhydrous
sodium sulfate. The solvent was removed under vacuum, and
the residue was purified by flash chromatography to give the
desired product.
on extending the synthetic scope and carrying out the
kinetic study of this reaction.
Experimental Section
Acknowledgment. We gratefully acknowledge
financial support of this work by the National
Science Foundation of China (Grant Nos. 20225318 and
20325208) and VivoQuest, Inc., through the sponsored
research program.
Typical Procedure for the Sonogashira Coupling Reac-
tion. PdCl2 (0.02 mmol), iodide (2.0 mmol), H2O (2.5 mL), and
pyrrolidine (0.83 mL, 10 mmol) were added to a flask under
aerobic conditions, and the resulting mixture was stirred at 50
°C for 5 min. To this solution was added acetylene (2.4 mmol),
and the reaction mixture was stirred at 50 °C for 24 h. The
reaction mixture was then extracted with EtOAc (3 × 10 mL),
Supporting Information Available: Experimental pro-
cedure and NMR and 13C NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) Th use of pyrrolidine as base in the Sonogashira reaction was
reported during the time our manuscript was being reviewed. See:
Wolf, C.; Lerebours, R. Org. Biomol. Chem. 2004, 2, 2161.
JO048599Z
J. Org. Chem, Vol. 70, No. 1, 2005 393