Modified palladium-catalyzed Sonogashira cross-coupling reactions under copper-, amine-, and solvent-free conditions

Article abstract of DOI:10.1021/jo051882t

PdCl₂(PPh₃)₂ combined with TBAF under solvent-free conditions provided general and fast Sonogashira cross-coupling reactions of aryl halides with terminal alkynes. In particular, this protocol could be applied to the reactions of deactivated aryl chlorides. In the presence of 3 mol % of PdCl₂(PPh₃)₂ and 3 equiv of TBAF, a number of ArX species (X = I, Br, Cl) were coupled with alkynes to afford the corresponding products in moderate to excellent yields under copper-, amine-, and solvent-free conditions.

Full text of DOI:10.1021/jo051882t

homocoupling reactions of alkynes readily.10 Buchwald and
Gelman have also found that CuI had a deleterious effect on
the Sonogashira cross-coupling reaction.8c Amines, another
additive, also have a characteristic foul smell and pungent flavor.
Furthermore, the scopes of these reactions performed with the
combination of PdCl2(PPh3)2 (PdCl2/PPh3 or Pd(PPh3)4), CuI,
and amines as the catalytic system are generally limited to aryl
iodides, bromides, and activated chlorides (particularly nitrogen-
containing heteroaryl chlorides).2,5k,8 For these reasons, a new
Modified Palladium-Catalyzed Sonogashira
Cross-Coupling Reactions under Copper-,
Amine-, and Solvent-Free Conditions
Yun Liang, Ye-Xiang Xie, and Jin-Heng Li*
Key Laboratory of Chemical Biology & Traditional Chinese
Medicine Research (Ministry of Education), College of
Chemistry and Chemical Engineering, Hunan Normal
UniVersity, Changsha 410081, China
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T.; Litter, A. F.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729. (c)
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jhli@hunnu.edu.cn
ReceiVed September 7, 2005
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PdCl2(PPh3)2 combined with TBAF under solvent-free
conditions provided general and fast Sonogashira cross-
coupling reactions of aryl halides with terminal alkynes. In
particular, this protocol could be applied to the reactions of
deactivated aryl chlorides. In the presence of 3 mol % of
PdCl2(PPh3)2 and 3 equiv of TBAF, a number of ArX species
(X ) I, Br, Cl) were coupled with alkynes to afford the
corresponding products in moderate to excellent yields under
copper-, amine-, and solvent-free conditions.
The Sonogashira cross-coupling reaction is well-known as
being one of the most important and utilized reactions for the
construction of carbon-carbon bonds, in particular for the
formation of alkynes.1-9 The most commonly used catalytic
systems for this transformation include PdCl2(PPh3)2, PdCl2/
PPh3, and Pd(PPh3)4 together with CuI as the cocatalyst and
large amounts of amines as the solvents or cosolvents.2-9
However, the presence of CuI can result in the formation of
some Cu(I) acetylides in situ that can undergo oxidative
(7) For a selected paper on the palladium/phosphine-free ligand/CuI/
amine system, see: Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002,
4, 1411.
(1) (a) Viehe, H. G. Chemistry of Acetylene; Marcel Dekker: New York,
1969; p 597. (b) Bohlmann, F.; Burkhart, F. T.; Zero, C. Naturally Occurring
Acetylenes; Academic Press: London, New York, 1973. (c) Trahanovsky,
W. S. Oxidation in Organic Chemistry; Academic Press: New York,
London, 1973; Vol. 5-B. (d) Hansen L.; Boll, P. M. Phytochemistry 1986,
25, 285. (e) Kim, Y. S.; Jin, S. H.; Kim, S. L.; Hahn, D. R. Arch. Pharm.
Res. 1989, 12, 207. (f) Matsunaga, H.; Katano, M.; Yamamoto, H.; Fujito,
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M. Oxidation in Organic Chemistry; ACS Monograph 186; American
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(2) For reviews, see: (a) Diederich, F.; Stang, P. J. Metal-Catalyzed
Cross-coupling Reactions; Wiley-VCH: Weinheim, Germany, 1998. (b)
Miyaura, N. Cross-Coupling Reaction; Springer: Berlin, 2002. (c) Littke,
A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176. (d) Tykwinski, R.
R. Angew. Chem., Int. Ed. 2003, 42, 1566.
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44, 4467. (b) Dieck, H. A. Heck, R. F. J. Organomet. Chem. 1975, 93,
259. (c) Cassar, L. J. Organomet. Chem. 1975, 93, 253.
(8) For representative papers on the palladium-catalyzed Sonogashira
cross-coupling reactions of aryl chlorides with alkynes, see: (a) Eberhard,
M. R.; Wang, Z.; Jensen, C. M. Chem. Commun. 2002, 818. (b) Choudary,
B. M.; Madhi, S.; Chowdari, N. S.; Kantam, M. L.; Sreedhar, B. J. Am.
Chem. Soc. 2002, 124, 14127. (c) Gelman, D.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2003, 42, 5993. (d) Kollhofer, A.; Pullmann, T.; Plenio, H.
Angew. Chem. 2003, 115, 1086; Angew. Chem., Int. Ed. 2003, 42, 1056.
(e) Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2005, 44, 6173.
(f) Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2004, 45,
8443.
(9) For papers on TBAF as an activator for the palladium-catalyzed
Sonogashira reaction, see: (a) Mori, A.; Kawashima, J.; Shimada, T.;
Suguro, M.; Hirabayashi, K.; Nishihara, Y. Org. Lett. 2000, 2, 2935. (b)
Mori, A.; Shimada, T.; Kondo, T.; Sekiguchi, A. Synlett 2001, 649.
(10) For selected papers on the palladium-catalyzed homocoupling
reactions of alkynes, see: (a) Siemsen, P.; Livingston, R. C.; Diederich, F.
Angew. Chem., Int. Ed. 2000, 39, 2632. (b) Li, J.-H.; Liang, Y.; Zhang,
X.-D. Tetrahedron 2005, 61, 1903. (c) Li, J.-H.; Liang, Y.; Wang, D.-P.;
Liu, W.-J.; Xie, Y.-X.; Yin, D.-L. J. Org. Chem. 2005, 70, 2832 and
references cited therein.
10.1021/jo051882t CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/18/2005
J. Org. Chem. 2006, 71, 379-381
379

TABLE 1. Palladium-Catalyzed Sonogashira Cross-Coupling of
1-Bromo-4-methoxybenzene (1a) with Phenylacetylene (2a)a
TABLE 2. PdCl2(PPh3)2-Catalyzed Sonogashira Cross-Coupling of
Aryl Halides (1) with Alkynes (2)a
entry
Pd cat. (amt, mol %)
time (h)
yield (%)b
1
2
3
4
5
6
PdCl2(PPh3)2 (3)
PdCl2 (3)/PPh3 (6)
Pd(PPh3)4 (3)
PdCl2 (3)
Pd(OAc)2 (3)
Pd(dba)2 (3)
PdCl2(PPh3)2 (3)
PdCl2(PPh3)2 (3)
PdCl2(PPh3)2 (3)
3
3
3
14
14
14
3
24
3
86
65
41
25
51
42
88
55
16
7c
8c,d
9e
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Pd, TBAF‚3H2O (6
equiv) at 80 °C under N2. b Isolated yield. c TBAF‚3H2O (3 equiv). d At
room temperature. The conversion of 1a was 61%. e KF (3 equiv) instead
of TBAF. 80% of 1a was recovered.
system for the Sonogashira cross-coupling reaction should be
developed. Recently, Mori and co-workers have reported that
TBAF is a useful promoter for the amine-free palladium-
catalyzed Sonogashira cross-coupling reaction; organic solvents
such as THF were still required, and only examples of aryl
iodides and bromides were described.9a Here we report that
PdCl2(PPh3)2 combined with TBAF can afford general and fast
Sonogashira cross-coupling reactions of a wide range of ArX
species (X ) I, Br, Cl) with terminal alkynes under copper-,
amine-, and solvent-free conditions (eq 1).
The palladium-catalyzed Sonogashira reaction of 1-bromo-
4-methoxybenzene (1a) with phenylacetylene (2a) using TBAF
as the base was first examined, and the results are summarized
in Table 1. It was found that while PdCl2(PPh3)2, PdCl2/PPh3,
Pd(PPh3)4, PdCl2, Pd(OAc)2 and Pd(dba)2 all catalyzed the
Sonogashira reaction without the aid of any solvents as the
media, PdCl2(PPh3)2 turned out to be the best catalyst in terms
of yields and reaction rates (entries 1-6). In the presence of 3
mol % of PdCl2(PPh3)2, treatment of 1 mmol of 1a with 1.2
mmol of 2a and 6 equiv of TBAF afforded an 86% yield of the
corresponding coupled product 3 in 3 h,11 whereas the yield of
3 was decreased to 65% when the combination of PdCl2 and
PPh3 was used as the catalytic system (entries 1 and 2). Low
yields of 3 were isolated after 3-14 h using Pd(PPh3)4, PdCl2,
Pd(OAc)2, and Pd(dba)2 as the catalysts (entries 3-6). Identical
results were still observed when the amount of TBAF was
reduced to 3 equiv (88% yield; entry 7). It was interesting to
find that although the substrate 1a could not be consumed
completely even after 24 h, the isolated yield of the expected
a Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), PdCl2(PPh3)2 (3
mol%), and TBAF‚3H2O (3 equiv) at 80 °C under N2. b Isolated yield.
c At room temperature. d 48% of 1j was recovered. e 2 (0.8 mmol). f 30%
of 1j was recovered. g 28% of 1j was recovered. h At 100 °C, 30% of 1j
was recovered. i 40% of 1j was recovered. j 30% of 1k was recovered. k 46%
of 1l was recovered. l 58% of 1m was recovered.
product 3 was desirable (entry 8). A relatively low yield was
isolated after 3 h when TBAF was replaced by KF (entry 9).
As demonstrated in Table 2, coupling of 1a with the other
alkynes 2b,c was also carried out smoothly to give the
corresponding products 4 and 5 in 98% and 80% yields,
respectively, in the presence of 3 mol % of PdCl2(PPh3)2 and 3
equiv of TBAF (entries 1 and 2). It is interesting to note that
(11) We also attempted to reuse the PdCl2(MeCN)2/TBAF system;
however, only a 45% yield of 3 was isolated after 12 h from the second
run of the reaction of 1a with 2a.
380 J. Org. Chem., Vol. 71, No. 1, 2006

formulated on the basis of the mechanism reported earlier.2,3,6a,9,12
The Pd(0) species could be generated readily from the reaction
of Pd(PPh3)2Cl2 with solvents, substrates, additives, and/or
ligands etc.,2 followed by the oxidative addition of Pd(0) with
ArX to form intermediate 4. Then replacement between
intermediate 16 and the acetylene anion 17, which was generated
by the reaction of alkyne 2 with TBAF, occurred to afford
intermediate 18. Finally, the reductive elimination of intermedi-
ate 5 took place to regenerate the active Pd(0) species and give
the desired product 3-15. Thus, several beneficial roles of
TBAF might occur in the reaction on the basis of the previous
results2,6a,9,12 and the present results: (i) activation of the active
Pd(0) species with the formation of anionic Pd species, (ii)
stabilization of the low-coordination Pd(0) species (16 and 18),
(iii) deprotonation of the acidic hydrogen in the alkyne (in
pathway II), and (iv) phase-transfer catalysis for the inorganic
base/substrate/product phases.2,10,12
SCHEME 1. Working Mechanism
In summary, we have developed a general method for the
rapid Sonogashira cross-coupling reaction of aryl halides with
terminal alkynes using PdCl2(PPh3)2 combined with TBAF. In
comparison with the earlier established palladium-catalyzed
Sonogashira cross-coupling reaction, this protocol proceeds
under copper-, amine-, and solvent-free conditions and is
extended to the deactivated aryl chlorides with moderate to
excellent yields.
the reactions of aryl iodides 1b,c with 2a, respectively, were
very rapid under the optimal reaction conditions (entries 3 and
4). For example, iodide 1c could be consumed completely in
0.25 h and a quantitative yield of the desired product 6 was
obtained. The results also indicated that the palladium-catalyzed
Sonogashira reaction tolerated a variety of functional groups,
and couplings of other aryl bromides 1d-i with alkynes 2a-e
occurred efficiently to produce excellent yields of the corre-
sponding products 6-15 in 1-6 h (entries 5-15). In comparison
with the results of entries 7 and 8 in Table 1, the coupling of
the activated bromide 1d with 2a could be conducted smoothly
at room temperature after 6 h to give a yield identical with that
at 80 °C (entries 5 and 6). It is noteworthy that moderate yields
of the desired products are observed in the reactions of aryl
chlorides, including activated and deactivated aryl chlorides
(entries 16-23). Treatment of 0.5 mmol of 1-chloro-4-nitroben-
zene (1j) with 0.6 mmol of phenylacetylene (2a), 3 mol % of
PdCl2(MeCN)2, and 3 equiv of TBAF afforded only a 45% yield
of 6 together with 48% of 1j (entry 16). As indicated in our
previous report,6d the amount of alkynes affected the reaction.
Thus, we expected to enhance the yield of the present reaction
by increasing the amount of alkyne. Indeed, although the
substrate 1j still could not be consumed completely, the yield
of 6 was enhanced to 65% when 0.8 mmol of 2a was added
(entry 17). Neither prolonged reaction time nor enhanced
reaction temperature affected the yield of 6 (entries 17-19).
Under the same reaction conditions, the reactions of chlorides
1k-m with 2a were also conducted smoothly in moderate yields
(entries 21-23).
Experimental Section
Typical Experimental Procedure for the Sonogashira Cross-
Coupling Reactions. A mixture of aryl halide 1 (0.5 mmol), alkyne
2 (0.6 mmol), PdCl2(PPh3)2 (3 mol %), and TBAF‚3H2O (3 equiv)
was stirred under N2 at 80 °C for the desired time until complete
consumption of starting material as monitored by TLC. After the
mixture was washed with water, extracted with ether, and evapo-
rated, the residue was purified by flash column chromatography
(hexane/ethyl acetate) to afford the corresponding coupled products
3-15.
Acknowledgment. We thank the National Natural Science
Foundation of China (Grant Nos. 20202002 and 20572020) and
Hunan Provincial Natural Science Foundation of China (Grant
No. 05JJ1002) for financial support.
Supporting Information Available: Text and figures giving
analytical data and spectra (1H and 13C NMR) for all the products
3-15 and a typical procedure for the palladium-catalyzed Sono-
gashira cross-coupling reaction. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO051882T
Although the effect of TBAF in these reactions was not clear,
TBAF acted as a base and phase-transfer catalysis (PTC) to
favor the desired reaction is confirmed. To elucidate the effect
of TBAF in the palladium-catalyzed Sonogashira cross-coupling
reaction, a working mechanism as outlined in Scheme 1 was
(12) For selected papers on the role of TBA- in the cross-coupling
reactions, see: (a) Calo´, V.; Nacci, A.; Monopoli, A.; Laera, S.; Cioffi, N.
J. Org. Chem. 2003, 68, 2929. (b) Reetz, M. T.; Maase, M. AdV. Mater.
1999, 11, 773. (c) Reetz, M. T.; de Vries, J. G. Chem. Commun. 2004,
1559 and references therein.
J. Org. Chem, Vol. 71, No. 1, 2006 381