Efficient and copper-free sonogashira cross-coupling reaction catalyzed by Pd(OAc)2/pyrimidines catalytic system

Article abstract of DOI:10.1002/ejoc.200500519

An efficient and copper-free catalyst system for Sonogashira cross-coupling reaction is presented. In the presence of 3 mol-% of Pd(OAc)₂ and 6 mol-% of 2-aminopyrimidine-4,6-diol, various aryl iodides and bromides can be coupled smoothly with

Full text of DOI:10.1002/ejoc.200500519

SHORT COMMUNICATION
Efficient and Copper-Free Sonogashira Cross-Coupling Reaction Catalyzed by
Pd(OAc)2/Pyrimidines Catalytic System
Jin-Heng Li,*[a] Xu-Dong Zhang,[a] and Ye-Xiang Xie[a]
Keywords: Palladium / Cross-coupling reaction / Homogeneous catalysis
An efficient and copper-free catalyst system for Sonogashira
cross-coupling reaction is presented. In the presence of
3 mol-% of Pd(OAc)2 and 6 mol-% of 2-aminopyrimidine-4,6-
diol, various aryl iodides and bromides can be coupled
smoothly with terminal alkynes to afford the corresponding
coupled alkynes in moderate to excellent yields under mild
conditions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
The acetylenic subunit is a commonly found motif in bio-
logically active molecules and a useful building block in or-
ganic synthesis. Accordingly, the construction of alkynes re-
mains an active area in organic synthesis. Besides the homo-
coupling reactions of terminal alkynes, the Pd-catalyzed
Sonogashira cross-coupling reaction represents another im-
portant method for the formation of alkynes.[1] Generally,
the combination of palladium, phosphane and CuI is used
as the catalytic system for the reaction.[2–5] However, many
phosphane ligands are air-sensitive and expensive.[6] Besides
these drawbacks, the other significant limits on their syn-
thetic applications is that the generation of some CuI ace-
tylides in situ by the reaction of CuI with alkyne can result
in oxidative homocoupling reaction of alkynes readily.[5f,7]
For these reasons, the development of an efficient, inexpen-
sive, copper- and phosphane-free catalytic system is still sig-
nificant. Generally, a number of N-heterocyclic compounds
is commercially available and these compounds (often pyri-
dines) can directly be used as ligands for palladium cata-
lysts.[2c] Thus, we tested these ligands in palladium-cata-
lyzed cross-coupling reactions. Indeed, we found that pyr-
imidines were efficient ligands for Pd(OAc)2-catalyzed Son-
ogashira cross-coupling reaction of aryl halides with ter-
minal alkynes. Here we report our initial results according
to Equation (1).
(1)
Results and Discussion
Efficiency of Pd(OAc)2/pyrimidines as the catalytic sys-
tem for coupling of 1-iodo-4-methoxybenzene (1a) with
phenylacetylene (2a) was first evaluated, and the results are
summarized in Table 1. Initially, a series of pyrimidines (L1–
L4) as ligands were tested (entries 1–5). The results showed
that the ligand 2-aminopyrimidine-4,6-diol (L1) was most
effective, and the amount of L1 also affected the yield to
some extent. Without any ligands, treatment of 1a with 2a,
Pd(OAc)2 and Cs2CO3 afforded a low yield of the corre-
sponding cross-coupled product 3 at room temperature (en-
try 1), whereas the yield of 3 was increased sharply to 80%
when 3 mol-% of L1 was added (entry 2). In the presence
of 3 mol-% of Pd(OAc)2 and 6 mol-% of L1, the yield of 3
was enhanced to 92% (entry 3). Identical results were ob-
served when the amount of L1 was further increased to
12 mol-% (entry 4). A set of bases, such as Cs2CO3, KOAc,
K2CO3, and Et3N, were then investigated, and Cs2CO3 as
the base gave the best results (entries 3 and 8–10). Finally,
some solvents including MeCN, acetone and DMF were
also examined and MeCN as the solvent provided the high-
est yield (entries 3, 11, and 12).
[a] Key Laboratory of Chemical Biology & Traditional Chinese
Medicine Research, College of Chemistry and Chemical Engi-
neering, Hunan Normal University,
As shown in Table 2, the combination of Pd(OAc)2 and 2-
aminopyrimidine-4,6-diol (L1) is an effective catalytic system
for the cross-coupling reactions of various aryl halides 1a–j
with alkynes 2a–e. In the presence of 3 mol-% of Pd(OAc)2,
6 mol-% of L1, and 1.2 equiv. of Cs2CO3, coupling of a
Changsha 410081, China
Fax: +86-731-8865 515
E-mail: jhli@hunnu.edu.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200500519
Eur. J. Org. Chem. 2005, 4256–4259

Efficient and Cu-Free Sonogashira Cross-Coupling Reaction
SHORT COMMUNICATION
Table 1. Palladium-catalyzed Sonogashira cross-coupling reaction of 1-iodo-4-methoxybenzene (1a) with phenylacetylene (2a).[a]
[a] Unless otherwise indicated, the reaction conditions were as follows: 1a (1 mmol), 2a (1.2 mmol), Pd(OAc)2 (3.0 mol-%), ligand (6.0 mol-
%), base (1.2 equiv.), and MeCN (4 mL) under N2 at room temperature. [b] Isolated yield. [c] Ligand (3 mol-%). [d] Ligand (12 mol-%).
[e] DMF (4 mL) instead of MeCN. [f] Acetone (4 mL) instead of MeCN.
number of aryl iodides 1a–f with alkynes 2a–c efficiently and 2-aminopyrimidine-4,6-diol, the reactions of a number
yields the corresponding alkynes 4–11 in good yields (entries of aryl iodides and bromides with terminal alkynes were car-
1–8). For example, when 1-iodo-4-nitrobenzene (1b) is cou- ried out efficiently to afford the desired products in moderate
pled with alkynes 2a–c the corresponding products 5–7 are to excellent yields under mild conditions. Further efforts to
obtained in yields of 100%, 95%, and 82%, respectively (en- extend the application of this catalytic system and this proto-
tries 2–4). The results indicate that the efficiency of the col in organic synthesis are underway in our laboratory.
Pd(OAc)2/L1 catalytic system for the reactions of aryl bro-
mides 1g–j is decreased to some extent, and both higher reac-
tion temperature and prolonged reaction time are required
(entries 9–16). For example, treatment of 1-bromo-4-nitro-
benzene (1g) with alkynes 1a, 1b, 1d, or 1e gives moderate to
good yields of the corresponding products after 20 h at 60°C
(entries 9–12), whereas the deactivated iodide 1f is consumed
completely within 9 h at room temperature (82% yield, entry
8). Unfortunately, the coupling of aryl chlorides 1k and 1l
with 2a, respectively, was unsuccessful (entries 17 and 18).
Experimental Section
1
General Remarks: H and 13C NMR spectra were recorded on an
INOVA-400 (Varian) spectrometers and a Bruker AMX-300 spec-
trometers with the use of CDCl3 as the solvent. All reagents were
directly used as obtained commercially. All products 3–14 are
known,[3–5] and their analytical data and spectra (1H and 13C
NMR) are available as Supporting Information (see also the foot-
note on the first page of this article).
Typical Experimental Procedure for the Pd(OAc)2/L1-Catalyzed
Sonogashira Cross-Coupling Reaction: A mixture of aryl halide 1
(1.0 mmol), alkyne 2 (1.2 mmol), Pd(OAc)2 (3.0 mol-%), 2-amino-
pyrimidine-4,6-diol (L1, 6.0 mol-%), Cs2CO3 (1.2 equiv.), and
MeCN (4 mL) was stirred under N2 at the indicated reaction tem-
perature for desired time until complete consumption of starting
Conclusions
In summary, we have developed an efficient Pd(OAc)2/2-
aminopyrimidine-4,6-diol catalytic system for the Sonoga-
shira cross-coupling reaction. In the presence of Pd(OAc)2 material as monitored by TLC. After the mixture was filtered and
Eur. J. Org. Chem. 2005, 4256–4259
www.eurjoc.org © 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4257

J.-H. Li, X.-D. Zhang, Y.-X. Xie
SHORT COMMUNICATION
Table 2. Palladium-catalyzed Sonogashira coupling reaction in the presence of 2-aminopyrimidine-4,6-diol (L1).[a]
[a] Unless otherwise indicated, the reaction conditions were as follows: 1 (1 mmol), 2 (1.2 mmol), Pd(OAc)2 (3.0 mol-%), L1 (6.0 mol-%),
Cs2CO3 (1.2 equiv.), and MeCN (4 mL) at room temperature under N2. [b] Isolated yield. [c] At 60°C.
evaporated, the residue was purified by flash column chromatog-
raphy (hexane/ethyl acetate) to afford the coupled products 3–14.
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Acknowledgments
We thank the National Natural Science Foundation of China (No.
20202002) for financial support.
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Efficient and Cu-Free Sonogashira Cross-Coupling Reaction
SHORT COMMUNICATION
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Received July 13, 2005
Published Online: September 1, 2005
Eur. J. Org. Chem. 2005, 4256–4259
www.eurjoc.org
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