Reusable Cu2O/PPh3/TBAB system for the cross-couplings of aryl halides and heteroaryl halides with terminal alkynes

Article abstract of DOI:10.1021/jo070538o

(Chemical Equation Presented) An efficient and reusable Cu ₂O/PPh₃/TBAB (n-Bu₄NBr) system for the cross-coupling reactions of aryl and heteroaryl halides with terminal alkynes has been developed. Four types of Cu₂O, including bulky Cu ₂O, cubic Cu₂O nanoparticles, octahedral Cu₂O nanoparticles, and spherical Cu₂O nanoparticles, were examined, and the octahedral Cu₂O nanoparticles were found to be the most effective catalyst for the reaction. In the presence of the octahedral Cu₂O nanoparticles, PPh₃, and TBAB, a variety of aryl and heteroaryl halides were reacted with alkynes including alkynols smoothly in moderate to good yields. Noteworthy is that the Cu₂O/ PPh₃/TBAB system can be recovered and reused several times without loss of any activities.

Full text of DOI:10.1021/jo070538o

amine,2d 2-aminopyrimidine-4,6-diol,2f and tertiary amines2g,h
are effective catalysts in the Sonogashira reaction, while Cu2O
is a less active. Miura and co-workers,2a for instance, have
reported the first catalytic Sonogashira-type cross-couplings
between aryl iodides or vinyl iodides with terminal alkynes using
CuI/PPh3 as the catalytic system and DMF as the solvent, but
the Cu2O/PPh3 catalytic system provided a rather low yield of
the Sonogashira product after 20 h even in the reaction of
iodobenzene with phenylacetylene at 120 °C. On the other hand,
the reported catalytic systems were not recovered and reused
because of the harmful organic solvents (often DMF) in all of
these copper-catalyzed transformations. Furthermore, alkynols
were found to be unsuitable substrates, and heteroaryl halides
as the substrates remain unexplored.1,2 Recently, the ligand-
free copper nanocluster-catalyzed Sonogashira reaction was
developed by Rothenberg and co-workers. However, no recy-
cling of the copper nanoclusters process was tested, and the
scope was still limited to the activated aromatic bromides.2i Very
recently, we have also reported solventless Cu(OAc)2-catalyzed
couplings between aryl halides and terminal alkynes using
TBAF as a base and 4,6-dimethoxypyrimidin-2-amine as a
ligand, and only aryl iodides and the activated aryl bromides
were suitable substrates for the Sonogashira coupling reaction.2f
From the point of economy and environment, the development
of some efficient and reusable copper catalytic systems for the
solventless Sonogashira reaction of a wide range of aryl halides
is still challenging. Here, we wish to report the combination of
the octahedral Cu2O nanoparticles with PPh3 and TBAB as an
efficient and reusable system for the Sonogashira-type cross-
coupling reaction under solventless conditions (eq 1). It is
noteworthy that the scope of the substrates is expanded to
heteroaryl halides and alkynols.
Reusable Cu2O/PPh3/TBAB System for the
Cross-Couplings of Aryl Halides and Heteroaryl
Halides with Terminal Alkynes
Bo-Xiao Tang, Feng Wang, Jin-Heng Li,*
Ye-Xiang Xie, and Man-Bo Zhang*
Key Laboratory of Chemical Biology & Traditional Chinese
Medicine Research (Ministry of Education), College of
Chemistry and Chemical Engineering, Hunan Normal
UniVersity, Changsha 410081, China
jhli@hunnu.edu.cn
ReceiVed March 15, 2007
An efficient and reusable Cu2O/PPh3/TBAB (n-Bu4NBr)
system for the cross-coupling reactions of aryl and heteroaryl
halides with terminal alkynes has been developed. Four types
of Cu2O, including bulky Cu2O, cubic Cu2O nanoparticles,
octahedral Cu2O nanoparticles, and spherical Cu2O nano-
particles, were examined, and the octahedral Cu2O nano-
particles were found to be the most effective catalyst for the
reaction. In the presence of the octahedral Cu2O nanopar-
ticles, PPh3, and TBAB, a variety of aryl and heteroaryl
halides were reacted with alkynes including alkynols smoothly
in moderate to good yields. Noteworthy is that the Cu2O/
PPh3/TBAB system can be recovered and reused several
times without loss of any activities.
Recently, much attention has been attracted to the use of
copper complexes as the catalysts for the Sonogashira-type
cross-coupling of aryl halides with terminal alkynes.1,2 This is
because palladium complexes, the most commonly used cata-
lysts for the Sonogashira-type cross-coupling reaction, are
considerably expensive, which limits their application in
industry.3 Recent studies show that ligated copper halides by
PPh3,2a 1,10-phenanthroline,2b,e N,N-dimethylglycine,2c ethylenedi-
Although many shapes of Cu2O nanoparticles, such as
octahedral,4 cube,5 wire, rod, and unformed amorphism,6 were
prepared, few papers have been reported on the use of Cu2O
(3) 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) de
Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions;
Wiley-VCH: Weinheim, Germany, 2004. (d) Doucei, H.; Hierso, J.-C.
Angew. Chem., Int. Ed. 2007, 46, 834. (e) Chinchilla, R.; Na´jera, C. Chem.
ReV. 2007, 107, 874.
(4) For representative papers on the preparation of the octahedral Cu2O
nanoparticles, see: (a) Xu, H.; Wang, W.; Zhu, W. J. Phys. Chem. B 2006,
110, 13829. (b) Ng, C. H. B.; Fan, W. Y. J. Phys. Chem. B 2006, 110,
20801.
(5) For representative papers on the preparation of the cubic Cu2O
nanoparticles, see: (a) Guo, L.; Murphy, C. J. Nano Lett. 2003, 3, 231. (b)
Zeng, X.-W.; Zhang, Y.-H.; Luo, C.-C.; Zeng, Y.-W.; Wang, Y.-G. Chin.
J. Inorg. Chem. 2005, 21, 1515. (c) Singh, D. P.; Neti, N. R.; Sinha, A. S.
K.; Srivastava, O. N. J. Phys. Chem. C 2007, 111, 1584.
(6) For representative papers on the preparation of the other shapes of
Cu2O nanoparticles, see: (a) Cao, M.; Hu, C.; Wang, Y.; Guo, Y.; Guo,
C.; Wang, E. Chem. Commun. 2003, 1884. (b) Zhang, J.; Liu, J.; Peng, Q.;
Wang, X.; Li, Y. Chem. Mater. 2006, 18, 867. (c) Wu, W.-T.; Wang, Y.;
Shi, L.; Pang, W.; Zhu, Q.; Xu, G.; Lu, F. J. Phys. Chem. B 2006, 110,
14702. (d) Yao, W.-T.; Yu, S.-H.; Zhou, Y.; Jiang, J.; Wu, Q.-S.; Zhang,
L.; Jiang, J. J. Phys. Chem. B 2005, 109, 14011.
(1) For special reviews on copper-catalyzed cross-couplings, see: (a)
Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int Ed. 2000,
39, 2632. (b) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. ReV. 2002, 102, 1359. (c) Ley, S. V.; Thomas, A. W. Angew. Chem.,
Int. Ed. 2003, 42, 5400. (d) Beletskaya, I. P.; Cheprakov, A. V. Coord.
Chem. ReV. 2004, 248, 2337.
(2) For papers on the Sonogashira cross-coupling reaction catalyzed by
a catalytic amount of copper, see: (a) Okuro, K.; Furuune, M.; Enna, M.;
Miura, M.; Nomura, M. J. Org. Chem. 1993, 58, 4716. (b) Gujadhur, R.
K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001, 3, 4315. (c) Ma, D,
Liu, F. Chem. Commun. 2004, 1934. (d) Wang, Y. F.; Deng, W.; Liu, L.;
Guo, Q. X. Chin. Chem. Lett. 2005, 16, 1197. (e) Saejueng, P.; Bates, C.
G.; Venkataraman, D. Synthesis 2005, 1706. (f) Xie, Y.-X.; Deng, C.-L.;
Pi, S.-F.; Li, J.-H.; Yin, D.-L. Chin. J. Chem. 2006, 24, 1290. (g) Guo,
S.-M.; Deng, C.-L.; Li, J.-H. Chin. Chem. Lett. 2007, 18, 13. (h) Li, J.-H.;
Li, J.-L.; Wang, D.-P.; Pi, S.-F.; Xie, Y.-X.; Zhang, M.-B.; Hu, X.-C. J.
Org. Chem. 2007, 72, 2053. (i) Thathagar, M. B.; Beckers, J.; Rothenberg,
G. Green Chem. 2004, 6, 215. (j) Li, J.-H.; Li, J.-L.; Xie, Y.-X. Synthesis
2007, 984.
10.1021/jo070538o CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/06/2007
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J. Org. Chem. 2007, 72, 6294-6297

TABLE 1. Screening Conditionsa
entry
[Cu2O]
ligand
yield (%)b
1
2
3
cubic Cu2O nanoparticles
bulky Cu2O
P(o-tol)3 (L1)
P(o-tol)3 (L1)
P(o-tol)3 (L1)
P(o-tol)3 (L1)
57
55
63
78
trace
90
54
55
48
70
41
65
76
73
81
91
81
35
spherical Cu2O nanoparticles
octahedral Cu2O nanoparticles
octahedral Cu2O nanoparticles
octahedral Cu2O nanoparticles
octahedral Cu2O nanoparticles
octahedral Cu2O nanoparticles
octahedral Cu2O nanoparticles
octahedral Cu2O nanoparticles
octahedral Cu2O nanoparticles
octahedral Cu2O nanoparticles
cubic Cu2O nanoparticles
bulky Cu2O
4
5
6c
7
PPh3 (L2)
PCy3 (L3)
8
9
P(2,6-diMeC6H4)3 (L4)
P(n-Bu)3 (L5)
POPh3 (L6)
1,1′-bipyridinyl (L7)
DABCO (L8)
PPh3 (L2)
PPh3 (L2)
PPh3 (L2)
PPh3 (L2)
PPh3 (L2)
10
11
12
13
14
15
16d
17e
18f
spherical Cu2O nanoparticles
octahedral Cu2O nanoparticles
octahedral Cu2O nanoparticles
octahedral Cu2O nanoparticles
PPh3 (L2)
a Reaction conditions: 1a (0.5 mmol), 2a (0.7 mmol), [Cu] (10 mol %), ligand (20 mol %), K2CO3 (1 mmol), and TBAB (1.5 g) at 135-140 °C for 24
h. b Isolated yield. c Average yield of three runs. d At 120 ˚C for 48 h. e Cs2CO3 (1 mmol) instead of K2CO3. f Et3N instead of K2CO3.
nanoparticles in organic synthesis.7 Thus, further application
of them as catalysts in organic synthesis should be intensively
pursued. Very recently, we have developed the cubic Cu2O
nanoparticles combined with P(o-tol)3 as an alternative Stille
cross-coupling catalytic system in TBAB.7a We then attempted
to apply the cubic Cu2O nanoparticles/P(o-tol)3 (L1)/TBAB
system in the Sonogashira-type reaction of 1-bromo-4-nitroben-
zene (1a) with phenylacetylene (2a). To our delight, a moderate
yield of the target product 3 was isolated after 24 h (entry 1).
It was found that the yield of 3 was reduced slightly using the
bulky Cu2O (entry 2). These results prompted us to further
evaluate the copper catalyst. After a series of trials, we observed
that the octahedral Cu2O nanoparticles were highly active in
the Sonogashira reaction (Table 1, entries 1-4). In the presence
of the octahedral Cu2O nanoparticles, L1, and TBAB, the yield
of 3 was enhanced to 78% (entry 4). Subsequently, a series of
other ligands were evaluated, and PPh3 (L2) provided the highest
yield (entries 5-12). Without any ligands, substrate 1a was
treated with alkyne 2a, the octahedral Cu2O nanoparticles, K2-
CO3, and TBAB at 135-140 °C for 24 h to afford a trace
amount of 3, whereas the yield was increased sharply to 90%
when PPh3 (L2) was added (entries 5 and 6). Interestingly, the
Cu2O/L2/TBAB system could be recovered and reused at least
three times without any loss of activity. The results of three
runs showed that they were almost consistent in yields and rates
(entry 6; run 1 ) 88%; run 2 ) 90%; and run 3 ) 93%). The
results showed that the cubic Cu2O nanoparticles, the spherical
Cu2O nanoparticles, and the bulky Cu2O were still inferior to
the octahedral Cu2O nanoparticles even in the presence of L2
(entries 6 and 13-15). Finally, both the reaction temperature
and base effects were investigated (entries 6 and 16-18). It
turned out that K2CO3 at 135-140 °C provided the best results
(entry 6). Note that high yield of the target product 3 is still
achieved when the reaction can be conducted at 120 °C after
prolonging the reaction time (entry 16).
As listed in Table 2, a variety of aryl halides could undergo
the reaction with terminal alkynes smoothly under the standard
reaction conditions, demonstrating the versatility of the octa-
hedral Cu2O nanoparticles. Aryl iodides 1b-1f, whether
electron-deficient or electron-rich, all worked well with alkynes
2a-2e bearing aryl, heteroaryl, alkyl, or hydroxy groups in the
presence of the octahedral Cu2O nanoparticles, PPh3 (L2),
K2CO3, and TBAB (entries 1-11). Moreover, the Cu2O/L2/
TBAB system in these couplings could be reused at least three
times without loss of any activity. 1-Iodo-2-methylbenzene (1d),
for instance, reacted with alkyne 2a efficiently to give similar
results in five runs using the recovered system (entry 5).
p-Iodoanisole (1e), a deactivated substrate, was also coupled
with alkynes 2a-2e, respectively, to afford the target products
8-12 in moderate to good yields (entries 6-10). It is interesting
to reveal that the reaction between 2-iodobenzaniline (1f) and
alkyne 2a gave the corresponding 2-(2-phenylethynyl)benzen-
amine 13, not the often reported 2-phenyl-1H-indole,2,3 in a 50%
yield (entry 11). It was found that the standard conditions were
also effective for the reaction of another activated aryl bromide
1g (entry 12). Although higher loadings of Cu2O were required,
moderate yields were still achieved in the couplings of the less
active bromides 1h and 1i (entries 13-15). While the reaction
of bromobenzene 1h with alkyne 2a produced the corresponding
desired product 4 in a rather low yield at a loading of 10 mol
% of Cu2O, the yield of 4 was increased to 55% in the presence
of 20 mol % of Cu2O (entries 13 and 14). Gratifyingly, the
coupling of 1-chloro-4-nitrobenzene (1j) with alkyne 2a was
conducted successfully in high yield in the presence of Cu2O,
L2, K2CO3, and TBAB (entry 16). Unfortunately, both chlorides
1k and 1l were not suitable substrates even in the presence of
20 mol % of Cu2O (entries 17 and 18).
To our delight, heteroaryl bromides and chlorides are suitable
substrates for the Sonogashira reaction under the standard
conditions (Table 3). In the presence of the octahedral Cu2O
nanoparticles, PPh3 (L2), K2CO3, and TBAB, 3-bromopyridine
(7) For selected papers, see: (a) Li, J.-H.; Tang, B.-X.; Tao, L.-M.; Liang,
Y.; Zhang, M.-B. J. Org. Chem. 2006, 71, 7488. (b) White, B.; Yin, M.;
Hall, A.; Sergey, D. L.; Rahman, T.; Turro, N.; O’Brien, S. Nano Lett.
2006, 6, 2095.
J. Org. Chem, Vol. 72, No. 16, 2007 6295

TABLE 2. Octahedral Cu2O Nanoparticles/PPh3 (L2)-Catalyzed Cross-Couplings of Aryl Halides (1) with Terminal Alkynes (2) in TBABa
a Reaction conditions: 1 (0.5 mmol), 2 (0.7 mmol), octahedral Cu2O nanoparticles (10 mol %), L2 (20 mol %), K2CO3 (1 mmol), and TBAB (1.5 g) at
135-140 °C. b Isolated yield. c Octahedral Cu2O (20 mol %) and ligand (40 mol %).
(1m) was reacted with alkyne 2a, 2b, 2e, or 2f smoothly to
afford the corresponding products 15, 16, 18, and 12 in moderate
to good yields (entries 1, 2, 4, and 5). However, alkynol 2c
was an unsuitable substrate for the reaction with bromide 1m
(entry 3). The other heteroaryl bromides 1n-q also underwent
the reaction successfully in moderate to good yields under the
same conditions (entries 6-9). Although 2-chloropyridine (1r)
provided a low yield, the other two heteroaryl chlorides 1s and
1t worked well with alkyne 2a to give the target products in
high yields (entries 10-12). It is worth noting that the Cu2O/
L2/TBAB system in the couplings of 1m and 1s with 2a could
also be recovered and reused (entries 1 and 11).
In conclusion, we have developed a novel copper catalytic
system for the Sonogashira cross-coupling reaction. In the
presence of the octahedral Cu2O nanoparticles, L2, K2CO3, and
TBAB, a variety of aryl and heteroaryl halides could perform
6296 J. Org. Chem., Vol. 72, No. 16, 2007

TABLE 3. The Cu2O/PPh3 (L2)/TBAB System for the Reactions of Heteroaryl Halides (1) with Terminal Alkynes (2)a
a Reaction conditions: 1 (0.5 mmol), 2 (0.7 mmol), octahedral Cu2O nanoparticles (10 mol %), L2 (20 mol %), K2CO3 (1 mmol), and TBAB (1.5 g) at
135-140 °C. b Isolated yield.
After initial experimentation, the residue (the Cu2O nanoparticles/
PPh3/TBAB system) was then solidified (evaporated in vacuo and
cooled) and subjected to a second run of the Sonogashira reaction
by charging with the same substrates (aryl halide, alkyne, and
K2CO3).
the coupling with terminal alkynes efficiently in moderate to
excellent yields. Furthermore, the Cu2O/L2/TBAB system could
be reused several times without loss of activity. Noteworthy is
that the couplings of alkynols are successful under the present
conditions. Efforts to apply the catalytic system in other cross-
coupling transformations are underway in our laboratory.
Acknowledgment. The authors thank the National Natural
Science Foundation of China (No. 20572020), Fok Ying Tung
Education Foundation (No. 101012), the Key Project of Chinese
Ministry of Education (No. 206102), New Century Excellent
Talents in University (No. NCET-06-0711), Hunan Provincial
Natural Science Foundation of China (No. 05JJ1002), and
Specialized Research Fund for the Doctoral Program of Higher
Education (No. 20060542007) for financial support.
Experimental Section
Typical Experimental Procedure for the Cu2O/PPh3/TBAB
(n-Bu4NBr) System for the Cross-Coupling Reactions of Aryl
and Heteroaryl Halides with Terminal Alkynes. A mixture of
aryl halide 1 (0.5 mmol), alkyne 2 (0.7 mmol), pyramid-like Cu2O
nanoparticles (10 mol %), PPh3 (L2; 20 mol %), K2CO3 (2 equiv),
and TBAB (1.5 g) was stirred at 135-140 °C for the desired time
(indicated in Table 2) until complete consumption of starting
material was monitored by TLC. After the reaction was finished,
diethyl ether was poured into the mixture, then washed with water,
extracted with diethyl ether, dried with anhydrous Na2SO4, and
evaporated under vacuum, and the residue was purified by flash
column chromatography (hexane or hexane/ethyl acetate) to afford
the desired coupled product.
Supporting Information Available: Analytical data and spectra
(1H and 13C NMR) for all the products 3-16, 18-22, and 24. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO070538O
J. Org. Chem, Vol. 72, No. 16, 2007 6297