Copper-catalyzed C(sp2)-C(sp) Sonogashira-type cross-coupling reactions accelerated by polycyclic aromatic hydrocarbons

Article abstract of DOI:10.1002/aoc.3298

Copper-catalyzed Sonogashira-type reactions were dramatically accelerated by introducing a catalytic amount of polycyclic aromatic hydrocarbon additive. This novel catalytic system features low copper loading (0.5mol% < Cu < 5mol%), broad reaction scope a

Full text of DOI:10.1002/aoc.3298

Full Paper
Received: 15 November 2014
Revised: 20 January 2015
Accepted: 24 January 2015
Published online in Wiley Online Library: 12 March 2015
(wileyonlinelibrary.com) DOI 10.1002/aoc.3298
2
Copper-catalyzed C(sp )–C(sp) Sonogashira-
type cross-coupling reactions accelerated by
polycyclic aromatic hydrocarbons
Wei Xu, Bo Yu, Huaming Sun, Guofang Zhang, Weiqiang Zhang*
and Ziwei Gao*
Copper-catalyzed Sonogashira-type reactions were dramatically accelerated by introducing a catalytic amount of polycyclic aro-
matic hydrocarbon additive. This novel catalytic system features low copper loading (0.5mol% < Cu < 5 mol%), broad reaction
scope and remarkable substrate tolerance. Both aromatic and aliphatic terminal alkynes as well as diverse aryl iodides were
employed in this transformation, affording respectable yields of the desired products. The novel Cu(OTf)2/pyrene system was
subsequently employed to synthesize phenylacetylene-based fluorescent compounds. Copyright © 2015 John Wiley & Sons, Ltd.
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
Keywords: copper catalysis; polycyclic aromatic hydrocarbons; Sonogashira-type cross-coupling reaction
ligands nor palladium catalysts. Specifically, we have discovered
Introduction
that C(sp2)–C(sp) Sonogashira coupling reactions proceed
Sonogashira coupling reactions are some of the most important
methods to furnish arylalkynes or conjugated enynes, which have
been used as key precursors for the syntheses of natural
products,[1–3] pharmaceuticals[4–6] as well as organic materials.[7,8]
Particularly, palladium complexes are the most commonly used
catalysts for such transformations, mostly due to their remarkable
catalytic efficiency.[9] Given the fact that palladium is a precious
metal with high toxicity, Pd-catalyzed Sonogashira coupling
reactions are prohibitively costly. Moreover, expensive phosphine
ligands synthesized via tedious multistep processes are usually
required to achieve decent reaction efficiency.[10] Consequently,
studies to identify inexpensive and nontoxic alternatives to palla-
dium catalysts are highly desirable. Indeed, it has been found that
cost-effective metals like copper can be fairly effective in C–C bond
formation reactions, and they seem to function similarly to
palladium catalysts in cross-coupling chemistry. Theoretically,
copper-catalyzed coupling reactions tend to be more versatile
and productive because copper possesses four oxidation states
from 0 to +3, whereas palladium species generally have four stable
oxidation states of 0, +1, +2 and +4.
It has been known for decades that aryl halides can couple with
copper(I) acetylides to afford arylacetylenes.[11] Recently, it was
found that copper(I) catalysts alone can also mediate the coupling
reaction of aryl halides and terminal alkynes, such as Cu(I)/amino
acid derivatives,[12–16] Cu(I)/DABCO,[17] Cu(I)/diamines,[18–20] copper
nanoparticles,[21–24] supported copper complexes[25–27] and other
copper-based catalytic systems.[28–32] So far, most Sonogashira cou-
pling reactions are still conducted in the presence of high loadings
of copper (5–30 mol%) catalysts and ligands. Therefore, an eco-
nomic but efficient catalytic system is definitely needed for such
C–C bond-forming processes.
smoothly in the presence of catalytic amounts of Cu(OTf)2 and poly-
cyclic aromatic hydrocarbons, using potassium carbonate as base
and DMF as solvent.
Experimental
General Remarks
All reactions were conducted using a standard Schlenk line. Aryl
halides and alkynes were purchased from Aldrich or Alfa Aesar.
CuI (99.999%) was purchased from Aldrich. NMR spectra were col-
lected in CDCl3 with a Bruker AVANCE 400 NMR spectrometer
(400MHz) using tetramethylsilane as the internal reference.
Typical Procedure for Cross-Coupling Reactions of Aryl Halides
and Terminal Alkynes with Cu/L Catalytic System
A mixture of aryl halide (1.0 mmol), alkyne (1.0mmol), CuI (4 mol%),
ligand L (10 mol%) and K2CO3 (1 mmol) in DMF (2.5) was stirred
for 12 h. The reaction solution was diluted with water, extracted
with diethyl ether, dried over anhydrous Na2SO4 and evaporated
to dryness. The residue obtained was purified using flash column
chromatography eluting with hexane or hexane–ethyl acetate.
*
Correspondence to: Weiqiang Zhang and Ziwei Gao, Key Laboratory of Applied
Surface and Colloid Chemistry, Ministry of Education, School of Chemistry
and Chemical Engineering, Shaanxi Normal University, 199 South Chang’an
Road, Xi’an 710062, People’s Republic of China. E-mail: zwq@snnu.edu.cn;
zwgao@snnu.edu.cn
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education,
School of Chemistry and Chemical Engineering, Shaanxi Normal University, 199
South Chang’an Road, Xi’an 710062, People’s Republic of China
Herein, we report the development of an alternative catalytic sys-
tem for Sonogashira reactions, which utilizes neither phosphine
Appl. Organometal. Chem. 2015, 29, 353–356
Copyright © 2015 John Wiley & Sons, Ltd.

W. Xu et al.
Table 1. Cu loading and ligand effect on the cross-coupling reaction of
Results and Discussion
PhI and PhCCHa
Using the coupling of iodobenzene and phenylacetylene as a
model reaction, the catalytic activity of a diverse set of CuI/L combi-
nations (Cu, 4 mol%; L1–L6 (Scheme 1), 10 mol%) was closely exam-
ined, affording a 45–96% yield of the desired product (Fig. 1).
Specifically, the yield of phenylacetylene was monitored using GC,
and then plotted as a function of the reaction time, as illustrated
in Fig. 1. To our delight, it appears that ligands L1–L6 can accelerate
the consumption of starting material to various extents, affording
yields ranging from 52 to 90%, which are significantly higher than
that observed in the control reaction (37%). In addition, it is found
that ligand L4 is superior to the others, affording a 76% yield of
the alkyne product.
Encouraged by these results, we next examined the effect of
other reaction parameters. The results are summarized in Table 1.
It appears that the catalytic activity of CuI/L is fairly sensitive to
the loading of copper catalyst (Table 1, entries 1–9), and those
reactions conducted in the presence of 0.5–3 mol% of CuI only af-
ford moderate yield of the desired product (entries 1–4). Surpris-
ingly, when the coupling reaction is carried out in the presence of
4 mol% CuI and 10 mol%L4, a 94% yield of the desired product is
obtained (entry 5). However, further increasing the loading of cop-
per catalyst (up to 30 mol%) does not improve the reaction effi-
ciency; instead, the yield is decreased to 42–45% (entries 6–9).
Therefore, the optimal copper loading is 4 mol%. Also, it is known
that the concentration of ligand or the ratio of catalyst to ligand
might have a substantial impact on catalytic activity.[26] Therefore,
we next investigated the effect of L4 concentration on the catalytic
coupling reaction. As evident from Table 1, a series of Cu-catalyzed
cross-coupling reactions were conducted using 4 mol% CuI and
1–30mol% ligand L4 (entries 11–18). When the loading of ligand
is lower than 10 mol%, the reaction yield is no more than 60%
Entry
CuI
L4
Yield Entry
CuI
L4
Yield
(mol%) (mol%) (%)b
(mol%) (mol%) (%)b
1
2
3
4
5
6
7
8
9
0.5
1
10
10
10
10
10
10
10
10
10
38
41
40
42
93
65
44
39
40
10
11
12
13
14
15
16
17
18
4
4
4
4
4
4
4
4
4
0.5
1
38
40
43
55
54
63
95
66
40
2
2
3
3
4
4
5
5
10
10
20
30
20
30
aReaction conditions: iodobenzene (1.0 mmol, 112 μl), phenylacetylene
(1.0 mmol, 109.8 μl), K2CO3 (2.0 mmol, 0.2760 g), DMF (2.5) under
nitrogen for 8 h.
bIsolated yield.
(entries 10–15), whereas the reaction yield can reach up to
96% when ligand loading was 10mol% (entry 16). However,
unlike conventional phosphine-based ligands, further increasing
the loading of L4 (10–30 mol%) does not enhance the efficiency
of the coupling reactions (entries 16–18).
With the optimal catalytic system in hand, we next investigated
the effects of solvent and base. These results are summarized in
Table 2. DMF is the most suitable solvent for this transformation,
affording a 95% yield of the desired product (Table 2, entry 3). In
contrast, solvents such as acetonitrile, toluene and DMSO are
found to produce inferior results (entries 1, 2, 4–8). Subse-
quently, we studied the effects of base on the efficiency of
cross-coupling reactions (entries 9–13). As can be seen, K2CO3
seems to be the most effective base, with other inorganic bases
such as Cs2CO3, K3PO4, KOt-Bu, KF and KOH producing unsatis-
factory results. We also explored the possibility of using organic
bases. However, neither of them affords satisfactory results
(entries 14 and 15). Finally, we systematically examined the ef-
fects of copper sources, in which both Cu(I) and Cu(II) catalysts
were employed. Notably, although copper salts such as CuBr,
CuCl, CuO and Cu(acac)2 are also capable of mediating the
Sonogashira coupling reaction, only moderate yields (40%) can
be obtained, indicating that Cu(OTf)2 should be the most appro-
priate copper source (entries 16–21, 20).
Scheme 1. Structures of polycyclic aromatic hydrocarbon ligands.
We then shifted our efforts to studies of the scope and limita-
tions of this novel catalytic system, using a diverse set of aryl
iodides and terminal alkynes (Table 3). Generally, both aryl and
aliphatic (1-octyne and 1-hexyne) alkynes can be employed to
react with 4-iodoanisole, affording 51–72% yields of the desired
products (Table 3, entries 1–4). Specifically, when arylalkynes
are allowed to react with aryl iodides, excellent yields of the
corresponding products are usually obtained (entries 5–17).
However, when p-nitroiodobenzene is employed, only a moderate
yield of the desired product is isolated (entry 13). It appears that
ortho-substitution on the aryl iodides does not seems to reduce
the reaction efficiency. The coupling reactions of o-Me-, o-OMe-
and o-CF3-substituted aryl iodides proceed smoothly under the
standard reaction conditions. Particularly, iodobenzene bearing
the strong electron-withdrawing o-CF3 group reacts very well,
Figure 1. Yield of phenylacetylene.
wileyonlinelibrary.com/journal/aoc
Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2015, 29, 353–356

Copper-catalyzed C(sp2)–C(sp) Sonogashira-type cross-coupling reactions
affording 79–92% yields of desired products (entries 9–12). We find
that aryl iodides bearing either electron-donating or electron-
withdrawing groups can readily react with arylalkynes, affording
good to excellent yields of desired products. Notably, the coupling
reaction between aryl iodide and aliphatic alkyne gives lower
yields (50%, entry 18). Finally, the coupling reactions using
bromobenzene and chlorobenzene with phenylacetylene under
the optimal reaction conditions turn out to give low yields of
24% and less than 5%, respectively.
Based on the well-established mechanism reported by Miura
and co-workers,[11] Rothenberg and co-workers[24] and Li and co-
workers[33] (Scheme 2), we propose a plausible mechanism for the
Cu(OTf)2/pyrene-catalyzed Sonogashira cross-coupling reaction. At
first, L coordinates with Cu(OTf)2 to generate a transition state inter-
mediate I, as proposed by Stephens and Castro.[34] Subsequently,
complex I reacts with alkyne to afford intermediate II in the
presence of potassium carbonate, followed by oxidative addition
reaction with PhI to give intermediate IV. Finally, IV undergoes re-
ductive elimination to afford the desired coupling product, accom-
panied by the regeneration of the active copper species I. In the
meantime, homocouplings of terminal alkynes proceeding through
the intermediacy of II can give diyne byproduct V.[35–38] Further
investigations to understand the mechanistic role of ligand L are
currently in progress.
Table 2. Optimization of Cu/pyrene-catalyzed Sonogashira coupling
reactionsa
Entry
Cu
Solvent
Base
K2CO3
Yield (%)b
1
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
1,4-Dioxane
THF
18
17
95, 36c
2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOH
3
DMF
4
DME
36
5
DMSO
Toluene
Acetonitrile
Ethanol
DMF
50
6
46
Because we are interested in the development of novel
fluorescent dyes, nonlinear optical materials and photorefractive
materials[39,40] with strong π–π conjugation, we hope to utilize the
7
24
8
20
9
38
10
11
12
13
14
15
16
17
18
19
20
21
DMF
Cs2CO3
KF
44
DMF
12
DMF
K3PO4
KOt-Bu
Et3N
11
DMF
53
DMF
25
DMF
Piperidine
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
40
CuCl
DMF
39
CuBr
DMF
40, 41c
35, 37c
42, 39c
94, 40c
40, 38c
CuO
DMF
Cu(OAc)2
Cu(OTf)2
Cu(acac)2
DMF
DMF
DMF
aReaction conditions: copper salt (4.0 mol%), L4 (0.1 mmol, 0.0016 g),
base (2 mmol), aryl iodide (1 mmol, 112 μl) and alkyne (1 mmol,
109.8 μl) in 2.5 ml solvent were stirred for 8 h under nitrogen.
bIsolated yield.
cNo additives.
Scheme 2. Proposed mechanism of Cu/L-catalyzed Sonogahria cross-
coupling.
Table 3. CuI/pyrene-catalyzed Sonogashira cross-coupling of aryl iodides and terminal alkynesa
Entry
R1
R2
Yield (%)b
Entry
R1
R2
Yield (%)b
1
2
3
4
5
6
7
8
9
p-MeO
p-MeO
p-MeO
p-MeO
m-CH3
m-CH3
m-CH3
m-CH3
o-CF3
Ph
68
72
51
55
77
89
84
79
92
10
11
12
13
14
15
16
17
18
o-CF3
o-CF3
o-CF3
p-NO2
H
p-MeC6H4
p-EthylC6H4
p-PentylC6H4
p-MeC6H4
Ph
86
79
85
70
96
88
90
82
50
p-MeC6H4
n-Pentyl
n-Ethyl
Ph
p-MeC6H4
p-EthylC6H4
p-PentylC6H4
Ph
H
p-MeC6H4
p-EthylC6H4
p-PentylC6H4
n-Pentyl
H
H
m-CH3
aReaction conditions: Cu(OTf)2 (4 mol%), pyrene (0.1 mmol, 0.0016 g), K2CO3 (2 mmol, 0.2760 g), aryl iodide (1 mmol), alkyne (1 mmol), in DMF (2.5), for
16 h.
bIsolated yield.
Appl. Organometal. Chem. 2015, 29, 353–356
Copyright © 2015 John Wiley & Sons, Ltd.
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W. Xu et al.
that of similar catalyst systems.[41] Finally, several fluorescent diynes
have been prepared using the protocol developed in our laboratory.
Acknowledgments
This work was financially supported by the 111 Project (B14041), Na-
tional Natural Science Foundation of China (21171112, 21271124,
21371112), Fundamental Doctoral Fund of Ministry of Education of
China (20120202120005), Natural Science Basic Research Plan in
Shaanxi Province of China (2012JM2006) and Shaanxi Innovative
Team of Key Science and Technology (2013KCT-17).
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Scheme 3. Coupling reaction between diiodobenzene/dibromobenzene
and phenylacetylene.
coupling reaction of phenylacetylene and 1,2-diiodobenzene or
1,3-diiodobenzene to furnish such molecules. Indeed, the coupling
reactions of aryl diiodides with phenylacetylene were carried out
using the standard Cu(OTf)2/L4 catalytic system, affording an excel-
lent yield of the diyne products, as shown in Scheme 3. Both
diiodobenzene and dibromobenzene were subject to the standard
coupling conditions, and the former seems to be more active for
the cross-coupling reaction. Notably, mono- and di-substituted
substrates are formed non-selectively by the coupling reaction of
1,3-diiodobenzene (1 equiv.) and phenylacetylene (1.5 equiv.). It is
found that increasing the amount of phenylacetylene (2.0 equiv.)
can lead to higher yield of bi-substituted product (a1, a3, a5 and a7).
The double cross-coupling reaction of 1,3-diiodobenzene (1 equiv.)
and phenylacetylene (2.0 equiv.) affords a3 with 84% yield, along
with mono-substituted product a4 in 11% yield. Therefore, we
conclude that the best results can only be obtained using the
optimal ratio of alkyne to diiodobenzene.
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Conclusions
A highly effective catalytic system using Cu(OTf)2 catalyst and
polycyclic aromatic hydrocarbon ligand L4 (pyrene) has been
developed for Sonogashira-type cross-coupling reactions. This novel
combination features broad reaction scope and remarkable substrate
tolerance, affording moderate to excellent yields of the desired prod-
ucts. In addition, this catalytic system is fairly affordable for both in-
dustrial and academic settings, since its cost is about one-tenth of
Supporting Information
Additional supporting information may be found in the online
version of this article at the publisher’s web-site.
wileyonlinelibrary.com/journal/aoc
Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2015, 29, 353–356