Efficient copper-catalyzed sonogashira couplings of aryl halides with terminal alkynes in water

Article abstract of DOI:10.1055/s-0030-1259542

An efficient copper-catalyzed method has been developed for Sonogashira couplings of aryl halides with terminal alkynes in water. The protocol uses inexpensive CuBr as the catalyst, 1,10-phenanthroline as the ligand, tetrabutylammonium bromide (TBAB) as the phase-transfer catalyst, environmentally friendly water as the solvent, and various internal alkynes were synthesized in good to excellent yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1259542

702
LETTER
Efficient Copper-Catalyzed Sonogashira Couplings of Aryl Halides with
Terminal Alkynes in Water
S
onogashira Coup
a
lings of
A
ry
o
l
H
alides
w
i
s
th Termin
h
al
A
lkynes in
a
W
ater n Yang,a,1 Bing Li,a,1 Haijun Yang,a Hua Fu,*a Liming Hu*b
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
b
College of Life Sciences and Bioengineering, Beijing University of Technology, Beijing 100124, P. R. of China
Fax +86(10)62781695; E-mail: fuhua@mail.tsinghua.edu.cn
Received 21 October 2010
Sonogashira couplings has become an important goal.
During the last decade, great progress on the copper-cata-
lyzed Ullmann-type reaction has been made, which relied
on the utilization of some special additives.14 The copper-
Abstract: An efficient copper-catalyzed method has been devel-
oped for Sonogashira couplings of aryl halides with terminal
alkynes in water. The protocol uses inexpensive CuBr as the cata-
lyst, 1,10-phenanthroline as the ligand, tetrabutylammonium bro-
mide (TBAB) as the phase-transfer catalyst, environmentally catalyzed Sonogashira couplings in water were recently
reported,15 unfortunately, toxic and readily oxidative Ph3P
friendly water as the solvent, and various internal alkynes were syn-
thesized in good to excellent yields.
was used as the ligand, which did not meet the environ-
Key words: copper, water, Sonogashira coupling, synthetic meth-
od, alkyne
mentally benign conditions. We have developed copper-
catalyzed cross-couplings in organic solvents16 and in
neatly aqueous medium.17 Herein, we report a simple and
highly efficient copper-catalyzed method for the synthesis
Many antimycotics,2 antibiotics,3 liquid crystals, poly- of internal aromatic alkynes using environmentally be-
mers, and optical or electronic materials4 were synthe- nign water as the solvent.
sized from the internal alkyne intermediates via the As shown in Tables 1, 1-iodo-4-methylbenzene and phe-
Sonogashira reaction,5 and the palladium/copper co-cata- nylacetylene were firstly chosen as the model substrates to
lyzed coupling is a popular strategy for the construction of optimize reaction conditions including catalysts, ligands,
C(sp2)–C(sp) bonds.6 However, the drawbacks of the cat- bases, and temperature under nitrogen atmosphere. Six
alyst systems, such as air sensitivity, high cost, and toxic- ligands were screened using 10 mol% of CuI as the cata-
ity, limit their applications for industrial processes, so it is lyst, 20 mol% of tetrabutylammonium bromide as the
highly desirable to develop readily available and inexpen- phase-transfer catalyst (PTC) and 2 equivalents of NaOH
sive catalyst systems instead of palladium catalysts to pro- as the base (relative to amount of 1-iodo-4-methylben-
mote the Sonogashira couplings. During the past more zene) in water at 110 °C (entries 1–6), and 1,10-phenan-
than ten years, several examples involving copper-,7 iron- throline (phen) provided the highest yield (entry 2). The
catalyzed,8
and
nickel/copper-,9
iron/copper- target product was obtained in 31% yield in the absence of
cocatalyzed10 Sonogashira reactions were reported. Al- ligand (entry 7). Several bases were investigated (com-
though the previous methods are effective, the coupling pare entries 2, 8–10), and NaOH showed best efficiency
reactions were performed in organic solvents. Therefore, (entry 2). When reaction temperature was increased to
it is necessary to search more convenient, practical, and 120 °C from 110 °C, higher yields were provided (com-
environmentally benign approach to internal alkynes. It is pare entries 2 and 11). Various copper salts were tested
well known to all that water is the most economical and (compare entries 11–14), and CuBr showed the highest re-
environmentally friendly solvent in the world,11 and the activity (entry 12) with small amount of homocoupling
wide applications of internal alkynes found in many fields product appearing. The coupling reaction afforded the tar-
have stimulated researches into the development of new get product in 63% yield in the absence of a phase-transfer
strategies for their synthesis in water. However, synthesis catalyst. Therefore, the following catalyst system (10
of organic molecules in water entails the additional chal- mol% of CuBr, 20 mol% of phen, 20 mol% of tetrabuty-
lenges of water tolerance for the catalyst/ligand systems lammonium bromide, 2 equiv of NaOH) was optimal at a
and the associated problems of substrate solubility and re- reaction temperature of 120 °C for the Sonogashira cou-
activity.12 Recently, palladium-catalyzed13a,b or micro- plings of aryl halides with terminal alkynes in water.
wave-mediated13c Sonogashira couplings in water have
As shown in Table 2, we investigated the coupling scope
been developed. Considering the readily availability and
of various aryl halides with terminal alkynes in water un-
low toxicity of copper catalysts and their ligands, the de-
der our standard conditions,18 and the examined substrates
velopment of a cheaper copper-catalyzed system enabling
provided the corresponding target products in good to ex-
cellent yields. For aryl halides, the substrates containing
electron-withdrawing groups showed higher activity than
ones containing electron-donating groups, and the reactiv-
ity order of the aryl halides was iodides > bromides. Aryl
SYNLETT 2011, No. 5, pp 0702–0706
Advanced online publication: 08.02.2011
DOI: 10.1055/s-0030-1259542; Art ID: W18410ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
1

LETTER
Sonogashira Couplings of Aryl Halides with Terminal Alkynes in Water
703
Table 1 Copper-Catalyzed Coupling of 1-Iodo-4-methylbenzene with Phenylacetylene: Optimization of Conditionsa
cat., ligand, PTC
base, temp, H2O, N2
+
I
1b
2a
3c
ligand =
COOH
N
N
N OH
H
N
N
A
B
C
O
O
O
NH HN
N
OH
D
E
F
Entry
1
Catalyst
Ligand
Base
Temp (°C)
110
Yield (%)b
CuI
A
B
C
D
E
F
–
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
KOH
50
72
44
60
34
25
31
50
30
35
77
83
66
74
63c
2
CuI
110
3
CuI
110
4
CuI
110
5
CuI
110
6
CuI
110
7
CuI
110
8
CuI
B
B
B
B
B
B
B
B
110
9
CuI
K2CO3
Cs2CO3
NaOH
NaOH
NaOH
NaOH
NaOH
110
10
11
12
13
14
15
CuI
110
CuI
120
CuBr
CuCl
CuCl2
CuBr
120
120
120
120
a Reaction conditions: 1-iodo-4-methylbenzene (1b, 1 mmol), phenylacetylene (2a, 2 mmol), catalyst (0.1 mmol), ligand (0.2 mmol), n-Bu4NBr
(0.2 mmol), base (2 mmol), H2O (1.5 mL) in a sealed Schlenk tube under nitrogen atmosphere, 24 h.
b Isolated yield.
c In the absence of n-Bu4NBr.
bromides could also provide the coupling products in (entries 5, 7, 14, 18, and 19), nitro (entries 20 and 23) in
moderate yields when 2 equivalents of KI and more the substrates. We attempted reaction of 2-iodophenol
TBAB were added to the reaction systems (see entries 21– (1r) with phenylacetylene (2a) under our standard condi-
24). For alkynes, aromatic ones showed higher reactivity. tions, and the cascade reaction provided 2-phenylbenzo-
The Sonogashira couplings could tolerate various func- furan (4) in 74% yield (Scheme 1).
tional groups including ether (entry 10), C–Cl bond (en-
tries 12–16 and 22), C–Br bond (entry 17), C–F bond
lyzed method for the synthesis of internal alkynes via
In summary, we have developed an efficient copper-cata-
CuBr (10 mol%), phen (20 mol%)
n-Bu4NBr (20 mol%), NaOH (2 equiv)
I
H2O (1.5 mL), 120 °C, N2, 24 h
+
Ph
74%
OH
O
1r
2a
4
Scheme 1 Cascade reaction of 2-iodophenol (1r) with phenylacetylene (2a) to provide 2-phenylbenzofuran (4)
Synlett 2011, No. 5, 702–706 © Thieme Stuttgart · New York

704
D. Yang et al.
LETTER
Sonogashira couplings of aryl halides with terminal various functional groups in the substrates, and it will at-
alkynes in water. The method is of good tolerance towards tract much attention in industrial and academic researches.
Table 2 Copper-Catalyzed Sonogashira Couplings of Aryl Halides with Terminal Alkynes in Watera
CuBr/phen, n-Bu4NBr
NaOH, H2O, 120 °C
R2
+
R2
X
phen =
N2, 24 h
2
3
N
N
R1
R1
1
F
2a
2b
2c
Entry
1
1
2
3
Yield (%)b
80
I
2a
3a
3b
3c
3d
3e
3f
1a
1a
2
3
4
5
6
7
2b
2a
2b
2c
2a
2c
53
83
75
78
80
75
I
1b
1b
F
1b
I
1c
1c
F
3g
I
I
8
9
2a
2a
81
80
1d
3h
1e
3i
72c
65
85
MeO
1f
I
MeO
10
11
12
2a
2a
2a
3j
I
Ph
1g
Cl
3k
Cl
I
1h
3l
Cl
13
1h
2b
76
3m
Synlett 2011, No. 5, 702–706 © Thieme Stuttgart · New York

LETTER
Sonogashira Couplings of Aryl Halides with Terminal Alkynes in Water
705
Table 2 Copper-Catalyzed Sonogashira Couplings of Aryl Halides with Terminal Alkynes in Watera (continued)
CuBr/phen, n-Bu4NBr
NaOH, H2O, 120 °C
R2
+
R2
X
phen =
N2, 24 h
2
3
N
N
R1
R1
1
F
2a
2b
2c
Entry
14
1
2
3
Yield (%)b
80
Cl
F
1h
2c
3n
I
15
16
2a
2b
83
75
Cl
Cl
1i
3o
1i
Cl
3p
Br
1j
F
I
Br
3q
F
17
18
2a
2a
84
88
I
1k
3r
F
F
I
19
2a
84
F
F
1l
3s
O2N
I
O2N
3t
20
21
22
23
2a
2a
2a
2a
92c
1m
58d
72d
52d,e
Br
3a
1n
Cl
Br
3l
3t
1o
O2N
1p
Br
Ph
Br
24
2a
48c,d
1q
3u
a Reaction condition: aryl halide 1 (1 mmol), alkyne 2 (2 mmol), CuBr (0.1 mmol), 1,10-phenanthroline (0.1 mmol), n-Bu4NBr (0.2 mmol),
NaOH (2 mmol), H2O (1.5 mL), 120 °C under nitrogen atmosphere, 24 h.
b Isolated yield.
c Addition of 0.8 mmol of n-Bu4NBr.
d Addition of 2 mmol of KI.
e Addition of 1 mmol of n-Bu4NBr.
Synlett 2011, No. 5, 702–706 © Thieme Stuttgart · New York

706
D. Yang et al.
LETTER
Synthesis 2006, 3955. (n) Carril, M.; SanMartin, R.;
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
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Acknowledgment
The authors wish to thank the National Natural Science Foundation
of China (Grant No. 20972083), and the Ministry of Science and
Technology of China (2009ZX09501-004) for financial support.
References and Notes
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A 10 mL Schlenk tube equipped with a magnetic stirring bar
was charged with CuBr (0.1 mmol, 15 mg), NaOH (2 mmol,
80 mg), 1,10-phenanthroline (0.2 mmol, 36 mg), TBAB
[0.2–1 mmol, see Table 2 for the details; note: an additional
KI (2 mmol) should be added for aryl bromide]. The tube
was evacuated and back-filled with nitrogen, and this
procedure was repeated three times. Aryl halide (1.0 mmol),
alkyne (2 mmol), and H2O (1.5 mL) were sequentially added
to the tube at r.t. under a stream of nitrogen, and the tube was
sealed and put into a pre-heated oil bath at 120 °C for 24 h
under nitrogen atmosphere. After the resulting solution was
cooled to r.t., and the solution was extracted with EtOAc
(3 × 3 mL). The combined organic phase was concentrated,
and the remained residue was purified by column chroma-
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