Microwave-assisted copper- and palladium-catalyzed sonogashira-type coupling of aryl bromides and iodides with trimethylsilylacetylene

Article abstract of DOI:10.1016/j.tetlet.2016.01.088

An efficient and rapid method was developed for the synthesis of 1-aryl-2-(trimethylsilyl)acetylene. Copper and palladium-catalyzed sonogashira-type coupling of trimethylsilylacetylene and aryl bromides or iodides in the presence of triethylamine as base

Full text of DOI:10.1016/j.tetlet.2016.01.088

Tetrahedron Letters xxx (2016) xxx–xxx
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Tetrahedron Letters
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Microwave-assisted copper- and palladium-catalyzed
sonogashira-type coupling of aryl bromides and iodides
with trimethylsilylacetylene
a,y
a,y
a
a
a
a
a,
⇑
Yonghua Lei , Tianhan Hu , Xingsen Wu , Yue Wu , Hua Xiang , Haopeng Sun , Qidong You ,
a,b,
⇑
Xiaojin Zhang
a
Jiangsu Key Laboratory of Drug Design and Optimization, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 210009, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and rapid method was developed for the synthesis of 1-aryl-2-(trimethylsilyl)acetylene.
Copper and palladium-catalyzed sonogashira-type coupling of trimethylsilylacetylene and aryl bromides
or iodides in the presence of triethylamine as base under microwave irradiation in acetonitrile afforded
the desired 1-aryl-2-(trimethylsilyl)acetylene. The use of microwave was found to significantly improve
the reaction yield and shorten the reaction time.
Received 11 December 2015
Revised 23 January 2016
Accepted 26 January 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Trimethylsilylacetylene
Microwave
Sonogashira
Arylalkynes are important intermediates for the preparation of
Pd cat., Cu+ cat.
base
ArX +
H
Si(CH
3
)
3
Ar
Si(CH3)3
a
variety of target compounds. Recent examples include
heterocyclic compounds, cathepsin inhibitors,2 naphthalene
1
derivatives, conjugated alkenes,4 enediyne antibiotics, bioactive
3
5
Scheme 1. Sonogashira coupling reaction of terminal alkynes and aryl halides.
6
natural products, and pharmaceuticals. Most of these compounds
were provided by sonogashira coupling (Scheme 1), which is a
palladium (0)-catalyzed coupling reaction of terminal alkynes
and aryl iodides in the presence of copper iodide and a base.
Recently, several sonogashira coupling methods using less reactive
aryl bromides have been developed.7 For example, Anne and
co-workers used dichlorobis(triphenylphosphine)palladium and
copper iodide as catalysts, triethylamine as the base to prepare
research groups. Comparing with classical methods, MAOS has sig-
nificant advantages that include simplicity in operation, increasing
reaction rates, and improving reaction yields. Unexceptionally,
9
microwave irradiations have been applied to sonogashira coupling
,8
10
reaction for diarylacetylene and arylfuropyridones and others.
Here, we focused our attention on the use of microwave irradiation
to Sonogashira coupling, and developed an efficient and rapid
method for the synthesis of 1-aryl-2-(trimethylsilyl)acetylene.
Initially, to investigate and optimize the copper and palladium-
catalyzed sonogashira-type coupling of trimethylsilylacetylene
and aryl bromides under microwave irradiation for the synthesis
of the representative 1-aryl-2-(trimethylsilyl)acetylene 2a, 4-bro-
mobenzonitrile 1a was chosen as the model substrate. The effects
of different catalysts, bases, solvent, temperatures, and reaction
times were examined on the model reaction and the results are
listed in Table 1.
7
the arylalkynes; similarly, Comoy and co-workers used dichloro-
bis(triphenylphosphine)palladium and copper iodide as catalysts,
8
triethylamine as the base to produce alkyne. All these developed
methods are typical sonogashira coupling, drawback of these
approaches, such as the demand for a reactive arene derivative,
long reaction times, and the limited choice of reaction medium,
lead us to improve this reaction.
Currently, microwave-assisted organic synthesis (MAOS) has
been a powerful and useful tool for rapid organic synthesis, and
has attracted great interests of many academic and industrial
3 2 2
First we performed the reaction in the presence of Pd(PPh ) Cl ,
CuI, and triethylamine in acetonitrile under microwave irradiation
at 80 °C in 2 min. The reaction did take place but only 70.3% yield
of product 2a was observed (Table 1, entry 1). With the hope of
increasing the yield we tried the reaction under different increased
⇑
Corresponding authors.
E-mail addresses: youqd@163.com (Q. You), zxj@cpu.edu.cn (X. Zhang).
These two authors contributed equally to this work.
y
http://dx.doi.org/10.1016/j.tetlet.2016.01.088
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0
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2
Y. Lei et al. / Tetrahedron Letters xxx (2016) xxx–xxx
Table 1
temperature and reaction time. As shown in Table 1, entries 2–7,
the reaction went better with higher temperature. The product
Microwave-assisted sonogashira-type coupling of 4-bromobenzonitrile 1a to 4-
(trimethylsilyl)ethynyl)benzonitrile 2a
(
2
a was obtained at 120 °C in 85.7% yield (Table 1, entry 3). And
Pd cat. CuI
base
it was found that 120 °C was the fitness temperature, further
increasing the temperature contributed little to improve the yield.
Notably, when the reaction time was prolonged from 2 min to
NC
Br
+
Si(CH3)3
NC
3 3
Si(CH )
1a
2a
5
min, the substrate 1a could be completely converted into 2a in
Entrya t (min) T (°C) Solvent
Baseb
Pd cat.
Yieldc (%)
a high yield of 95.8% (Table 1, entry 6). Further prolonging the reac-
tion time to 10 min did not contribute to the yield (Table 1, entry
7). In order to find an optimal solvent, we tried different solvents
such as methanol, water, DMF, 1, 4-dioxane, and THF. As shown
in Table 1, entries 8–12, our experiments indicated that acetoni-
trile is the optimal solvent of this reaction. In addition, we tried
the coupling reaction in the presence of different inorganic bases
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
5
10
5
5
5
5
5
5
5
5
5
5
5
80
100
120
130
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
CH
CH
CH
CH
CH
CH
CH
CH
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
OH
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
3
N
3
N
3
N
3
N
3
N
3
N
3
N
3
N
3
N
3
N
3
N
3
N
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
3
)
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
70.3
80.4
85.7
85.5
88.5
95.8
95.4
43.8
40.5
80.4
50.2
75.0
64.9
33.1
62.9
-
such as K
TBAOH, DIPEA, and Et
2
CO
3
, NaOAc, as well as organic bases such as DMAP,
NH (Table 1, entries 13–18). And without
2
H O
DMF
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
the bases the reaction did not occur (Table 1, entry 19). With the
optimal solvent and base in hand, three other common palladium
1,4-Dioxane Et
THF Et
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
K
2
CO
3
catalysts Pd(OAc)
(Table 1, entries 20–22). Among them, Pd(PPh
2
, Pd(PPh
3
)
4
, and Pd(PhCN
2
)Cl
2
were screened
Cl provided the
NaOAc Pd(PPh
DMAP Pd(PPh
TBAOH Pd(PPh
3
)
2
2
best reactivity under otherwise an identical condition. In addition,
the influence of MWI power on the reaction was also tested. Fur-
ther increasing the MWI power from 150 W to 300 W contributed
little to the reaction (Table 1, entry 24). However, when the MWI
power was decreased to 100 W, it should take more reaction time
DIPEA
Pd(PPh
Pd(PPh
Pd(PPh
Pd(OAc)
Pd(PPh
Pd(PhCN
Pd(PPh
Pd(PPh
Pd(PPh
78.7
15.1
-
Et NH
2
-
5
5
5
5
480
5
8
3
Et N
3
Et N
3
Et N
3
Et N
3
Et N
3
Et N
2
8.1
3
)
4
2
2
2
2
85.4
25.2
85.0
95.3
94.9
(
8 min) to make the reaction completed (Table 1, entry 25). It must
)Cl
2
d
e
f
be emphasized that the reaction gave only 85.0% yield of product
2a when carried out under conventional heating using the same
sealed microwave tube at 120 °C after a greatly prolonged reaction
time of 480 min (8 h) (Table 1, entry 23). This suggested that the
sonogashira coupling reaction could be significantly accelerated
by MWI.
3
)
3
)
3
)
Cl
Cl
Cl
2
2
2
a
Reaction conditions: (1a) 4-bromobenzonitrile (1.5 mmol), trimethylsily-
lacetylene (1.5 mmol), base (7.2 mmol), Pd catalysts (5 mol %), CuI (10 mol %), sol-
vent (1.0 mL) at the specified temperature and reaction time. Microwave irradiation
(
MWI) power = 150 W.
With the optimized conditions in hand (Table 1, entry 6), we
next began to extend the scope of this microwave-assisted sono-
gashira coupling reaction to a variety of substrates. As shown in
Table 2, these substrates were efficiently converted into the
desired 1-aryl-2-(trimethylsilyl)acetylene products in excellent
b
DMAP: 4-dimethylaminopyridine; TBAOH: tetrabutylammonium hydroxide;
DIPEA: N,N-diisopropylethylamine.
c
Yield of isolated product.
d
Reaction was carried out under conventional heating in a sealed tube.
Microwave irradiation power = 300 W.
Microwave irradiation power = 100 W.
e
f
11
yields within a short reaction time under MWI. Compared to
Table 2
Synthesis of 1-aryl-2-(trimethylsilyl)acetylene derivatives
B
A
B
A
Pd(PPh
3
)
2
Cl
CN, Et
MW, 5 min
2
, CuI
C
X
+
Si(CH3)3
C
3 3
Si(CH )
R D
CH
N
R D
3
3
1
X= Br, I
A,B,C,D= CH or N
2
Entry a
Substrate 1
Product 2
Yieldb (%)
9
9
5.8
NC
X
NC
Si(CH
3
)
3
6.2c
1
1a
X = Br
2a
1aa X = I
Br
3 3
Si(CH )
2
3
92.0
95.0
1
b
2b
H
H
3
C
Br
H
H
3
C
3 3
Si(CH )
1
c
2
c
3
C
3
C
4
5
Br
Si(CH
3
)
3
91.1
95.0
1d
2d
C
2
H
5
Br
C
2
H
5
3 3
Si(CH )
2e
1e
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Y. Lei et al. / Tetrahedron Letters xxx (2016) xxx–xxx
3
Table 2 (continued)
Entry a
Substrate 1
CO
Product 2
Yieldb (%)
90.2
H
3
Br
H
3
CO
3 3
Si(CH )
6
7
1f
2f
OCH
3
OCH
3
X
3 3
Si(CH )
87.9
95.1
2
g
2g
X=Br
2gg X=I
H
3
CO
3
H CO
9
7.0c
X
3 3
Si(CH )
8
9
2
h
X=Br
2h
2hh X=I
9
9
3.9
Cl
Cl
Br
Cl
Cl
Si(CH
3
)
3
7.0c
2
i
1
i
1
0
Br
Si(CH
3
)
3
91.5
1j
2j
Cl
Cl
11
12
13
Br
Si(CH
3
)
3
90.6
95.1
92.0
1k
2k
F
F
Br
F
F
3 3
Si(CH )
2l
1
l
Br
3 3
Si(CH )
F
1m
N
F
2m
2n
2o
N
Br
Br
Si(CH3)3
1
1
4
5
93.0
89.9
1n
N
N
3 3
Si(CH )
1
o
N
N
N
N
NC
Br
NC
3 3
Si(CH )
1
1
6
7
91.2
92.2
1p
2p
N
N
H
N
3
C
Br
H
N
3
C
3 3
Si(CH )
N
1
N
q
2q
Br
3 3
Si(CH )
1
1
8
9
88.0
1r
2r
8
8
3.6
1.5
d
Br
3 3
Si(CH )
1s
2s
H
3
C
H
3
C
CH
3
CH
3
2
0
80.3
Br
3 3
Si(CH )
1t
2t
a
3
Reaction conditions: substrate (1) (1.5 mmol), trimethylsilylacetylene (1.5 mmol), Pd catalysts (5 mol %), CuI (10 mol %), Et N (7.2 mmol), acetonitrile (1.0 mL), 120 °C.
Reaction time: 5 min. MWI power = 150 W.
b
Yield of isolated product.
Reaction time: 2 min.
Reaction time: 10 min.
c
d
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Y. Lei et al. / Tetrahedron Letters xxx (2016) xxx–xxx
4
-bromobenzonitrile substrate 1a, 4-iodobenzonitrile (1aa) sub-
References and notes
strate also afforded quantitative yields (Table 2, entry 1). More-
over, several functional groups such as methyl, ethyl, methoxyl,
ethoxyl, and chloro or fluoro were well tolerated under our condi-
tions and excellent yields were obtained in all the cases (Table 2,
entries 2–13, 20). Among them, sterically crowded acetylenes pro-
duced the coupled product in slightly lesser yields, as shown in
1
.
(a) Jacubert, M.; Provot, O.; Peyrat, J.; Hamze, A.; Brion, J.; Brion, M. Tetrahedron
2010, 66, 3775; (b) Peixoto, D.; Begouin, A.; Queiroz, R. P. Tetrahedron 2012, 68,
7082; (c) Zhang, H.; Jiang, L. Tetrahedron Lett. 2015, 56, 2777; (d) Lingam, P. R.;
Vinodkumar, R.; Mukkanti, K.; Thomas, A.; Gopalan, B. Tetrahedron Lett. 2008,
9, 4260.
4
2
.
Ameriks, M. K.; Axe, F. U.; Bemnenek, S. D.; Edward, J. P.; Gu, Y.; Karlsson, L.;
Randal, M.; Sun, S.; Thurmond, R. L.; Zhu, J. Bioorg. Med. Chem. Lett. 2009, 19, 6131.
(
Table 2, entries 7, 11, 20). Good results were also obtained from
heterocyclic aryl halides or naphthalene halides (Table 2, entries
4–19). The two pyridine derivatives 2n and 2o and the two
3. (a) Zeidan, T. A.; Kovalenko, S. V.; Manoharan, M.; Alabugin, I. V. J. Org. Chem.
2006, 71, 962; (b) Balamurugan, R.; Gudla, V. Org. Chem. 2009, 11, 3116.
4
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(a) Karunakar, G. V.; Periasamy, M. J. Org. Chem. 2006, 71, 7463; (b) Girard, D.;
Broussous, S.; Provot, O.; Brion, J.; Alami, M. Tetrahedron Lett. 2007, 48, 6022.
(a) Lo, Y. H.; Lin, I. L.; Lin, C. F.; Hsu, C. C.; Yang, S. H.; Lin, S. R.; Wu, M. J. Bioorg.
Med. Chem. Lett. 2007, 15, 4528; (b) Hu, W. P.; Liang, J. J.; Kao, C. L.; Chen, Y. C.;
Chen, C. Y.; Tsai, Y. F.; Wu, M. J.; Chang, L. S.; Chen, Y. L.; Wang, J. J. Bioorg. Med.
Chem. 2009, 17, 1172.
(a) Du, Y.; Creighton, C. J.; Yan, Z.; Gauthier, D. A.; Dahl, J. P.; Zhao, B.;
Belkowski, S. M.; Reitz, A. B. Bioorg. Med. Chem. 2005, 13, 5936; (b) Giorgio, E.;
Tanaka, K.; Ding, W.; Krishnamurthy, G.; Pitts, K.; Ellestad, G. A.; Rosini, C.;
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2014, 70, 5848.
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(a) Santagada, V.; Frecentese, F.; Perissutti, E.; Fiorino, F.; Severino, B.; Caliendo,
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1
pyrimidine derivatives 2p and 2q were prepared from their corre-
sponding bromides 1n, 1o and 1p, 1q in a high yield. Lower yields
were obtained in the case of 4-bromoisoqunoline (1r) and 2-
bromonaphthalene (1s). The naphthalene derivative 2s was
obtained in lesser yield than others, even after continuing the reac-
tion to 15 min. Furthermore, it should be mentioned that both phe-
nyl bromide and phenyl iodide can give the desired products, and
phenyl iodide is known to be a more efficient substrate. As shown
in Table 2, entries 7, 8, the desired products 2gg, 2hh were pro-
duced by the two phenyl iodide substrates 1gg and 1hh in quanti-
tative yield in 2 min.
5
.
6
.
.
7
8
9
.
.
1
0. (a) Sørensen, U. S.; Pombo-Villar, E. Tetrahedron 2005, 61, 2697; (b) Joy, M. N.;
Bodke, Y.D.;Khader,K.A.;Sajith,A.M. TetrahedronLett. 2014, 55, 2355;(c)Markina,
N. A.; Chen, Y.; Larock, R. C. Tetrahedron 2013, 69, 2701; (d) Conreaux, D.; Delaunay,
T.; Desbordes, P.; Monteiro, N.; Balme, G. Tetrahedron Lett. 2009, 50, 3299.
In summary, we have developed an efficient and high yielding
method based on copper and palladium-catalyzed sonogashira-
type coupling processes under microwave-assisted irradiation in
short reaction time to access to the appealing 1-aryl-2-
11. General procedure for the rapid synthesis of 1-aryl-2-(trimethylsilyl)acetylene
under MWI in acetonitrile in the presence of triethylamine: A sealed 10 mL
glass tube containing substrate 1a–1s (1.5 mmol), trimethylsilylacetylene
(
trimethylsilyl)acetylene from the corresponding aryl iodides or
bromides and trimethylsilylacetylene. This method provides excel-
lent yields and purities of products in a short time, making it a use-
ful strategy for the synthesis of structurally diverse 1-aryl-2-
(
3 2 2
1.5 mmol), triethylamine (7.5 mmol), Pd(PPh ) Cl (5 mol %), CuI (10 mol %),
and acetonitrile (1 mL) was placed in the cavity of a microwave reactor and
irradiated for 2–10 min, at 120 °C and power 150 W. After cooling to room
temperature by an N -flow, the tube was removed from the rotor. The reaction
2
(
trimethylsilyl)acetylene.
mixture was combined with dichloromethane (30 mL) and water (30 mL). The
organic layer was separated and washed with water (2 ꢀ 30 mL), dried over
sodium sulfate, and concentrated. Purification by column chromatography,
eluting with petroleum ether gave 1-aryl-2-(trimethylsilyl)acetylenes (2a–2s)
Acknowledgments
1
as coloured oils or solids. All the products 2a–2s were characterized by H NMR
and EI-MS. (See Supporting Information file for characterization data of 1
NMR and EI-MS spectrum.)
H
We are thankful for the financial support of the National Natu-
ral Science Foundation of China (No. 81302636), the Natural
Science Foundation of Jiangsu Province of China (No.
BK20130656), and the Priority Academic Program Development
of Jiangsu Higher Education Institutions (PAPD).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.01.
0
88.
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