Effective Synthesis of Benzyl 3-Phenylpropiolates Via Copper(I)-Catalyzed Esterification of Alkynoic Acids with Benzyl Halides under Ligand-Free Conditions

Article abstract of DOI:10.1007/s10562-015-1690-5

We developed an efficient way to prepare benzyl 3-phenylpropiolates via copper-catalyzed coupling between corresponding benzyl halides and alkynoic acids under ligand-free condition. This methodology is also suitable for aromatic and α,β-unsaturated acids. The desired esters could be obtained in good yields.

Full text of DOI:10.1007/s10562-015-1690-5

Catal Lett
DOI 10.1007/s10562-015-1690-5
Effective Synthesis of Benzyl 3-Phenylpropiolates Via Copper(I)-
Catalyzed Esterification of Alkynoic Acids with Benzyl Halides
Under Ligand-Free Conditions
Jincheng Mao1,2 Xiaojiang Yang1 Hong Yan2 Yue He2 Yongming Li1
Jinzhou Zhao1
•
•
•
•
•
Received: 18 December 2015 / Accepted: 24 December 2015
Ó Springer Science+Business Media New York 2016
Abstract We developed an efficient way to prepare
benzyl 3-phenylpropiolates via copper-catalyzed coupling
between corresponding benzyl halides and alkynoic acids
under ligand-free condition. This methodology is also
suitable for aromatic and a,b-unsaturated acids. The
desired esters could be obtained in good yields.
Keywords Esterification reactions Á Benzyl halides Á
Carboxylic acids Á Ligand-free Á Benzyl 3-phenylpropiolate
1 Introduction
As we know that esterification which is one of the most
useful synthetic transformations has attracted great atten-
tions [1]. Moreover, alkyl esterification is also an usual
approach to protect carboxyl group in the total synthesis.
Among alkyl esterbenzyl esters were more stable under
acidic and basic conditions and generally cleaved under
Graphical Abstract We developed an efficient way to
prepare benzyl 3-phenylpropiolates via copper-catalyzed
coupling between corresponding benzyl halides and alky-
noic acids under ligand-free condition. This methodology
is also suitable for aromatic and cinnamic acids. The
desired esters could be obtained in good yields.
catalytic hydrogenolysis [2, 3]. Furthermore, benzyl
3-phenylpropiolates are important building blocks of
heterocycles [4–10], so that many researchers devote
themselves to investigating alternative methods to synthe-
size them (Fig. 1) [11–14]. Not long ago, Coleman and co-
workers reported phase-transfer esterification of carboxylic
acids. But unsaturated acids only afforded the desired
esters in moderate yields [15].
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-015-1690-5) contains supplementary
material, which is available to authorized users.
& Jincheng Mao
jcmao@suda.edu.cn
1
State Key Laboratory of Oil and Gas Reservoir Geology and
Exploitation, Southwest Petroleum University,
Chengdu 610500, People’s Republic of China
In the past several years, most methods for esterification
were developed [16–27]. For example, copper-catalyzed
oxidative or direct esterification was found to be an
effective approach by Patel and co-workers [16–23]. In
2
Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou 215123, People’s
Republic of China
123

J. Mao et al.
addition, ionic liquid was employed as the solvent, which
has many advantages, such as low volatility, good thermal
stability [24–27]. However, ionic liquid needs to be pre-
pared exclusively and some kinds of ionic liquid are
moisture sensitive. A simpler, wider and more practical
way in industrial chemicals synthesis is always highly
appreciated. Transition metal catalysts can activate many
reactions under mild conditions. Among these transition
metal catalysts, copper salts are ideal catalysts and exten-
sively used in chemical industry due to their readily
available, cheap and environmental friendly characters
[28–31]. In recent years, our group have made many efforts
on copper-catalyzed coupling reactions [32, 33]. These
coupling reactions effectively construct C–C and C–N
bond. Lately, we have reported an example of highly
effective synthesis of methyl esters from benzylic alcohols,
aldehydes and acids via copper-catalyzed C–C cleavage
from tert-butyl hydroperoxide [34]. It arouses our great
interest in studying esterifications. In continuation of our
research of copper-catalyzed esterification, herein, we
report an efficient approach to synthesize unsaturated
benzyl esters from phenylpropiolic acids catalyzed by
copper(I).
2 Experimental
2.1 General Information
All reactions were carried out under air. Solvents were
dried and degassed by standard methods. All of the benzyl
halides and carboxylic acids are readily available. Flash
column chromatography was performed using silica gel
(300–400 mesh). Analytical thin-layer chromatography
was performed using glass plates pre-coated with 200–400
mesh silica gel impregnated with a fluorescent indicator
(254 nm). NMR spectra were measured in CDCl3 on a
Varian Inova-400 NMR spectrometer (400 or 300 MHz)
with TMS as an internal reference. Products were charac-
terized by comparison of H NMR, 13C NMR and TOF–
1
MS data in the literature.
2.2 General Procedure for Esterification of Benzyl
Halide and Alkynoic Acid
A mixture of benzyl halide (0.4 mmol), alkynoic acid
(0.6 mmol), Cs2CO3 (2 equiv), CuI (10 mol%), and CH3CN
(2 mL) in a tube was stirred in air at 60 °C for 24 h. After that
Fig. 1 Preparation of some
useful compounds from benzyl
3-phenylpropiolates
123

Effective Synthesis of Benzyl 3-Phenylpropiolates Via Copper(I)-Catalyzed Esterification…
the mixture was poured into ethyl acetate, then washed with
water, extracted with ethyl acetate, dried by anhydrous
Na2SO4, then filtered and evaporated under vacuum, the
residue was purified by flash column chromatography (pet-
roleum ether or petroleum ether/ethyl acetate) to afford the
corresponding coupling products. The characterization of
the corresponding products was shown in Supporting
Materials.
Table 1 Screening various conditions for copper-catalyzed reaction
between
benzylic
chloride
and
phenylpropiolic
O
acid
Copper cat. (10 mol%)
base, solvent
Cl
O
+
COOH
Entry Copper cat. Base
Solvent
T (°C)/t (h) Yield (%)a
1
CuI
K2CO3 MeCN
K2CO3 MeCN
K2CO3 MeCN
K2CO3 DMF
K2CO3 DMSO
30/24
60/24
60/12
60/24
60/24
11
70
2
CuI
3
CuI
44
4
CuI
NR
13.1
NR
NR
13
3 Results and Discussions
5
CuI
6
CuI
K2CO3 Dioxane 60/24
K2CO3 Toluene 60/24
K2CO3 PEG-400 60/24
We initiated our studies by investigating the reaction of
benzyl chloride with phenylpropiolic acid. In the presence
of 10 mol% copper iodide and 2 equivalents potassium
carbonate in the acetonitrile at 30 °C, benzyl 3-phenyl-
propiolate was obtained in 11 % yield (Table 1, entry 1).
Temperature influenced the reaction obviously. Elevating
the reaction temperature to 60 °C, a big improvement in
the reaction yield was obtained (entry 2). Several solvents
were examined next. As a result, acetonitrile showed
uniquely good acceleration to the reaction (entries 4–8).
Besides, reactions carried out with carbonates as bases
gave remarkably higher yield than any other bases did
(entry 2 vs. entries 9–14). Especially when cesium car-
bonate was employed as the base, almost quantitative ester
was obtained (entry 9). We also probed various commer-
cially available copper salts and copper powder (entries
14–18), and copper (I) iodide was proved as the best cat-
alyst (entry 19). Furthermore, reagents containing iodine
were screened, including tetramethylammoniumiodide
(TMAI), tetrabutylammoniumiodide (TMBI), iodine, NaI,
KI and iodobenzene diacetate. It can be seen that moderate
yields of desired ester were acquired (entries 19–24). Blank
experiment exhibited that no copper (I) catalyst was added,
nearly no reaction could occur (entry 25). Varying the
amount of catalyst or base was not favorable for the cat-
alytic reaction (entries 26–28). Finally, we used copper
iodide (99.999 %) instead of analytically pure copper
iodide, and the same yield was got (entry 29).
7
CuI
8
CuI
9
CuI
Cs2CO3 MeCN
K3PO4 MeCN
tBuOK MeCN
60/24
60/24
60/24
60/24
60/24
60/24
60/24
60/24
60/24
60/24
60/24
60/24
60/24
60/24
60/24
60/24
60/24
40/24
40/24
40/24
60/24
[99
45
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27b
28c
29d
CuI
CuI
56
CuI
CsF
MeCN
MeCN
MeCN
11
CuI
Et3N
DBU
NR
46
CuI
CuCl
CuBr
Cu(OAc)2
Cs2CO3 MeCN
Cs2CO3 MeCN
Cs2CO3 MeCN
53
39
43
Cu powder Cs2CO3 MeCN
34
TMAI
TBAI
I2
Cs2CO3 MeCN
Cs2CO3 MeCN
Cs2CO3 MeCN
Cs2CO3 MeCN
Cs2CO3 MeCN
79
30
82
NaI
KI
82
83
PhI(OAc)2 Cs2CO3 MeCN
54
–
Cs2CO3 MeCN
Cs2CO3 MeCN
Cs2CO3 MeCN
Cs2CO3 MeCN
Cs2CO3 MeCN
trace
61
CuI
CuI
CuI
CuI
73
24
[99
Reaction conditions: Benzyl chloride (0.3 mmol), phenylpropiolic
acid (0.3 mmol), copper catalyst (10 mol%), base (2 equiv), solvent
(2 mL), 30–60 °C, 24 h, air
a
GC-yield based on phenylpropiolic acid (n-decane)
b
With the optimized conditions in hand, we further
expanded this copper-catalyzed esterification to a wide
range of substrates. In the course of experiments, excessive
phenylpropiolic acid was found to give better results. As
summarized in Table 2, whether the phenyl ring of benzyl
chlorides with electron-withdrawing group or electron-do-
nating group were investigated, the corresponding products
were acquired in excellent yields (Table 2, entries 2–5).
We also examined various phenylpropiolic acids. It can be
seen that para-substituted phenylpropiolic acids gave
moderate yields, whereas meta- as well as ortho-substituted
phenylpropiolic acids gave the corresponding products in
good yields (entries 6–10). In order to broaden this
CuI (5 mol%)
c
Cs2CO3 (1 equiv)
d
CuI (99.999 %) from Aldrich was employed
methodology, various benzyl bromides and carboxylic
acids were investigated subsequently. Reactions of
phenylpropiolic acid with benzyl bromide bearing different
substituents occurred in good to excellent yields (entries
11–16). Generally, the benzyl halides with electron-with-
drawing groups afforded better results than those with
electron-donating groups. Unfortunately, aliphatic propi-
olic acid was unreactive under the same conditions (entry
123

J. Mao et al.
Table 2 CuI-catalyzed esterification of benzyl halide and alkynoic
acid
Table 2 continued
O
X
CuI (10 mol%)
Entry
16
Benzyl halide
Alkynoic acid
Yield (%)a
93
R
R'
COOH
+
O
R
Cs2CO3, CH3CN
60 oC, 24 h, air
R'
Br
(X = Br, Cl)
COOH
Me
Me
Br
COOH
17
NR
Entry
1
Benzyl halide
Alkynoic acid
Yield (%)a
Br
Cl
COOH
COOH
18
19
77
72
COOH
99
90
87
Cl
Br
COOH
COOH
2
3
MeO
I
Cl
20
66(34b)
COOH
COOH
F
Cl
Cl
COOH
COOH
4
92
Br
21
22
99
99
Cl
Me
Me
Cl
Me
5
6
90
55
COOH
Br
Br
Cl
F
COOH
COOH
23
24
99
34
Cl
MeO
COOH
7
65
Me
Me
O
MeO
Br
Cl
OH
8
79
64
84
99
78
87
76
COOH
O
Cl
Cl
Br
Me
COOH
9
Reaction conditions: Benzyl halide (0.4 mmol), alkynoic acid
(0.6 mmol), CuI (10 mol%), Cs2CO3 (2 equiv), CH3CN (2 mL),
60 °C, 24 h, air
Me
10
11
12
13
14
COOH
a
Isolated yield based on benzyl halide
COOH
COOH
COOH
COOH
b
In the absence of CuI
Cl
Br
F
Br
17). However, aliphatic bromides such as allyl bromide and
butyl bromide and (2-iodoethyl) benzene proved to be
suitable substrates (entries 18–20). For the (2-iodoethyl)
benzene as the substrate, the control experiment was per-
formed in the absence of CuI. It can be seen that only 34 %
yield of the corresponding ester could be obtained (entry
20). This could show the high catalytic effect of CuI for
this reaction. Interestingly, cinnamic acid, cinnamal acetic
acid and benzoic acid could offer the corresponding
Br
Br
F
Br
COOH
15
79
F3C
123

Effective Synthesis of Benzyl 3-Phenylpropiolates Via Copper(I)-Catalyzed Esterification…
esterified products in excellent yields (entries 21–23),
while benzoyl formic acid gave the desired product within
poor yield (entry 24).
out at 60 and 100 °C without copper iodide, respectively
(Scheme 4). As we expected, electrophilic esterification
reluctantly happened at the higher temperature whereas it
hardly occurred at the lower temperature. A proposed
mechanism based on previous studies is shown in
Scheme 5. Two possible catalytic cycles may be involved
in this reaction. Firstly, copper iodide is coordinated with
acetonitrile to form L3CuI. Then substitution of L3CuI by a
phenylpropiolic acid generates cupric phenylpropiolate
complex I (in path A) or L3CuI inserts to C–Cl bond to
afford intermediate II (in path B). Subsequently, interme-
diate III is smoothly generated by the working of inter-
mediate I with benzyl chloride or by the working of
intermediate II with phenylpropiolic acid [16, 35]. Finally,
reductive elimination of intermediate III regenerates L3CuI
and give benzyl 3-phenylpropiolate. Certainly, during the
reaction, it is believed that using catalytic amount of CuI,
Gratifyingly, the esterification of phenylpropiolic acids
and cinnamic acid to 4,40-bis(chloromethyl)-1,10-biphenyl
was performed to access the corresponding diesterified
products in 39 and 81 %, respectively (Scheme 1). We
were also pleased to find that 0.94 g of benzyl 3-phenyl-
propiolate was obtained when 5 mmol benzyl chloride was
reacted with phenylpropiolic acid under the optimized
conditions (Scheme 2). It can be seen that this methodol-
ogy provided an alternative and practical way to synthesize
benzyl esters. Finally we studied the reactivity of alkenyl
halide and phenyl halide. Unfortunately, they did not pro-
ceed at all under these conditions (Scheme 3).
To get more information of the mechanism, the reaction
of benzyl chloride with phenylpropiolic acid was carried
Scheme 1 Diesterifications of
4,40-bis(chloromethyl)-1,10-
biphenyl
Scheme 2 Benzyl esrerification
of phenylpropiolic acid in a
large scale
O
CuI (10 mol%)
Cl
O
COOH
+
Cs2CO3, CH3CN
60 oC, 24 h, air
0.94 g, 80%
Scheme 3 CuI-catalyzed
esterification of alkenyl halide
and phenyl halide
O
O
Br
OMe
CuI (10 mol%)
O
COOH
+
Cs2CO3, CH3CN
60 oC, 24 h, air
O
MeO
Br
Scheme 4 Electrophilic
esterification without copper
catalyst
123

J. Mao et al.
Scheme 5 Proposed
mechanism of benzyl
esterification
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In summary, we have demonstrated an efficient protocol
for the benzyl esterifications of phenylpropiolic acid under
mild conditions. Compared with previous methods, the
present methodology not only uses simple readily available
copper salts as catalyst but also can synthesize benzyl
3-phenylpropiolate in a large scale, which provides
potential value in industrial application. We have also
developed a way to prepare benzyl benzoate, benzyl cin-
namate and benzyl cinnamal acetate. Ongoing efforts to
attractive esterification in the synthesis of some biologi-
cally active molecules are currently underway in our group.
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Acknowledgments The research is supported by Open Fund
(PLN1409) of State Key Laboratory of Oil and Gas Reservoir
Geology and Exploitation (Southwest Petroleum University), the
Major Program of the National Natural Science Foundation of China
(51490653) and 973 Program (2013CB228004). We are grateful to
the Grants from the Scientific Research Foundation for the Returned
Overseas Chinese Scholars, State Education Ministry and the Key
Laboratory of Organic Synthesis of Jiangsu Province.
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