2
F.-W. Li et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 2
ent work, a new environment-friendly pathway for the carboxyla-
tion of terminal alkynes in supercritical CO2 (ScCO2) was developed,
in which ScCO2 functions as both a reactant and solvent.
a
DBU-mediated direct carboxylation of phenylacetylene with CO2
HCl
DBU(200mol%)
+ CO
COOH
H
2
The carboxylation of phenylacetylene in ScCO2 was chosen as a
model reaction to optimize the reaction conditions and the opti-
mized results are listed in Table 1. The reactions were conducted
at 50 °C under 8 MPa unless stated otherwise. The effect of bases
on the yields of desired products was evaluated by using 5 mol %
copper(I) salt as a catalyst. No desired product was obtained using
NEt3 and Cs2CO3 alone in ScCO2 (entries 1 and 2). Poor but prom-
ising yields of 20% and 25% were obtained with 10 mol % DBU plus
NEt3 or Cs2CO3, respectively in the reaction system (entries 3 and
4). The yield was significantly increased to 62% when the amount
of DBU increased to 120 mol % (entry 5). Interestingly, it was also
found that 120 mol % DBU alone gave 41% yield in the absence of
copper catalyst (entry 6).
1a
1b
Time (h)
Entry
Pressure (MPa)
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8c
8
8
8
8
60
70
80
90
80
80
80
80
24
24
24
24
24
24
16
16
64
78
84
71
73
86
90
72
6
12
12
12
a
b
c
Reaction conditions: phenylacetylene (2.0 mmol), DBU (200 mol %), CO2.
Isolated yield.
In the presence of 1 mol % CuI.
Using 120 mol % DBU as base, the yield of product 1b could be
improved to 72% by changing the catalyst from CuCl to CuI (entry
7). The yield of the reaction increased from 72% to 84% with the
increase of DBU amount from 120 mol% to 200 mol% (entries 7
and 8). The yield remained unchanged when the amount of DBU
was further increased to 300 mol % (entry 9). An excellent yield
of 92% was obtained with 0.02 equiv CuI (entry 10) but the yield
decreased to 65% with the further decreasing of CuI amount from
0.02 equiv to 0.01 equiv (entry 11). Furthermore, a higher reaction
temperature (100 °C) resulted in a lower yield under same condi-
tions (entry 12). It indicates that the decarboxylative function of
copper(I) salt under high temperature conditions.9
Notably, organic solvents, such as DMF and THF, can be used as
a co-solvent of ScCO2 for the reaction but give lower yields. As
shown in entries 13 and 14, the yields decreased to 82% and 75%
with adding DMF and THF, respectively. It might be explained that
organic solvents reduce the CO2 capturing capability of DBU during
the reaction. The yield of product 1b (entry 15) was increased to
95% using TMEDA as a ligand under the same reaction conditions.
In a word, the yield of carboxylation could be enhanced by the
reaction of terminal alkynes with ScCO2 (Supplementary data,
Table S1).
salt catalyst. Moreover, DBU was proved to be the optimum base
among those bases examined (Supplementary data, Table S2). To
exclude the potential copper contamination in the reactor, we car-
ried out the experiments in clean autoclave with special Teflon lin-
ing and stirrer bars. The Cu metal contents in reaction reagents
including terminal alkynes and DBU were analyzed by flame
atomic absorption and found negative. Subsequently, the reaction
conditions for the direct carboxylation of terminal alkynes with
CO2 in the presence of DBU alone were optimized as shown in
Table 2. The yields of phenylpropiolic acid were dramatically
increased from 64% to 84% with the increasing of reaction temper-
ature from 60 °C to 80 °C (entries 1–3) but dropped to 71% with the
further increasing of reaction temperature to 90 °C (entry 4). It was
found that the yield of phenylpropiolic acid increased from 73% to
86% with increasing the CO2 pressure from 6 MPa to 12 MPa at
80 °C (entries 3, 5, 6). The highest yield was obtained with a reac-
tion time of 16 h under 12 MPa at 80 °C (90%, entry 7). Notably, the
addition of CuI (1 mol %) has a negative effect (entry 8) on carbox-
ylation reaction mediated by DBU alone, which is caused by the
decarboxylative function of copper(I) salt at higher temperatures.
The reaction conditions optimized above were further tested for
the carboxylation of various terminal alkynes with CO2 in the pres-
ence of CuI/DBU as shown in Table 3. Aromatic alkynes containing
electron-donating or electron-withdrawing groups at the para-
position afforded the corresponding propiolic acid products in
moderate to excellent yield from 81% to 96% (entries 1–5, column
A) under the optimized conditions. Among of them, 4-Fluorophe-
nylacetylene gave the highest yield of 96%, which might be
ascribed to the good solubility of fluoro-substituent in ScCO2. The
carboxylation reactions of aliphatic alkyne (1-octyne) and the ter-
minal alkyne of heterocycle (2-ethynylthiophene) with CO2 gener-
ated the corresponding propiolic acid products in good yields of
90% and 83%, respectively (entries 6 and 7, column A). The carbox-
ylation reactions of cyclopropyl acetylene with CO2 gave lower
yields of 70% (entry 8, column A). The corresponding propiolic acid
product was obtained in 76% yield while the solid ferrocenylacety-
lene that is almost insoluble in liquid DBU was used as substrate
(entry 9, column A). However, only a trace amount of the product
was isolated below the critical point of pressure (entry 10, column
A). The results show that ScCO2 acts as a solvent rather than a
liquid DBU in the reaction system. Terminal alkynes with ester
group cannot be carboxylated by CO2 under same conditions (entry
11, column A). It might be caused by the Michael-type addition
occurring predominantly between the reaction of alkynyl esters
and DBU.17
As mentioned above, DBU itself can promote the direct carbox-
ylation of terminal alkynes with CO2 in the absence of copper(I)
Table 1
a
Cu(I)-catalyzed carboxylation of phenylacetylene with CO2
catalyst, base
HCl
+ CO2
H
COOH
8 MPa, 50 ഒ, 12 h
1a
1b
Entry
Catalyst (mol %)
Base (mol %)
Yieldb (%)
1
2
CuCl(5)
CuCl(5)
CuCl(5)
CuCl(5)
CuCl(5)
None
CuI(5)
CuI(5)
CuI(5)
CuI(2)
CuI(1)
CuI(2)
CuI(2)
CuI(2)
CuI(2)
NEt3(120)
Cs2CO3(120)
NEt3(120)
Cs2CO3(120)
DBU(120)
DBU(120)
DBU(120)
DBU(200)
DBU(300)
DBU(200)
DBU(200)
DBU(200)
DBU(200)
DBU(200)
DBU(200)
0
0
3c
4c
5
20
25
62
41
72
84
82
92
65
70
82
75
95
6
7
8
9
10
11
12d
13e
14f
15g
a
b
c
d
e
f
Reaction conditions: phenylacetylene (2.0 mmol), CO2 (8 MPa), 50 °C.
Isolated yield.
DBU (10 mol %) was added.
100 °C.
5 mL DMF was added.
5 mL THF was added.
In the presence of 5 mol % TMEDA.
The carboxylation reactions of various terminal alkynes with
ScCO2 were also investigated in the absence of CuI under same
conditions to explore the role of DBU in the reaction (entries
1–9, column B). The results indicate that DBU-mediated
g