H. Kato and N. Tsukada
Tetrahedron Letters 67 (2021) 152869
Table 1
10–14). In the same way as the reaction of 2-substituted thio-
phenes, carbonyl groups decreased the yield (entry 13).
Direct Alkynylation of 2-Ethylthiophene.a
Since C3-substituted thiophenes are alkynylated at the C2-posi-
tion selectively in the above reaction, two functional groups can be
serially installed by a combination of a b-selective reaction and the
a-selective alkynylation. The arylation of 1a in the presence of pal-
ladium dinuclear complex 4 [6] and then the alkynylation of the
product 6 afforded trisubstituted thiophene 7 with high regioselec-
tivity (Scheme 2).
Chlorosilylacetylene 2b could be also used instead of 2a
(Scheme 3). The reaction of 2b gave 3a in 60% yield. Bromoacetyle-
nes having smaller silyl groups were not effective for the alkynyla-
tion. The reaction of 1-bromo-2-(tert-butyldimethylsilyl)acetylene
2c gave alkynylthiophene 3p in 27% yield. No product was
obtained in the reaction of 1-bromo-2-(triethylsilyl)acetylene 2d.
Although the alkynylation of 2-formylthiophene 1f gave no
desirable product (Table 2, entry 5), a formal synthesis of an
alkynylformylthiophene was achieved by the reaction of 1 h, which
can be easily prepared by reduction and silylation of 1f [11], and
the following transformation (Scheme 4). Desilylation and oxida-
tion of 3 h, which is the product of the reaction of 1 h, gave 2-ethy-
nyl-5-formylthiophene 8.
Since TIPS of the product 3 can be easily removed by tetra-n-
butylammonium fluoride (TBAF), alkynyl thiophenes having vari-
ous substituents at the terminal of alkyne can be synthesized.
Treatment of 3c with TBAF gave desilylated thiophene 9 in high
yield (Scheme 5). Cu-catalyzed Sonogashira-type reaction of 9
afforded (arylethynyl)thiophene 10 [12]. 1-Propynylthiophene 11
entry
variation from the standard conditions
yieldb (%)
1
2
3
4
5
6
7
8
–
63
49
54
54
6
Pd(OCOCF3)2 instead of Pd(OAc)2
Pd(OCOtBu)2 instead of Pd(OAc)2
Pd(dba)2 instead of Pd(OAc)2
4 instead of Pd(OAc)2
Ni(OAc)2 instead of Pd(OAc)2
Cu(OAc)2 instead of Pd(OAc)2
addition of DMAP (5 mol%)
Ag2CO3 instead of AgOAc
KOAc instead of AgOAc
NaOAc instead of AgOAc
50 °C, 15 h
0
0
67
28
30
21
63
58
9
10
11
12
13
rt, 48 h
a
A mixture of 1a (0.30 mmol), 2a (0.30 mmol) and AgOAc (0.30 mmol) in ace-
tonitrile (1.5 mL) was stirred at 80 °C in the presence of Pd(OAc)2 (5.0 mol%).
b
GC yield.
Table 2
Direct Alkynylation of Thiophenes.a
afforded an
a-alkynylated thiophene 3a in 63% yield as a single
regioisomer (Table 1, entry 1). Lower yields were found when
using other palladium carboxylate such as Pd(OCOCF3)2 and Pd
(OCOtBu)2 (entries 2 and 3). Dinuclear palladium complex 4, which
showed b-selectivity in direct arylation reactions of thiophenes [6],
was not effective for the alkynylation (entry 5). No product was
obtained when using Ni(OAc)2 or Cu(OAc)2 (entries 6 and 7). Addi-
tion of 5 mol% of DMAP slightly increased the yield although larger
amounts inhibited the reaction (entry 8). The yield was not varied
with addition of pyridines such as 2,6-dimethylpyridine and 2,6-
di-tert-butylpyridine, carboxylic acids such as acetic acid and piva-
lic acid, and N-acetyl and N-tert-butoxycarbonyl amino acids. Addi-
tion of K2CO3 and Cs2CO3 decreased the yield. The yield was lower
in the reactions with other silver or acetate salts (entries 9–11).
The reactions at lower temperature gave similar results although
longer reaction time was necessary at room temperature (entries
12 and 13). The use of excess amount (1.5–2.0 equiv) of 1a or 2a
did not improved the yield.
Entry
R
R’
Product
Yieldb (%)
1
2
3
4
5
6
7
8
CH3
Ph
Cl
Br
CHO
COCH3
CH2OTBS
CH(OTBS)CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
52
62
43
45
trace
<7c
49
44
9
H
CH3
OCH3
Cl
COCH3
CH(OTBS)CH3
36d
45e
61
10
11
12
13
14
44
<18c
37
Table 2 summarizes the results of direct alkynylation of various
thiophenes. The reaction of 2-methylthiophene or 2-phenylthio-
phene gave
a-alkynylated products selectively (entries 1 and 2).
a
A mixture of 1 (0.30 mmol), 2a (0.30 mmol) and AgOAc (0.30 mmol) in ace-
Halogen substituents at the C2-position of thiophene were toler-
ated although product yields were lower (entries 3 and 4). Car-
bonyl groups conjugated with thiophene inhibited the
alkynylation (entries 5 and 6). Although hydroxy groups also inhib-
ited the alkynylation, the reaction of thiophenes having the corre-
sponding silyl ethers gave the alkynylated products (entries 7 and
8). In the reaction of non-substituted thiophene, monoalkynylated
product 3j was obtained in moderate yields with small amounts of
dialkynylated products 5j (entry 9). The reaction of C3-substituted
thiophenes afforded 2-alkynylated products selectively (entries
tonitrile (1.5 mL) was stirred at 50 °C in the presence of Pd(OAc)2 (5.0 mol%).
b
Isolated yield.
Including an inseparable TIPS impurity.
Obtained as an inseparable mixture with 5j (6%).
c
d
e
A mixture of 3k and 5k (89:11).
2
Kato, Hayate
