A new [2+2+1] heterocyclization for the synthesis of 2,3,5-trisubstituted thiophenes under microwave irradiation

Article abstract of DOI:10.1055/s-0033-1339917

A new three-component strategy for the efficient synthesis of 2,3,5-trisubstituted thiophene derivatives through a [2+2+1] heterocyclization between 3-(2-aryl-2-oxoethylidene)-2-oxindoles and α-thiocyanato ketones under microwave irradiation is described.

Full text of DOI:10.1055/s-0033-1339917

3392▌
PAPER
paper
A New [2+2+1] Heterocyclization for the Synthesis of 2,3,5-Trisubstituted
Thiophenes under Microwave Irradiation
Synthesis of 2,3,5-Trisubstituted Thiophenes
Hai-Wei Xu, Guan-Hua Ma, Bo Jiang,* Shu-Jiang Tu*
School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials,
Jiangsu Normal University, Xuzhou, 221116, Jiangsu, P. R. of China
Fax +86(516)83500065; E-mail: jiangchem@jsnu.edu.cn; E-mail: laotu@jsnu.edu.cn
Received: 10.08.2013; Accepted after revision: 16.09.2013
ment of new multicomponent domino reactions that can
Abstract: A new three-component strategy for the efficient synthe-
provide easy access to new core structures of chemical
sis of 2,3,5-trisubstituted thiophene derivatives through a [2+2+1]
and pharmaceutical interest.19 As a result of our continued
efforts on these domino processes, herein we disclose a
heterocyclization between 3-(2-aryl-2-oxoethylidene)-2-oxindoles
and α-thiocyanato ketones under microwave irradiation is de-
scribed. The bond-forming efficiency, accessibility, and generality new base-promoted [2+2+1] cyclization of 3-(2-aryl-2-
of this synthesis make it highly valuable to assemble thiophene
scaffolds.
oxoethylidene)-2-oxindoles 1 and α-thiocyanato ketones
2 under microwave irradiation (MW) yielding 2,3,5-tri-
Key words: heterocyclization, substituted thiophene, three-compo-
nent reactions, α-thiocyanato ketone, 3-(2-aryl-2-oxoethylidene)-2-
oxindole
substituted thiophene derivatives 3 (Scheme 1). The nota-
ble feature of the present domino strategy is that, it
demonstrates the formation of a thiophene skeleton with
the concomitant achievement of polyfunctionalization re-
siding at different sites of the thiophene unit. This is read-
ily achieved in a domino fashion involving [3+2]
cycloaddition, ring-opening of in situ generated thio-
phenes, SN2 reaction, and Knoevenagel condensation se-
quence, forming up to three σ-bonds in a one-pot
operation from common and preformed starting materials
(Schemes 1 and 2). This strategy is very useful in synthet-
ic organic chemistry.
Thiophene derivatives are undoubtedly an important class
of sulfur heterocycles, possessing a wide range of biolog-
ical activities such as anticancer activity1and protein inhi-
bition.2 They are also used as conducting polymers3 and
photochromic molecular switches.4 The incorporation of
the thiophene moiety into organic semiconducting materi-
als is a highly active topic.5 Thiophenes and their deriva-
tives are arguably the most important monomers for
semiconducting polymers6 and oligomers,5a,7 which have
widespread utility in the preparation of plastic solar
cells,6a,8 and organic field effect transistors.5a,7a,c,9 Owing
to their unique biological and chemical characteristics,
some modern methodologies for the construction of poly-
substituted thiophenes have been developed. Most of
them involves the Gewald method,10 the Hinsberg synthe-
sis,11 thio-Claisen rearrangement reaction,12 cyclization of
α-bromoacetophenone derivatives12d,13 or 1-mercapto-3-
yn-2-ols,14 [3+2]-self annulation of bis(aroylmethyl) sul-
fide,15 Fiesselmann thiophene synthesis,16 and other meth-
ods.17 Despite these methodologies, an exploration of a
facile protocol for the direct formation of thiophenes, and
their efficient multifunctionalization in particular, is high-
ly desirable.
O
Ar1
SCN
Ar1
Ar2
Ar2
O
O
2
O
t-BuOK, DMF
+
S
O
60 °C
MW
Ar2
O
N
SCN
Ar2
H
3
2
1
Scheme 1 Synthesis of 2,3,5-trisubstituted thiophenes
α-Thiocyanato ketones have attracted great attention as
interesting intermediates due to their easy transformation
into highly valuable molecules that can be applied to both
organosulfur and heterocyclic chemistry.20 Our strategy
for the synthesis of 2,3,5-trisubstituted thiophenes is
through the reaction of 3-(2-aryl-2-oxoethylidene)-2-ox-
indoles 1 and α-thiocyanato ketones 2. Our initial experi-
ments focused on the three-component domino reaction of
3-[2-(4-fluorophenyl)-2-oxoethylidene]-1,3-dihydro-2H-
indol-2-one (1a) and 1-(4-chlorophenyl)-2-thiocyanato-
ethanone (2a) in a ratio of 1:2 using a wide range of read-
ily available base promoters (e.g., Et3N, K2CO3, Cs2CO3,
NaOH, and NaOEt) at 60 °C under microwave irradiation
(Table 1). The reaction scarcely proceeded to provide the
expected product 3a in the presence of triethylamine at
60 °C (entry 1). Very poor yields (24% and 27%) of prod-
uct 3a were observed when potassium or cesium carbon-
Multicomponent domino reactions (MDRs) have gained
considerable popularity in the synthetic community. They
provide efficient access to complex molecules from read-
ily available starting materials.18 They also form an ideal
platform for the rapid generation of both complexity and
diversity in a collection of compounds with predefined
functionality, such as ligands for catalysis or bioactive
compounds. Recently, we have engaged in the develop-
SYNTHESIS 2013, 45, 3392–3398
Advanced online publication: 08.10.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339917; Art ID: SS-2013-H0559-OP
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of 2,3,5-Trisubstituted Thiophenes
3393
ate were used as base promoters (entries 2 and 3). The 3a (entry 6). Subsequently, different solvents were
reaction promoted by sodium hydroxide or sodium ethox- screened, and it was found that the reaction worked more
ide generated a slightly higher yield of 3a (entries 4 and efficiently in N,N-dimethylformamide than in acetonitrile
5). Gratifyingly, the identical reaction performed in N,N- or ethanol (entries 7 and 8). Further increases in the reac-
dimethylformamide using potassium tert-butoxide as a tion temperature failed to improve the yield of the desired
base promoter provided a higher yield (67%) of product product 3a (entries 9 and 10).
Table 1 Optimization of the Reaction Conditionsa
C6H4-4-F
C6H4-4-F
O
O
O
O
SCN
SCN
base
MW
4-ClC6H4
4-ClC6H4
4-ClC6H4
+
+
S
O
C6H4-4-Cl
N
O
H
1a
2a
2a
3a
Entry
Base
Solvent
Temp (°C)
Time (min)
Yieldb (%)
1
2
Et3N
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
EtOH
DMF
DMF
60
60
60
60
15
15
15
15
15
15
15
15
15
15
trace
17
K2CO3
Cs2CO3
NaOH
3
24
4
38
5
NaOEt
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
60
60
43
6
67
7
60
trace
23
8
60
9
80
60
10
100
51
a Reaction conditions: molar ratio 1/2 (1:2), base (1.0 equiv).
b Isolated yield was based on substrate 1.
O
Ar1
base
O
H
Ar2
O
O
O
NH
O
S
N
O
O
H
S
Ar2
O
1
tautomerism
base
S
NH
Ar2
C
S
Ar2
C
O
Ar1
N
NH
[3+2] cycloaddition
N
HN
2
Ar1
A
B
O
O
O
NH
O
S
NCS
Ar2
O
O
Ar1
S
Ar2
Ar2
O
– H2O
2
base
S
O
Ar2
Ar2
O
O
N
H
SN2
Ar1
Ar1
C
N
S
Ar2
O
Ar1
Ar2
B
O
3
D
CN
Scheme 2 Proposed mechanism for the formation of products 3
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3392–3398

3394
H.-W. Xu et al.
PAPER
Table 2 Domino Synthesis of Substituted Thiophenes 3a
With the above optimized conditions in hand, we then
proceeded to explore the substrate diversity of this potas-
sium tert-butoxide promoted domino reaction of 3-(2-
aryl-2-oxoethylidene)-2-oxindoles 1 and α-thiocyanato
ketones 2. All the reactions proceeded efficiently and af-
forded the desired products in moderate to good yields.
The results are presented in Table 2. The substituents on
the phenyl ring of α-thiocyanato ketones did not hamper
the reaction process. Reactions of chloro-, bromo-,
methoxy-, or nitro-substituted α-thiocyanato ketones 2
with 1 worked well to provide the desired products in
good yields (Table 2). It was found that there was a little
difference between the substitution effect of an electron-
donating group and that of an electron-withdrawing
group, although it seemed as if electron-donating substit-
uents favored this reaction more than strong electron-
withdrawing substituents such as the nitro group. Subse-
quently, the scope of this interesting transformation with
different 3-(2-aryl-2-oxoethylidene)-2-oxindoles was in-
vestigated (Table 2). Several different substituents on the
aryl ring were compared and substituents bearing elec-
tron-withdrawing (4-fluoro, 1a; 4-chloro, 1b), or electron-
donating (4-methyl, 1d; 4-methoxy, 1e; 3,4-dimethoxy,
1f) groups were found to be suitable for this domino reac-
tion. Moreover, naphthalen-2-yl substituted 2-oxindoles
1g were also converted into the corresponding naphtha-
len-2-yl-substituted thiophenes 3r and 3t in 67% and 69%
yields, respectively. The tolerance of functionalities such
as chloro and bromo in this protocol provides the oppor-
tunity for various further chemical manipulations in the
products. It is worth mentioning that this protocol pro-
vides a straightforward pathway to synthesize polysubsti-
tuted thiophenes with concomitant achievement of C2, C5
bis-aroylations, and C3-arylation in a one-pot operation.
Moreover, it also gives a new example for the construc-
tion of polysubstituted thiophene motif in an economical
fashion, providing a valuable strategy to discover new
bioactive compounds.
O
Ar1
Ar1
SCN
Ar2
O
Ar2
O
2
t-BuOK, DMF
+
S
O
O
Ar2
60 °C
O
N
MW
SCN
H
Ar2
3
1
2
Entry Product Ar1
Ar2
Yieldb
(%)
1
2
3a
3b
3c
3d
3e
3f
4-FC6H4 (1a)
4-FC6H4 (1a)
4-ClC6H4 (1b)
4-ClC6H4 (1b)
4-ClC6H4 (1b)
4-ClC6H4 (1b)
Ph (1c)
4-ClC6H4 (2a)
4-BrC6H4 (2b)
4-ClC6H4 (2a)
4-BrC6H4 (2b)
Ph (2c)
67
75
77
79
69
3
4
5
6
4-MeOC6H4 (2d) 72
7
3g
3h
3i
4-ClC6H4 (2a)
4-BrC6H4 (2b)
4-ClC6H4 (2a)
3-ClC6H4 (2e)
4-BrC6H4 (2b)
62
73
67
55
78
8
Ph (1c)
9
4-MeC6H4 (1d)
4-MeC6H4 (1d)
4-MeC6H4 (1d)
4-MeC6H4 (1d)
4-MeC6H4 (1d)
4-MeOC6H4 (1e)
4-MeOC6H4 (1e)
4-MeOC6H4 (1e)
10
11
12
13
14
15
16
17
18
19
3j
3k
3l
4-MeOC6H4 (2d) 70
3m
3n
3o
3p
3q
3r
3s
4-O2NC6H4 (2f)
4-ClC6H4 (2a)
3-ClC6H4 (2e)
4-BrC6H4 (2b)
3-ClC6H4 (2e)
4-ClC6H4 (2a)
4-BrC6H4 (2b)
51
68
66
74
55
67
69
3,4-(MeO)2C6H3 (1f)
naphthalen-2-yl (1g)
naphthalen-2-yl (1g)
In all cases, the products can be precipitated out after the
reaction mixture was poured into cold water and was neu-
tralized by diluted acidic solution. The structural elucida-
tion of the products was determined from its IR, 1H NMR,
13C NMR, and HRMS spectra. The structure of compound
3i was unambiguously confirmed by X-ray analysis (Fig-
ure 1).
a Reaction conditions: molar ratio 1/2 (1:2), t-BuOK (1.0 equiv), DMF
(1.5 mL), 60 °C.
b Isolated yield was based on the substrates 1.
On the basis of experimental results, a plausible reaction
mechanism for this domino reaction is postulated in
Scheme 2. α-Thiocyanato ketones 2 deprotonated by po-
tassium tert-butoxide undergo [3+2] cycloaddition of 3-
(2-aryl-2-oxoethylidene)-2-oxindoles 1 to convert them
into intermediate A, followed by base-promoted ring
opening of in situ generated thiophenes A to yield inter-
mediate B. The subsequent tautomerism and elimination
reaction affords intermediate C; 2-oxo-2,3-dihydro-1H-
indole-3-carbonitrile was detected by gas chromatogra-
phy–mass spectrometry (GC-MS) analysis. Then, an SN2-
type reaction between intermediate C and α-thiocyanato
ketone 2 occurs, affording intermediate D, which is trans-
Figure 1 ORTEP drawing of 3i21
Synthesis 2013, 45, 3392–3398
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of 2,3,5-Trisubstituted Thiophenes
3395
131.3 (JCF2 = 6.2 Hz), 131.3, 131.2, 130.3 (JCF3 = 3.1 Hz), 130.2,
127.4, 127.2, 115.1 (JCF4 = 21.6 Hz).
HRMS (EI): m/z [M]+ calcd for C24H13Br2FO2S: 541.8987; found:
formed into final product 3 through a Knoevenagel con-
densation reaction.
In conclusion, we have developed a new [2+2+1] hetero-
cyclization between 3-(2-aryl-2-oxoethylidene)-2-oxin-
541.8965.
doles and α-thiocyanato ketones as an alternative method [3-(4-Chlorophenyl)thiophene-2,5-diyl]bis[(4-chlorophe-
nyl)methanone] (3c)
for the efficient synthesis of 2,3,5-trisubstituted thio-
phenes. This domino strategy allows us to build blocks of
thiophene derivatives with a wide variety of substituents.
The relatively mild reaction conditions, selective modifi-
cation of thiophene skeleton, and high bond-forming effi-
ciency (BFE) make this domino strategy highly viable for
future applications. A detailed investigation of the mech-
anism and the applications of this reaction are currently in
White solid; yield: 0.363 g (77%); mp 182–183 °C (Lit.12d
178.2 °C).
IR (KBr): 1649, 1586, 1484, 1400, 1365, 1286, 1266, 1173, 1088
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.01 (d, J = 8.4 Hz, 2 H, HAr),
7.94 (s, 1 H, CH), 7.69–7.65 (m, 4 H, HAr), 7.43 (d, J = 8.4 Hz, 2 H,
HAr), 7.36 (d, J = 8.4 Hz, 2 H, HAr), 7.31 (d, J = 8.4 Hz, 2 H, HAr).
13C NMR (100 MHz, DMSO-d6): δ = 188.7, 186.7, 145.1, 145.0,
progress.
142.2, 138.9, 138.7, 137.0, 135.5, 135.4, 133.6, 133.3, 131.8, 131.7,
131.4, 129.5, 129.0, 128.7.
HRMS (EI): m/z [M]+ calcd for C24H13Cl3O2S: 469.9702; found:
469.9733.
Microwave irradiation was carried out with initiator from Biotage
Company, Sweden. Melting points were determined in open capil-
laries and were uncorrected. IR spectra were taken on an FT-IR-
Tensor 27 spectrophotometer in KBr pellets. 1H NMR spectra were
measured on a Bruker DPX 400 MHz spectrometer in DMSO-d6
relative to TMS as internal standard. HRMS (ESI) was determined
by using microTOF-Q II, HRMS/MS instrument (Bruker). X-ray
crystallographic analysis was performed with a Siemens SMART
CCD and a Siemens P4 diffractometer.
[3-(4-Chlorophenyl)thiophene-2,5-diyl]bis[(4-bromophe-
nyl)methanone] (3d)
White solid; yield: 0.441 g (79%); mp 172–174 °C (Lit.12d 179 °C).
IR (KBr): 1638, 1588, 1458, 1303, 1286, 1217, 1121, 1011 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.93 (d, J = 8.8 Hz, 3 H, HAr,
CH), 7.82 (d, J = 8.0 Hz, 2 H, HAr), 7.58 (s, 4 H, HAr), 7.36 (d,
J = 8.4 Hz, 2 H, HAr), 7.31 (d, J = 8.0 Hz, 2 H, HAr).
13C NMR (100 MHz, DMSO-d6): δ = 188.3, 186.3, 144.5, 144.4,
141.7, 136.4, 135.3, 135.2, 133.1, 132.7, 131.9, 131.4, 131.3, 131.2,
130.8, 128.2, 127.5, 127.2.
[3-(4-Fluorophenyl)thiophene-2,5-diyl]bis[(4-chlorophe-
nyl)methanone] (3a); Typical Procedure
3-[2-(4-Fluorophenyl)-2-oxoethylidene]-1,3-dihydro-2H-indol-2-
one (1a, 1 mmol, 0.267 g, 1.0 equiv) was introduced into a 10-mL
InitiatorTM reaction vial, 1-(4-chlorophenyl)-2-thiocyanatoethanone
(2a, 2.0 mmol, 0.422 g, 2.0 equiv), t-BuOK (1.0 mmol, 0.112 g, 1.0
equiv), and DMF (1.5 mL) were then successively added. Subse-
quently, the reaction vial was closed and then pre-stirred for 20 s.
The mixture was irradiated (time: 15 min, temp: 60 °C; absorption
level: high; fixed hold time) until TLC (petroleum ether–EtOAc,
3:1) revealed that conversion of the starting material 1a was com-
plete. The mixture was then cooled to r.t. and diluted with cold H2O
(20 mL). The solid product was collected by Büchner filtration and
it was purified by recrystallization (95% EtOH) to afford pure 3a as
a white solid; yield: 0.305 g (67%); mp 152–153 °C.
HRMS (EI): m/z [M]+ calcd for C24H13Br2ClO2S: 557.8692; found:
557.8699.
[3-(4-Chlorophenyl)thiophene-2,5-diyl]bis(phenylmethanone)
(3e)
White solid; yield: 0.277 g (69%); mp 191–192 °C.
IR (KBr): 1626, 1587, 1509, 1491, 1360, 1220, 1168, 1025 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.14 (d, J = 7.2 Hz, 2 H, HAr),
8.04 (d, J = 7.2 Hz, 4 H, HAr), 7.72 (d, J = 7.2 Hz, 1 H, CH), 7.66–
7.59 (m, 4 H, HAr), 7.52–7.48 (m, 4 H, HAr).
HRMS (EI): m/z [M]+ calcd for C24H15ClO2S: 402.0481; found:
402.0509.
IR (KBr): 1650, 1586, 1504, 1365, 1287, 1266, 1219, 1173, 1088
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.02 (d, J = 8.4 Hz, 2 H, HAr),
7.93 (s, 1 H, CH), 7.69–7.63 (m, 4 H, HAr), 7.42–7.32 (m, 4 H, HAr),
7.10–7.06 (m, 2 H, HAr).
[3-(4-Chlorophenyl)thiophene-2,5-diyl]bis[(4-methoxyphe-
nyl)methanone] (3f)
White solid; yield: 0.333 g (72%); mp 138–139 °C.
13C NMR (100 MHz, DMSO-d6): δ = 188.8, 186.7, 162.4
(JCF1 = 244.7 Hz), 145.3, 144.9, 142.1, 138.7, 138.6, 137.1, 135.5,
135.3, 131.8 (JCF2 = 8.8 Hz), 131.7, 131.4, 130.9 (JCF3 = 3.2 Hz),
129.5, 129.0, 115.7 (JCF4 = 21.6 Hz).
HRMS (EI): m/z [M]+ calcd for C24H13Cl2FO2S: 453.9997; found:
454.0023.
IR (KBr): 1622, 1589, 1570, 1509, 1295, 1266, 1168, 1123 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.03 (d, J = 8.4 Hz, 2 H, HAr),
7.90 (s, 1 H, CH), 7.71 (d, J = 8.8 Hz, 2 H, HAr), 7.40–7.33 (m, 4 H,
HAr), 7.14 (d, J = 8.8 Hz, 2 H, HAr), 6.93 (d, J = 8.8 Hz, 2 H, HAr),
3.89 (s, 3 H, OCH3), 3.80 (s, 3 H, OCH3).
13C NMR (100 MHz, DMSO-d6): δ = 188.2, 186.0, 164.1, 163.8,
144.8, 143.6, 142.1, 135.7, 133.6, 133.3, 132.7, 132.4, 131.1, 129.4,
129.3, 128.9, 114.7, 114.4, 56.1, 56.1.
[3-(4-Fluorophenyl)thiophene-2,5-diyl]bis[(4-bromophe-
nyl)methanone] (3b)
White solid; yield: 0.406 g (75%); mp 150–151 °C.
HRMS (EI): m/z [M]+ calcd for C26H19ClO4S: 462.0693; found:
IR (KBr): 1649, 1583, 1542, 1508, 1397, 1281, 1265, 1175, 1096
cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.96–7.92 (m, 3 H, HAr), 7.82
(d, J = 8.4 Hz, 2 H, HAr), 7.57 (d, J = 9.0 Hz, 4 H, HAr), 7.44 (d,
J = 8.4 Hz, 1 H, CH), 7.40–7.36 (m, 1 H, HAr), 7.29 (d, J = 8.54 Hz,
1 H, HAr), 7.10–7.06 (m, 1 H, HAr).
462.0666.
(3-Phenylthiophene-2,5-diyl)bis[(4-chlorophenyl)methanone]
(3g)
Pale yellow solid; yield: 0.270 g (62%); mp 175–177 °C.
IR (KBr): 1642, 1586, 1534, 1399, 1287, 1259, 1213, 1087 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.02 (d, J = 7.6 Hz, 2 H, HAr),
7.93 (s, 1 H, CH), 7.69–7.63 (m, 4 H, HAr), 7.41–7.30 (m, 4 H, HAr),
7.24 (s, 3 H, HAr).
13C NMR (100 MHz, DMSO-d6): δ = 188.4, 186.3, 161.9
(JCF1 = 244.9 Hz), 144.8, 144.3, 141.5, 136.5, 135.3, 135.1, 131.9,
© Georg Thieme Verlag Stuttgart · New York
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H.-W. Xu et al.
PAPER
13C NMR (100 MHz, DMSO-d6): δ = 189.0, 186.8, 146.3, 144.8,
142.1, 138.7, 138.6, 137.0, 135.6, 135.3, 134.4, 131.75, 131.70,
129.6, 129.5, 128.9, 128.8, 128.7.
[3-(p-Tolyl)thiophene-2,5-diyl]bis[(4-methoxyphenyl)metha-
none] (3l)
Pale yellow solid; yield: 0.309 g (70%); mp 138–139 °C.
IR (KBr): 1633, 1598, 1507, 1421, 1285, 1261, 1168, 1034 cm–1.
HRMS (EI): m/z [M]+ calcd for C24H14Cl2O2S: 436.0092; found:
1H NMR (400 MHz, DMSO-d6): δ = 8.02 (d, J = 8.4 Hz, 2 H, HAr),
7.86 (s, 1 H, CH), 7.71 (d, J = 8.4 Hz, 2 H, HAr), 7.25 (d, J = 7.6 Hz,
2 H, HAr), 7.15–7.08 (m, 4 H, HAr), 6.91 (d, J = 8.4 Hz, 2 H, HAr),
3.89 (s, 3 H, OCH3), 3.79 (s, 3 H, OCH3), 2.23 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 188.0, 185.5, 163.5, 163.2,
144.1, 143.8, 140.9, 137.4, 135.1, 132.1, 131.7, 131.3, 129.0, 128.9,
128.8, 128.5, 114.1, 113.8, 55.5, 20.6.
436.0087.
(3-Phenylthiophene-2,5-diyl)bis[(4-bromophenyl)methanone]
(3h)
White solid; yield: 0.382 g (73%); mp 163–164 °C.
IR (KBr): 1639, 1583, 1475, 1396, 1257, 1211, 1171, 1066 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.94–7.92 (m, 3 H, HAr, CH),
7.82 (d, J = 8.4 Hz, 2 H, HAr), 7.58–7.50 (m, 4 H, HAr), 7.34–7.29
(m, 2 H, HAr), 7.24–7.23 (m, 3 H, HAr).
13C NMR (100 MHz, DMSO-d6): δ = 189.2, 186.9, 146.3, 144.8,
142.0, 137.0, 135.9, 135.6, 134.4, 132.4, 131.9, 131.8, 130.3, 129.6,
128.8, 128.5, 128.0, 127.7.
HRMS (EI): m/z [M]+ calcd for C27H22O4S: 442.1239; found:
442.1231.
[3-(p-Tolyl)thiophene-2,5-diyl]bis[(4-nitrophenyl)methanone]
(3m)
Yellow solid; yield: 0.241 g (51%); mp 197–198 °C.
IR (KBr): 1650, 1600, 1520, 1406, 1347, 1268, 1228, 1105 cm–1.
HRMS (EI): m/z [M]+ calcd for C24H14Br2O2S: 523.9081; found:
523.9083.
1H NMR (400 MHz, DMSO-d6): δ = 8.42 (d, J = 8.4 Hz, 2 H, HAr),
8.21 (d, J = 8.4 Hz, 2 H, HAr), 8.10 (d, J = 8.4 Hz, 2 H, HAr), 7.93 (s,
1 H, CH), 7.82 (d, J = 8.4 Hz, 2 H, HAr), 7.20 (d, J = 7.6 Hz, 2 H,
HAr), 7.00 (d, J = 7.6 Hz, 2 H, HAr), 2.17 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 188.5, 186.4, 149.8, 149.4,
147.0, 144.6, 141.5, 141.4, 141.4, 138.1, 137.5, 137.3, 130.6, 129.8,
129.2, 128.8, 123.9, 123.3, 20.6.
[3-(p-Tolyl)thiophene-2,5-diyl]bis[(4-chlorophenyl)metha-
none] (3i)
White solid; yield: 0.302 g (67%); mp 208–209 °C.
IR (KBr): 1643, 1585, 1541, 1400, 1259, 1210, 1173, 1086 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.01 (d, J = 8.0 Hz, 2 H, HAr),
7.90 (s, 1 H, CH), 7.69–7.64 (m, 4 H, HAr), 7.40 (d, J = 8.0 Hz, 2 H,
HAr), 7.21 (d, J = 7.6 Hz, 2 H, HAr), 7.05 (d, J = 7.8 Hz, 2 H, HAr),
2.22 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 189.1, 186.8, 146.2, 144.6,
141.5, 138.8, 138.6, 138.3, 136.9, 135.6, 135.3, 131.8, 131.7, 131.5,
129.5, 129.4, 129.4, 129.0, 21.1.
HRMS (EI): m/z [M]+ calcd for C25H16N2O6S: 472.0729; found:
472.0722.
[3-(4-Methoxyphenyl)thiophene-2,5-diyl]bis[(4-chlorophe-
nyl)methanone] (3n)
Pale yellow solid; yield: 0.317 g (68%); mp 129–131 °C.
IR (KBr): 1646, 1586, 1509, 1398, 1257, 1212, 1173, 1086 cm–1.
HRMS (EI): m/z [M]+ calcd for C25H16Cl2O2S: 450.0248; found:
450.0253.
1H NMR (400 MHz, DMSO-d6): δ = 8.01 (d, J = 8.0 Hz, 2 H, HAr),
7.89 (s, 1 H, CH), 7.69–7.63 (m, 4 H, HAr), 7.40 (d, J = 8.0 Hz, 2 H,
HAr), 7.25 (d, J = 8.0 Hz, 2 H, HAr), 6.78 (d, J = 8.0 Hz, 2 H, HAr),
3.69 (s, 3 H, OCH3).
13C NMR (100 MHz, DMSO-d6): δ = 188.7, 186.3, 159.3, 145.6,
144.1, 140.6, 138.2, 138.1, 136.5, 135.1, 134.9, 131.2, 131.2, 130.5,
129.0, 128.5, 126.3, 113.8, 55.2.
[3-(p-Tolyl)thiophene-2,5-diyl]bis[(3-chlorophenyl)metha-
none] (3j)
Pale yellow solid; yield: 0.247 g (55%); mp 132–133 °C.
IR (KBr): 1649, 1578, 1525, 1435, 1350, 1259, 1126, 1020 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.65 (s, 1 H, HAr), 8.54 (d,
J = 8.0 Hz, 1 H, HAr), 8.42 (d, J = 7.6 Hz, 1 H, HAr), 8.28 (d, J = 8.8
Hz, 1 H, HAr), 8.20 (s, 1 H, CH), 8.04 (d, J = 7.6 Hz, 1 H, HAr), 8.00
(s, 1 H, HAr), 7.91 (d, J = 8.0 Hz, 1 H, HAr), 7.61 (d, J = 8.0 Hz, 1 H,
HAr), 7.17 (d, J = 8.0 Hz, 2 H, HAr), 6.95 (d, J = 8.0 Hz, 2 H, HAr),
2.15 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 187.7, 185.8, 147.9, 147.0,
146.9, 144.7, 141.5, 138.0, 137.5, 137.3, 137.2, 135.3, 135.2, 130.9,
130.7, 130.2, 129.3, 128.7, 127.3, 127.0, 124.1, 123.9, 20.6.
HRMS (EI): m/z [M]+ calcd for C25H16Cl2O3S: 466.0197; found:
466.0216.
[3-(4-Methoxyphenyl)thiophene-2,5-diyl]bis[(3-chlorophe-
nyl)methanone] (3o)
Yellow solid; yield: 0.307 g (66%); mp 121–122 °C.
IR (KBr): 1644, 1578, 1526, 1436, 1351, 1256, 1135, 1029 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.66 (s, 1 H, HAr), 8.56 (d,
J = 8.0 Hz, 1 H, HAr), 8.42 (d, J = 7.8 Hz, 1 H, HAr), 8.28 (d, J = 8.0
Hz, 1 H, CH), 8.21 (s, 1 H, HAr), 8.05–7.98 (m, 2 H, HAr), 7.93–7.89
(m, 1 H, HAr), 7.62–7.58 (m, 1 H, HAr), 7.22 (d, J = 8.8 Hz, 2 H,
HAr), 6.69 (d, J = 8.8 Hz, 2 H, HAr), 3.63 (s, 3 H, OCH3).
HRMS (EI): m/z [M]+ calcd for C25H16Cl2O2S: 450.0248; found:
450.0230.
[3-(p-Tolyl)thiophene-2,5-diyl]bis[(4-bromophenyl)metha-
none] (3k)
White solid; yield: 0.421 g (78%); mp 168–169 °C (Lit.12d
162.4 °C).
HRMS (EI): m/z [M]+ calcd for C25H16Cl2O3S: 466.0197; found:
466.0222.
IR (KBr): 1643, 1582, 1539, 1396, 1259, 1209, 1173, 1067 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.95–7.89 (m, 3 H, HAr, CH),
7.82 (d, J = 7.6 Hz, 2 H, HAr), 7.59–7.53 (m, 4 H, HAr), 7.20 (d,
J = 7.2 Hz, 2 H, HAr), 7.05 (d, J = 7.6 Hz, 2 H, HAr), 2.23 (s, 3 H,
CH3).
13C NMR (100 MHz, DMSO-d6): δ = 188.8, 186.4, 145.7, 144.1,
140.9, 137.7, 136.4, 135.3, 135.1, 131.9, 131.4, 131.2, 131.2, 130.9,
128.85, 128.81, 127.4, 127.1, 20.6.
[3-(4-Methoxyphenyl)thiophene-2,5-diyl]bis[(4-bromophe-
nyl)methanone] (3p)
Pale yellow solid; yield: 0.410 g (74%); mp 152–153 °C (Lit.12d
167.5 °C).
IR (KBr): 1646, 1583, 1395, 1367, 1257, 1211, 1174, 1066 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.95–7.88 (m, 3 H, HAr, CH),
7.82 (d, J = 8.0 Hz, 2 H, HAr), 7.55 (s, 4 H, HAr), 7.25 (d, J = 8.0 Hz,
2 H, HAr), 6.78 (d, J = 8.0 Hz, 2 H, HAr), 3.69 (s, 3 H, OCH3).
HRMS (EI): m/z [M]+ calcd for C25H16Br2O2S: 537.9238; found:
537.9260.
Synthesis 2013, 45, 3392–3398
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 2,3,5-Trisubstituted Thiophenes
3397
13C NMR (100 MHz, DMSO-d6): δ = 189.3, 187.0, 159.8, 146.1,
144.6, 141.1, 137.0, 135.9, 135.9, 132.4, 131.9, 131.8, 131.8, 131.0,
127.9, 127.7, 126.8, 114.3, 55.7.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
HRMS (EI): m/z [M]+ calcd for C25H16Br2O3S: 553.9187; found:
553.9163.
References
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Toxicol. 2008, 21, 1570. (b) Romagnoli, R.; Baraldi, P. G.;
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Approach; SPIE: Bellingham, 2008.
[3-(3,4-Dimethoxyphenyl)thiophene-2,5-diyl]bis[(3-chlorophe-
nyl)methanone] (3q)
White solid; yield: 0.273 g (55%); mp 132–133 °C.
IR (KBr): 1637, 1578, 1528, 1435, 1349, 1244, 1124, 1022 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.82 (s, 1 H, CH), 8.52 (d, J = 8.0
Hz, 1 H, HAr), 8.35–8.28 (m, 2 H, HAr), 8.22 (d, J = 8.0 Hz, 1 H,
HAr), 8.06 (d, J = 7.6 Hz, 1 H, HAr), 7.80–7.76 (m, 2 H, HAr), 7.51–
7.47 (m, 1 H, HAr), 6.79 (d, J = 8.0 Hz, 1 H, HAr), 6.64 (d, J = 7.6
Hz, 2 H, HAr), 3.77 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3).
13C NMR (100 MHz, DMSO-d6): δ = 188.2, 186.3, 149.4, 148.6,
148.3, 147.6, 147.3, 145.2, 141.9, 138.0, 137.8, 135.8, 135.5, 131.2,
130.6, 127.8, 127.3, 126.9, 124.5, 124.4, 122.7, 113.5, 111.9, 56.0,
55.8.
HRMS (EI): m/z [M]+ calcd for C26H18Cl2O4S: 496.0303; found:
496.0286.
[3-(Naphthalen-2-yl)thiophene-2,5-diyl]bis[(4-chlorophe-
nyl)methanone] (3r)
White solid; yield: 0.326 g (67%); mp 152–153 °C.
IR (KBr): 1642, 1585, 1537, 1399, 1263, 1207, 1119, 1012 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.10–8.02 (m, 3 H, HAr, CH),
7.92 (s, 1 H, HAr), 7.83 (s, 2 H, HAr), 7.77 (d, J = 8.4 Hz, 1 H, HAr),
7.72–7.66 (m, 4 H, HAr), 7.52–7.43 (m, 3 H, HAr), 7.30 (d, J = 8.0
Hz, 2 H, HAr).
13C NMR (100 MHz, DMSO-d6): δ = 188.6, 186.4, 145.8, 144.4,
141.7, 138.2, 136.7, 135.1, 135.0, 132.4, 132.1, 131.3, 131.2, 131.1,
129.0, 128.5, 128.4, 128.0, 127.8, 127.4, 126.7 (2), 126.6 (6), 126.5.
HRMS (EI): m/z [M]+ calcd for C28H16Cl2O2S: 486.0248; found:
486.0218.
[3-(Naphthalen-2-yl)thiophene-2,5-diyl]bis[(4-bromophe-
nyl)methanone] (3s)
White solid; yield: 0.396 g (69%); mp 149–150 °C.
IR (KBr): 1648, 1588, 1526, 1462, 1366, 1260, 1174, 1041 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 8.07 (s, 1 H, CH), 7.96 (d,
J = 8.4 Hz, 2 H, HAr), 7.92 (s, 1 H, HAr), 7.83 (d, J = 8.4 Hz, 4 H,
HAr), 7.77 (d, J = 8.4 Hz, 1 H, HAr), 7.60 (d, J = 8.4 Hz, 2 H, HAr),
7.51–7.49 (m, 2 H, HAr), 7.44 (d, J = 8.4 Hz, 3 H, HAr).
13C NMR (100 MHz, DMSO-d6): δ = 189.2, 187.0, 146.3, 144.9,
142.1, 137.2, 135.9, 135.8, 132.9, 132.6, 132.5, 131.9, 131.8, 131.8,
131.7, 129.0, 128.5, 128.3, 127.9, 127.8, 127.2, 127.1, 127.0.
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HRMS (EI): m/z [M]+ calcd for C28H16Br2O2S: 573.9238; found:
573.9266.
Acknowledgment
(12) (a) Moghaddam, F. M.; Zali-Boinee, H. Tetrahedron Lett.
2003, 44, 6253. (b) Mohan, C.; Kumar, V.; Mahajan, M. P.
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We are grateful for the financial support from the National Science
Foundation of China (21072163, 21232004, 21272095, and
21102124), PAPD of Jiangsu Higher Education Institutions, the
NSF of Jiangsu Education Committee (11KJB150016), Jiangsu Sci-
ence and Technology Support Program (No. BE2011045), the Qing
Lan Project (12QLG006), Graduate Education Innovation Project
of Jiangsu Province (No. CXZZ13_0975), and Graduate Science
Research Foundation of Jiangsu Normal University (No.
2013YYB119).
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J. Sulfur Chem. 2008, 29, 575.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 3392–3398

3398
H.-W. Xu et al.
PAPER
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2547.
(21) Single-crystal growth was carried out in co-solvent of EtOH
and DMF at r.t. Crystal data for 3i: C25H16Cl2O2S, crystal
dimension 0.30 × 0.26 × 0.12 mm, Triclinic, space group
P1, a = 8.4815(7) Å, b = 11.1246(11) Å, c = 11.7946(9) Å,
α = 105.568(2)°, β = 92.2080(10)°, γ = 101.557(2)°,
V = 1045.26(16) Å3, Mr = 451.34, Z = 2, λ = 0.71073 Å, μ
(MoKα) = 0.431 mm–1, F(000) = 464, R1 = 0.0544,
wR2 = 0.1256.
Synthesis 2013, 45, 3392–3398
© Georg Thieme Verlag Stuttgart · New York