Trithiocarbonate Anion as a Sulfur Source for the Synthesis of 2,5-Disubstituted Thiophenes and 2-Substituted Benzo[ b]thiophenes

Article abstract of DOI:10.1021/acs.joc.0c01516

The trithiocarbonate anion (CS32-) was generated in situ from CS2 and KOH in dimethyl sulfoxide by a simple method and used as a novel synthetic equivalent of the S2- synthon for the synthesis of 2,5-disubstituted thiophenes from 1,3-butadiynes. Additionally, this system was employed for the metal-free synthesis of 2-substituted benzo[b]thiophenes from 2-haloalkynyl (hetero)arenes. These compounds were obtained from a cheap and readily available sulfur source in moderate to good yields, with good functional group tolerance.

Full text of DOI:10.1021/acs.joc.0c01516

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Article
Trithiocarbonate anion as a sulfur source for the synthesis of 2,5-
disubstituted thiophenes and 2-substituted benzo[b]thiophenes
Douglas Bernardo Paixão, Daniel S Rampon, Helena D Salles,
Eduardo G. O. Soares, Filipe N. Bilheri, and Paulo H Schneider
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01516 • Publication Date (Web): 17 Sep 2020
Downloaded from pubs.acs.org on September 19, 2020
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Trithiocarbonate anion as a sulfur source for the synthesis of 2,5-disubstituted
thiophenes and 2-substituted benzo[b]thiophenes
Douglas B. Paixão,a Daniel S. Rampon,b Helena D. Salles,a Eduardo G. O. Soares,a Filipe N. Bilheri,a
Paulo H. Schneidera*
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a Instituto de Química, Departamento de Química Orgânica, Universidade Federal do Rio Grande do Sul
(UFRGS), P.O. Box 15003, 91501-970, Porto Alegre-RS, Brazil.
Corresponding Author: Paulo Henrique Schneider, E-mail: paulos@iq.ufrgs.br
b Laboratório de Polímeros e Catálise (LAPOCA), Departamento de Química, Universidade Federal do
Paraná (UFPR), P.O. Box 19061, 81531-990, Curitiba-PR, Brazil.
2-
ABSTRACT: The trithiocarbonate anion (CS3 ) was generated in situ from CS2 and KOH in DMSO by a
simple method and used as a novel synthetic equivalent of the S2- synthon for the synthesis of 2,5-
disubstituted thiophenes from 1,3-butadiynes. Additionally, this system was employed for the metal-free
synthesis of 2-substituted benzo[b]thiophenes from 2-haloalkynyl (hetero)arenes. These compounds were
obtained from a cheap and readily available sulfur source in moderate to good yields, with good functional
group tolerance.
INTRODUCTION
Thiophenes and benzo[b]thiophenes are classes of compounds of increasing interest, since they
present several uses in the fields of biochemistry,1 physical organic chemistry,2 materials chemistry3 and
organic synthesis.4 In particular, 2,5-diarylthiophenes have been reported as pharmacological agents and in
the core structure of liquid crystals,5,6 semiconducting oligothiophenes and polythiophenes,7,8 organic light-
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emitting diodes (OLEDs)9 and organic field-effect transistors (OFETs).10 Furthermore, the electron-rich
2,5-diarylthiophene scaffold has been efficiently applied as a hole-transporting layer in perovskite-based
solar cells.11 Likewise, the π-extended benzo[b]thiophenes show relevant pharmacological applications12
and promising properties as semiconducting materials for optoelectronic devices.13
9
The outstanding achievements related to these heterocycles inspired the development of various
reactions for the synthesis of thiophenes and benzo[b]thiophenes, which include intramolecular
condensations14 or nucleophilic additions,15 electrophile-promoted nucleophilic cyclizations,16 radical
cyclizations,17 or cross-coupling reactions.18 With respect to 2,5-disubstituted thiophenes, the addition of
nucleophilic sulfur sources to 1,3-butadiynes is straightforward, since few synthetic steps are employed
using reagents with recognized stability and easy access,19 and the already described methods used NaHS
(Scheme 1a),15a Na2S.9 H2O (Scheme 1b),15d or elemental sulfur in basic media (Scheme 1c).17b These
compounds have also been subject of recent exciting developments, since they can be synthesized from
internal alkynes17e and butenes.17f On the other hand, 2-haloalkynyl benzenes could also be converted to 2-
substituted benzo[b]thiophenes with the use of nucleophilic sulfur sources under metal-free20 or transition-
metal catalyzed conditions.21
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Scheme 1. Previous synthesis of 2,5-disubstituted thiophenes from 1,3-butadiynes.
(a)
NaHS (3.0 equiv.)
R1
R1
DMF
r.t. or 80 ºC
1_48 h
(b)
R1
Na2S.9H2O (2.0 equiv.)
KOH (30 mol%)
R1
DMSO
80 ºC, 4.0 h
R
R
S
(c)
S8 (3.0 equiv.)
t-BuONa (6.0 equiv.)
R1
R1
DMF/t-BuOH
r.t. or 80 ºC
5.0 h
R1 = aryl
R2 = aryl or alkyl
This Work:
CS2 (4.0 equiv.)
KOH (4.0 equiv.)
H2O (4.0 equiv.)
R2
R2
DMSO
50_100 ºC
2.5_24 h
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With this in mind and considering our continuous interest in the synthesis of organochalcogen
compounds,22 herein we report the use of the trithiocarbonate anion (CS3 ) as an inexpensive synthetic
equivalent of the S2- synthon for metal-free cyclization reactions of 1,3-butadiynes and 2-haloalkynyl
benzenes, in order to prepare 2,5-disubstituted thiophenes and 2-substituted benzo[b]thiophenes,
respectively. Salts of CS32- (M2CS3) can be prepared and isolated;23 however, in most synthetic organic
applications, CS32- is generated in situ by mixing a base and CS2 in polar aprotic solvents,24 and successfully
applied for the synthesis of transition metal complexes25 (Scheme 2a) or dialkyl26 and diaryl27
trithiocarbonates (Scheme 2c), as an efficient method for constructing the valuable thiocarbonyl group.28
In fact, the synthesis of thieno[2,3-b]quinoxalines29 is the only example where the trithiocarbonate anion is
used as a synthetic equivalent of the S2- synthon (Scheme 2b) in cyclization reactions. Therefore, there are
still many opportunities for the sophisticated use of this cheap in situ prepared reagent.
2-
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Scheme 2. Synthetic applications of the trithiocarbonate anion.
a) Synthesis of transition metal complexes
b) Synthesis of thieno[2,3-b]quinoxalines
Br
S
Ni(OAc)2
2-
N
N
R1
N
N
S
S
S
S
S
S
K2PtCl4
R
Br
S
S
M
1
S
trithiocarbonate
anion
PdCl2
R1 = alkyl or aryl
M = Ni, Pt or Pd
Could be a synthetic
equivalent of S2- synthon
in other
c) Synthesis of dialkyl or diaryl trithiocarbonates
This Work
S
R2 Y
2
cyclizations?
R2
R2
R1
S
S
S
S
R1
R1
R1
S
R2 = alkyl
R3 = aryl
Y = Br or I
Cu(I)
or
or
S
R1
R3
R3
R1
R1 = alkyl or aryl
R3 Y
2
S
X
X = F or Br
RESULTS AND DISCUSSION
As shown in Table 1, 1,4-diphenyl-1,3-butadiyne (1a) was chosen as the model substrate to optimize
the reaction conditions. The purpose of these initial investigations was the previous in situ preparation of
2-
the CS3 anion (dark red colour solution)30 by the combination of KOH and CS2 in DMSO and the
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subsequent addition of 1a, in other words, to evaluate the use of this anion as a synthetic equivalent of the
S2- synthon for the cyclization process and the resulting formation of 2a (2,5-diphenylthiophene).
Considering that each nucleophilic addition at the C-C triple bond is followed by a protonation step, a
known amount of water was added along with 1a in these reactions, since it is a more acidic proton source
than DMSO.31
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Initially, the stoichiometry of KOH and CS2 at 70 oC in DMSO was evaluated (Table 1, entries 1-
10). The desired product, 2a, was isolated in only 30% yield after 24 h of reaction when 1.0 equivalent of
KOH and CS2 were used (Table 1, entry 1), and the remaining unreacted starting material, 1a, was observed
without any other side products. It is important to note that under these conditions the formation of 2,5-
diphenylfuran was not detected,15d which suggests that the hydroxyl anion acts directly in the production of
the CS32- anion. The use of 2.0 equivalents of KOH and CS2 gave a similar yield of 2a (Table 1, entry 2);
however, the yield increased to 67% when 4.0 equivalents of KOH and CS2 were used during only 2.5 h of
reaction (Table 1, entry 3), and a longer reaction time did not enhance the result (Table 1, entry 4). Based
on recent studies,15 the reaction yield could be improved with a higher nucleophile concentration, and this
effect was indeed observed with entry 4. However, this effect was not observed when 8.0 equivalents of
KOH and CS2 were used (Table 1, entry 5). The role of the relative stoichiometry between KOH and CS2
was also examined, and it was observed that when excess of KOH (Table 1, entries 6 and 7) or CS2 (Table
1, entry 8) were employed, the yields of 2a did not change. Product formation was not observed with a
catalytic amount of KOH (Table 1, entry 9) or when 0.5 equivalent of KOH and CS2 were used (Table 1,
entry 10). A higher yield of 2a was not observed when CS32- was generated during a longer reaction time
(Table 1, entry 11).
Table 1. Stoichiometry optimization of KOH and CS2 for the synthesis of 2a.
Ph
Ph
S
KOH (equiv.)
1a
CS2
Ph
Ph
S
S
S
2a
DMSO
DMSO
(equiv.)
r.t., 0.25 h
H2O (2.0 equiv.)
70 ºC
dark red
solution
Time (h)
Entrya
KOH (equiv.)
CS2 (equiv.)
Time (h)
24
Yield (%)c
1
2
3
4
1.0
2.0
4.0
4.0
1.0
2.0
4.0
4.0
30
34
67
66
24
2.5
5.0
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6.0
8.0
4.0
0.1
0.5
4.0
8.0
4.0
4.0
8.0
4.0
0.5
4.0
2.5
2.5
2.5
2.5
2.5
5.0
2.5
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62
0
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11b
0
66
a
Reaction conditions: Argon atmosphere, CS2 (equiv.), KOH (equiv.), DMSO (2.0 mL), room
temperature, 0.25 h; then 1a (0.3 mmol) and H2O (2.0 equiv., 0.6 mmol) for the respective reaction times
indicated in table 1 at 70 ºC. b Reaction conditions: Argon atmosphere, CS2 (4.0 equiv.), KOH (4.0 equiv.),
DMSO (2.0 mL), room temperature, 1 h; then 1a (0.3 mmol) and H2O (2.0 equiv., 0.6 mmol) for 2.5 h at
70 ºC. c Isolated yields.
With the optimized stoichiometry of KOH, CS2, and 1a in hand (Table 1, entry 3), other reaction
parameters were studied, such as time, temperature, and the amount of water (Table 2). A slightly higher
yield of 2a, with an increase in the amount of water to 4.0 equivalents, was obtained (Table 2, entry 1).
Additionally, when the temperature was raised to 90 ºC or 120 ºC, the reaction yields of 2a decreased (Table
2, entries 2 and 3). Surprisingly, the desired product was isolated in 78% yield when the reaction
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temperature was maintained at 50 C for 5.0 h (Table 2, entry 4), but only 5% yield after 5.0 h (Table 2,
entry 5) or 38% yield after 24 h (Table 2, entry 6) was obtained at room temperature. Reaction times shorter
or longer than 5.0 h did not significantly change the yields at the temperature of 50 ºC (Table 2, entries 7
and 8). An additional experiment without water gave product 2a in 60% yield (Table 2, entry 9), which
indicates that DMSO could also act as a proton donor in this methodology. These results show that the
addition of water is required to ensure a good yield of 2a; however, the increase in the amount of water up
to 8.0 equivalents was not efficient to further enhance the results (Table 2, entry 10).
Table 2. Optimization of the reaction time, temperature, and amount of water for the synthesis of
2a.
Ph
Ph
S
KOH (4.0 equiv.)
1a
CS2
Ph
Ph
S
S
S
2a
DMSO
r.t., 0.25 h
DMSO
H2O (equiv.)
(4.0 equiv.)
dark red
solution
Temperature (ºC)
Time (h)
Entrya
H2O (equiv.)
4.0
Time (h)
2.5
T (oC)
Yield (%)c
1
70
70
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3
4.0
4.0
4.0
4.0
4.0
4.0
4.0
-
2.5
2.5
5.0
5.0
24
90
120
50
62
56
78
5
4b
5
r.t.
r.t.
50
6
38
75
78
60
78
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4.0
6.0
5.0
5.0
8
50
9
50
10
8.0
50
a Reaction conditions: Argon atmosphere, CS2 (4.0 equiv.), KOH (4.0 equiv.), DMSO (2.0 mL),
room temperature, 0.25 h; then 1a (0.3 mmol) and H2O (equiv.) at the temperatures and reaction
times indicated in Table 2. b The reaction progress was monitored by TLC. c Isolated yields.
In the next step, different bases, solvents, and additives were investigated (Table 3). Starting with
bases of MOH type (M = Li, Na, Cs), it was observed that CsOH.H2O provided the best results, probably
due to its higher solubility and the best cation solvation in DMSO, which consequently increased the
system’s basicity (Table 3, entries 1-3).32 In subsequent attempts to improve the reaction yields, different
bases were also applied (Table 3, entries 4-18). Interesting, t-BuOK furnished 80% of product 2a (Table 3,
entry 5), in contrast to its lithium counterparts, which gave 66% (Table 3, entry 4). Furthermore, bases with
low solubility in DMSO were ineffective (Table 3, entries 6-9), and considering the moderate yields of 2a
with milder and more soluble bases in this solvent, such as Cs2CO3 and K3PO4 (Table 3, entries 10 and 11),
it is clearly demonstrated that the base solubility is also an important issue in this methodology. Since KOH,
CsOH.H2O, and t-BuOK produced product 2a in similar yields, KOH was chosen for the next experiments,
considering its lower cost, ready availability, and easier handling. Further experiments also showed that the
reaction was faster when 10 mol % of dibenzo-18-crown-6 was used as an additive (Table 3, entry 12),
which suggests that its recognized binding affinity to the potassium cation33 played a role in this system.
However, the reaction yield of 2a did not improve. Finally, solvent screening (Table 3, entries 13-18)
demonstrated that only DMF can be used as an alternative solvent for the developed cyclization, but in
modest yield (Table 3, entry 13). Gratifyingly, a gram scale reaction of 1a (5 mmol, 1.01 g) and KOH/CS2
system afforded the desired product 2a in 77% yield (0.91 g), which demonstrates the practical utility of
the method (Scheme 3).
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Table 3. Optimization of bases and solvents for the synthesis of 2a.
4
5
6
7
8
9
Ph
Ph
S
Base (4.0 equiv.)
1a
CS2
Ph
Ph
S
S
S
Solvent
r.t., 0.25 h
Solvent
(4.0 equiv.)
2a
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H2O (4.0 equiv.)
50 ºC
5 h
Entrya
Base
Solvent
Time (h)
Yield (%)b
1
2
LiOH.H2O
NaOH
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
5
5
5
5
5
5
5
5
5
5
5
2
5
5
5
5
5
5
32
48
80
66
80
0
3
CsOH.H2O
t-BuOLi
t-BuOK
Ca(OH)2
Ba(OH)2
Na2CO3
K2CO3
Cs2CO3
K3PO4
KOH
4
5
6
7
0
8
0
9
0
10
11
12c
13
14
15
16
17
18
62
44
72
34
0
KOH
KOH
MeCN
THF
KOH
0
KOH
DCM
0
KOH
Toluene
0
KOH
EtOH
0
a Reaction conditions: Argon atmosphere, CS2 (4.0 equiv.), KOH (4.0 equiv.), DMSO (2.0
mL), room temperature, 0.25 h; then 1a (0.3 mmol) and H2O (4.0 equiv.) at 50 ºC for the
reaction times indicated in table 3. b Isolated yields. c 10 mol% of dibenzo-18-crown-6. The
reaction progress was monitored by TLC.
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Scheme 3. Gram Scale Synthesis of 2a.
4
5
6
7
8
Ph
Ph
1a
S
KOH (4.0 equiv.)
1.01 g, 5.0 mmol
CS2
Ph
Ph
S
S
S
2a
9
DMSO
r.t., 0.25 h
DMSO
H2O (4.0 equiv.)
50 ºC
(4.0 equiv.)
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dark red
solution
77% (0.91 g)
5 h
Reaction conditions: CS2 (4.0 equiv.), KOH (4.0 equiv.), DMSO (35 mL), room temperature, 0.25 h; then, 1a (5.0 mmol) and
H2O (4 equiv.) at 50 ºC for 5.0 h under argon atmosphere.
In order to evaluate the hydrogen source in the protonation step that follows the nucleophilic
additions at the C-C triple bond, two controlled experiments were carried out (Scheme 4b,c) with deuterated
reagents (D2O or DMSO-d6). The deuterium incorporation into 2a was monitored by the signals between
7.31 ppm and 7.24 ppm (see the Supporting Information for details), relative to the hydrogens highlighted
in blue (Scheme 4a). The base t-BuOK was used in these two reactions since no hydrogen source other than
DMSO (or DMSO-d6) or H2O (or D2O) became available under the conditions. In both experiments, DMSO
(or DMSO-d6) was the major hydrogen source, and a similar deuterium or hydrogen incorporation
(experiment A, 5.5%; experiment B, 6.5%) from D2O or H2O was observed, respectively, which suggests
the transient deprotonation of the solvent under these cyclization conditions.20c, 34b In this way, the addition
of H2O in the system is not directly associated to the protonation step, but is required for the slight increase
in K2CS3 solubility35 and probably is related to a known enhance in reactivity of cyclizations conducted in
DMSO/H2O mixtures,34b where the presence of H2O may contribute for significant polar interactions able
to stabilize the reaction’s transition state.
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Scheme 4. Controlled deuterium or hydrogen incorporation experiments.
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5
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a Reaction conditions: Argon atmosphere, CS2 (4 equiv.), t-BuOK (4 equiv.), DMSO (2.0 mL), room temperature, 0.25 h; then 1a
(0.3 mmol) and D2O (4 equiv.) for 5.0 h at 50 ºC. b Reaction conditions: Argon atmosphere, CS2 (4 equiv.), t-BuOK (4 equiv.),
DMSO-d6 (2.0 mL), room temperature, 0.25 h; then 1a (0.3 mmol) and H2O (4 equiv.) for 5.0 h at 50 ºC. c Isolated yield.
After identifying the optimal reaction conditions, the scope and limitations of this reaction were
evaluated with a range of different 1,3-butadiynes for the synthesis of several 2,5-disubstituted thiophenes
(Scheme 5). The target compound, 2b, could not be isolated when the reaction was developed at 50 ºC, and
an inseparable mixture of the respective starting material (1b) and 2b was observed. Although the 1,3-
butadiyne, 1b, was completely consumed at 80 ºC after only 3.5 h, and the desired product, 2b, was isolated
in 74% yield. It was reported that 1,3-diarylbutadiynes have limited solubility in polar aprotic solvents or
in mixtures of polar protic and aprotic solvents,17a and that could also be an important factor influencing
the reaction yields in our system when the molecular structure of the starting material is changed. To avoid
º
any related issue, the next reactions were carried out at 80 C and carefully followed by thin layer
chromatography. Fortunately, product 2c was isolated in comparable yields when the reaction was
performed at 50 ºC and 80 ºC. Additionally, both products with either electron-donating (2d, 2f, 2i, 2h, 2g,
2k, 2l) or electron-withdrawing (2c, 2j, 2m) groups on the benzene ring were obtained in moderate to good
yields, and some of these were unsymmetrical 2,5-diarylthiophenes (2j and 2k). Sterically hindered o-
substituted compounds (2f, 2g, 2l) were also obtained in moderate to low yields after longer reaction times.
The reaction also worked well with heteroaromatic 1,3-butadiynes for the synthesis of 2e in 71% yield after
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4.0 h of reaction; however, only a modest yield of the expected compounds, 2n and 2o, containing vinyl or
4
5
alkyl groups at position 2 and 5, was obtained even at higher temperatures.
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7
8
Scheme 5. Substrate scope of 2,5-disubstituted thiophenesa,b.
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R
R
S
KOH (4.0 equiv.)
1
CS2
R
R
S
S
S
2
DMSO
r.t., 0.25 h
DMSO
(4.0 equiv.)
H2O (4.0 equiv.)
Temperature (ºC)
Time (h)
dark red
solution
S
S
S
Me
Me
F
F
2a
78% (50 ºC, 5.0 h)
2c
2b
70% (50 ºC, 5.0 h)
70% (80 ºC, 2.5 h)
74% (80 ºC, 3.5 h)
Me
Me
S
S
S
S
C5H11
S
C5H11
2f
2d
2e
60% (80 ºC, 6.0 h)
80% (80 ºC, 4.0 h)
71% (80 ºC, 4.0 h)
OMe
MeO
MeO
OMe
S
S
S
MeO
OMe
OMe
2i
2h
2g
42% (80 ºC, 6.0 h)
71% (80 ºC, 5.0 h)
65% (80 ºC, 6.0 h)
Me
Me
S
S
S
MeO
NC
MeO
2j
2k
2l
52% (80 ºC, 5.0 h)
75% (80 ºC, 5.0 h)
21% (80 ºC, 24 h)
F3C
CF3
C7H15
C7H15
S
S
S
2nc
2m
2oc
F3C
CF3
60% (80 ºC, 5.0 h)
44% (100 ºC, 10 h)
40% (100 ºC, 5.0 h)
a Reaction conditions: Argon atmosphere, CS2 (4.0 equiv.), KOH (4.0 equiv.), DMSO (2.0 mL), room temperature, 0.25 h; then
b
c
1 (0.25 mmol) and H2O (4.0 equiv.), at temperatures and reaction times indicated in scheme 5. Isolated yields. Reaction
performed in a sealed Schlenk tube.
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To expand the applicability of the trithiocarbonate anion as a synthetic equivalent of the S2- synthon
1
2
3
4
for other cyclizations, the synthesis of 2-substituted benzo[b]thiophenes was also evaluated. Some valuable
metal-catalyzed methods for the preparation of these compounds from 2-haloalkynyl benzenes were
developed, usually employing catalytic amounts of a transition metal and sulfur sources such as
Na2S.9H2O,21a, 21e thiourea,21c potassium thioacetate21f, 21g or xanthate.21d, 21h In addition, only few metal-
free successful methodologies were developed,20 despite of the many recognized advantages of this kind of
approach.34 Notably, the trithiocarbonate anion was successfully exploited for the metal-free synthesis of
5a from 3a or 4a (see Supporting Information, Table S1) and extended to the synthesis compounds 5b-i,
obtained from 2-bromo or 2-fluoroalkynyl (hetero)arenes in modest to good yields (Scheme 6). In general,
it was observed that the reaction yield could be improved by increasing the reaction temperature or by the
use of a fluorine substituent (4a-4i), which supports an SNAr mechanism. Moreover, a benzo[b]thiophene
substituted with an alkyl group at position 2 (5d) was also synthesized. Unfortunately, the attempts to
synthesize 5i were not successful, and the starting material was recovered under this condition, which
indicates a significant role of steric hindrance in the ring closure step.
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Scheme 6. Substrate scope of 2-substituted benzo[b]thiophenesa,b.
R
7
8
9
X
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3a-3d
(X = Br)
(X = F)
S
4a 4i
-
KOH (4.0 equiv.)
CS2
R
S
S
DMSO
r.t., 0.25 h
DMSO
S
(4.0 equiv.)
H2O (2.0 equiv.)
Temperature (ºC)
24 h
dark red
solution
5
Me
F
S
S
S
5b
5a
5c
X = F, 76% (100 oC), 76% (120 oC)
X = Br, 40% (100 oC)
X = F, 93% (100 oC)
X = Br, 68% (100 oC)
X = Br, 90% (120 oC)
X = F, 45% (100 oC), 61% (120 oC)
X = Br, 45% (120 oC)c
X = Br, 35% (120 oC)
n-Bu
Cl
S
S
S
S
5d
5e
5f
X = F, 21% (120 oC)
X = Br, 17% (120 oC)c
X = F, 41% (120 oC)
X = F, 61% (100 oC)
Me
S
N
S
S
S
n-Bu
5h
5i
5g
X = F, 66% (100 oC)
X = F, 51% (100 oC)
X = F, 0% (100 oC)
X = F, 0% (120 oC)
a Reaction conditions: Argon atmosphere, sealed Schlenk tube, CS2 (4.0 equiv.), KOH (4.0 equiv.), DMSO (2.0 mL), room
b
temperature, 0.25 h; then 3 or 4 (0.25 mmol) and H2O (2.0 equiv.) for 24 h at temperatures indicated in scheme 6. Isolated
yields. c 8.0 Equivalents of KOH and CS2.
2-
Since there have been no reports of CS3 involvement in nucleophilic addition to the C-C triple
bond or in an SNAr reaction, we proposed plausible mechanisms for the developed cyclizations (Scheme
2-
7). For 2,5-disubstituted thiophene synthesis (Scheme 7a), the in situ generated CS3 promotes a
nucleophilic attack to the C-C triple bond of the 1,3-butadiyne 1 followed by transient solvent
deprotonation, suggested by deuterated experiments (Scheme 4). After the formation of intermediate A, the
loss of CS2 generates intermediate B, a (Z)-enynethiolate which is able to undergo a 5-endo-dig cyclization
followed by transient solvent deprotonation, producing the compound 2. As previously described,20c, 20d, 21h
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2-fluoroalkynyl (hetero)arenes can undergo SNAr reactions followed by a 5-endo-dig cyclization. In this
4
5
2-
way, we propose the formation of intermediate C from CS3 and compound 3 via an SNAr mechanism
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7
8
(Scheme 7b), which, after the loss of CS2, produces intermediate D. The expected product 5 could be
produced by a sequential 5-endo-dig cyclization on this intermediate.
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Scheme 7. Proposed reaction mechanisms.
(a) 2,5-dissubstituted thiophenes
S
KOH
CS2
S
S
DMSO
R
S
H
S
1
S
S
R
R
A
S
S
R
H
-CS2
S
O
R
S
H
H
H
5-endo-dig
(or H2O)
H
O
R
R
S
S
R
2
B
(b) 2-substituted benzo[b]thiophenes
S
KOH
CS2
S
F
S
R
DMSO
R
R
S
F
SNAr
S
S
C
S
- F
S
S
3
S
S
S
-CS2
O
H
R
S
H
5-endo-dig
(or H2O)
R
S
S
5
D
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CONCLUSIONS
4
5
6
7
8
9
In conclusion, we applied the trithiocarbonate anion, generated in situ, as a cheap and readily
available synthetic equivalent of the S2- synthon in cyclization reactions to afford 2,5-disubstituted
thiophenes and 2-substituted benzo[b]thiophenes under mild and metal-free reaction conditions, with
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1
transient solvent deprotonation confirmed by H-NMR experiments. Even if in the first moment the
molecular structure of CS3 may not seem to be an adequate synthetic equivalent of S2- synthon, the loss of
2-
a CS2 molecule in A and C (Scheme 7) probably is the key step to generate reactive thiolates B and D
(Scheme 7), whose C-S disconnections lead to the S2- synthon. Furthermore, this work may be the first
report of CS32- involved in a nucleophilic addition to the C-C triple bond and the SNAr reaction pathway,
which may offer possibilities to apply the simple KOH/CS2 system in sulfuration/cyclization reactions for
the synthesis of other compound classes containing the thiophene nucleous.
EXPERIMENTAL SECTION
General Information
Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further
purification. DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), MeCN (acetonitrile), THF
(tetrahydrofuran), DCM (dichloromethane), toluene and ethanol were purified and dried under classical
methods.36 Solvents used in liquid-liquid extraction and as eluents for chromatographic purification were
distilled before use. The reactions were monitored by thin-layer chromatography (TLC) using silica gel 60
F254 aluminum sheets, and the visualization of the spots were done under UV light (254 nm), stained with
iodine, or by the mixture between 5% of vanillin in 10% of H2SO4 and heat as developing agents. Column
chromatography was performed on silica gel (230-400 mesh). 1H NMR, 19F{1H} NMR and 13C{1H} NMR
were recorded on 400 MHz spectrometer Varian Inova 400 and Bruker Avance 400. Chemical shifts (δ)
are expressed in ppm downfield from TMS as internal standard in spectra made in CDCl3. Coupling
constants are reported in Hz. Hydrogen coupling patterns are described as singlet (s), doublet (d), triplet (t),
quartet (q), quintet (quint), doublet of doublets (dd), doublet of doublet of doublets (ddd), doublet of triplets
(dt), multiplet (m) and broad signal (bs) as soon as appears. Melting points were recorded on a Buchi
Melting Point M-560 equipment. High resolution mass spectra (HRMS) were recorded on a Micromass Q-
Tof spectrometer, using electrospray ionization (ESI).
Starting Materials. Substrates 1a-1i,37 1j,38 1k,38 1l,37 1m,37 1n,39 1o,39 3a-3d,21c 4a-4i21c were prepared
according to the literature.
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2-Butyl-5-((2-fluorophenyl)ethynyl)thiophene (4g). The product was obtained by column chromatography
(hexane) as a yellow oil (233 mg, 60% yield). 1H NMR (400 MHz, CDCl3): δ 7.48 (td, J = 7.4, 1.8 Hz, 1H),
7.34 – 7.26 (m, 1H), 7.16 – 7.06 (m, 3H), 6.68 (d, J = 3.6 Hz, 1H), 2.80 (t, J = 7.6 Hz, 2H), 1.72 – 1.61 (m,
2H), 1.47 – 1.34 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.3 (d, 1JC–F
=
9
251.7 Hz), 148.8, 133.1 (d, 4JC–F = 1.0 Hz), 132.4, 129.8 (d, 3JC–F = 7.9 Hz), 124.3, 123.9 (d, 3JC–F = 3.7
Hz), 120.0, 115.5 (d, 2JC–F = 20.9 Hz), 111.9 (d, 2JC–F = 15.7 Hz), 88.1 (d, 3JC–F = 3.2 Hz), 85.6, 33.6, 29.9,
22.1, 13.8. HRMS (ESI) m/z: [M + Na]+ calcd for C16H15FSNa 281.0771; found 281.0779.
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Gram Scale Synthesis of 2a. In a dried schlenk tube under argon atmosphere, DMSO (35 mL), CS2 (1.2
mL, 20 mmol, 4 equiv) and KOH powder (1.12 g, 20 mmol, 4 equiv) were added. The mixture was stirred
at room temperature for 15 minutes, and then became a dark red solution. After this time, 1a (1.01 g, 5
mmol) and H2O (0.36 mL, 20 mmol, 4 equiv) were added. The reaction mixture was stirred under argon
atmosphere at 50 ºC (temperature of the oil bath) for 5 h. Then, the reaction was cooled to room temperature,
and ethyl acetate (120 mL) was added. The mixture was washed with saturated aqueous NaCl solution (3x
80 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced
pressure. The crude was further purified by column chromatography on silica gel (hexane) to give the
desired product 2a in 77% yield (0.91 g).
General Procedure for the Synthesis of 2,5-dissubstituted thiophenes 2a-o. In a dried schlenk tube
under argon atmosphere, DMSO (2 mL), CS2 (60 µL, 1 mmol, 4 equiv) and KOH powder (56 mg, 1 mmol,
4 equiv) were added. The mixture was stirred at room temperature for 15 minutes, and then became a dark
red solution. After this time, the corresponding 1,4-dissubstituted-1,3-diyne 1 (0.25 mmol) and H2O (18
µL, 1 mmol, 4 equiv) were added. Under argon atmosphere, the reaction mixture was stirred and heated in
an oil bath (50 ºC for 2a, 80 ºC for 2b-m and 100 ºC for 2n and 2o) for the time indicated on the scheme 5.
Then, the reaction was cooled to room temperature, and ethyl acetate (60 mL) was added. The mixture was
washed with saturated aqueous NaCl solution (3x 30 mL). The organic layer was dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure. The crude was further purified by column
chromatography on silica gel to give the desired 2,5-dissubstituted thiophenes 2a-o.
2,5-Diphenylthiophene (2a).17b The product was isolated by column chromatography (hexane) as a white
solid (46 mg, 78% yield); mp 149–151 ºC. 1H NMR (400 MHz, CDCl3): δ 7.64 – 7.60 (m, 4H), 7.40 – 7.34
(m, 4H), 7.31 – 7.24 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ 143.6, 134.3, 128.9, 127.5, 125.6, 124.0.
2,5-Di-p-tolylthiophene (2b).17b The product was isolated by column chromatography (hexane) as a white
solid (49 mg, 74% yield); mp 177–179 ºC. 1H NMR (400 MHz, CDCl3): δ 7.51 (d, J = 8.2 Hz, 4H), 7.21
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(s, 2H), 7.18 (d, J = 8.2 Hz, 4H), 2.36 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 143.2, 137.2, 131.6,
4
5
129.5, 125.5, 123.4, 21.2.
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8
9
2,5-Bis(4-fluorophenyl)thiophene (2c).17b The product was isolated by column chromatography (hexane)
as a white solid (48 mg, 70% yield); mp 177–179 ºC. 1H NMR (400 MHz, CDCl3): δ 7.60 – 7.54 (m, 4H),
7.19 (s, 2H), 7.11 – 7.05 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.3 (d, 1JC–F = 247.5 Hz), 142.5,
130.5 (d, 4JC–F = 3.5 Hz), 127.3 (d, 3JC–F = 8.0 Hz), 124.0, 115.9 (d, 2JC–F = 21.9 Hz).
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2,5-Bis(4-pentylphenyl)thiophene (2d).17b The product was isolated by column chromatography (hexane)
as a white solid (75 mg, 80% yield); mp 142–144 ºC. 1H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 8.1 Hz,
4H), 7.21 (s, 2H), 7.17 (d, J = 8.1 Hz, 4H), 2.64 – 2.57 (m, 4H), 1.69 – 1.57 (m, 4H), 1.38 – 1.29 (m, 8H),
13
0.90 (t, J = 6.9 Hz, 6H). C{1H} NMR (100 MHz, CDCl3): δ 143.2, 142.3, 131.8, 128.9, 125.45, 123.4,
35.6, 31.5, 31.1, 22.5, 14.0.
2,2’:5’,2”-Terthiophene (2e).17b The product was isolated by column chromatography (hexane) as a green
solid (44 mg, 71% yield); mp 93–95 ºC. 1H NMR (400 MHz, CDCl3): δ 7.21 (dd, J = 5.1, 1.1 Hz, 2H), 7.17
(dd, J = 3.6, 1.1 Hz, 2H), 7.07 (s, 2H), 7.02 (dd, J = 5.1, 3.6 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ
137.1, 136.2, 127.9, 124.5, 124.3, 123.7.
2,5-Di(o-tolyl)thiophene (2f).40 The product was isolated by column chromatography (hexane) as a
colorless oil (40 mg, 60% yield). 1H NMR (400 MHz, CDCl3): δ 7.53 – 7.42 (m, 2H), 7.33 – 7.18 (m, 6H),
7.05 (s, 2H), 2.49 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 142.9, 135.9, 134.1, 130.8, 130.3, 127.7,
126.4, 125.9, 21.3.
2,5-Bis(2-methoxyphenyl)thiophene (2g).41 The product was isolated by column chromatography (hexane
1
90:10 ethyl acetate) as a purple solid (48 mg, 65% yield); mp 90–92 ºC. H NMR (400 MHz, CDCl3): δ
7.60 (dd, J = 7.6, 1.6 Hz, 2H), 7.41 (s, 2H), 7.19 – 7.14 (m, 2H), 6.94 – 6.88 (m, 4H), 3.85 (s, 6H). 13C{1H}
NMR (100 MHz, CDCl3): δ 155.7, 139.2, 128.4, 128.1, 125.7, 123.6, 120.9, 111.7, 55.6.
2,5-Bis(3-methoxyphenyl)thiophene (2h).40 The product was isolated by column chromatography (hexane
90:10 ethyl acetate) as a yellow solid (53 mg, 71% yield); mp 74–76 ºC. 1H NMR (400 MHz, CDCl3): δ
7.29 (t, J = 7.9 Hz, 2H), 7.27 (s, 2H), 7.25 – 7.20 (m, 2H), 7.17 – 7.14 (m, 2H), 6.83 (ddd, J = 8.1, 2.5, 1.0
Hz, 2H), 3.85 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 159.9, 143.4, 135.5, 129.9, 124.1, 118.2, 113.0,
111.2, 55.3.
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2,5-Bis(4-methoxyphenyl)thiophene (2i).42 The product was isolated by column chromatography (hexane
4
5
6
7
1
90:10 ethyl acetate) as a light yellow solid (31 mg, 42% yield); mp 214–216 ºC. H NMR (400 MHz,
CDCl3): δ 7.54 (d, J = 8.7 Hz, 4H), 7.14 (s, 2H), 6.92 (d, J = 8.7 Hz, 4H), 3.84 (s, 6H). 13C{1H} NMR (100
MHz, CDCl3): δ 159.1, 142.5, 127.3, 126.8, 122.9, 114.3, 55.4.
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4-(5-Phenylthiophen-2-yl)benzonitrile (2j).5c The product was isolated by column chromatography (hexane
95:5 ethyl acetate) as a yellow solid (34 mg, 52% yield); mp 173–175 ºC. 1H NMR (400 MHz, CDCl3): δ
7.73 – 7.69 (m, 2H), 7.69 – 7.62 (m, 4H), 7.44 – 7.39 (m, 3H), 7.36 – 7.31 (m, 2H). 13C{1H} NMR (100
MHz, CDCl3): δ 146.1, 141.0, 138.5, 133.7, 132.7, 129.0, 128.1, 126.1, 125.8, 125.7, 124.4, 118.9, 110.4.
HRMS (ESI) m/z: [M + Na]+ calcd for C17H11NSNa 284.0505; found 284.0510.
2-(4-Methoxyphenyl)-5-phenylthiophene (2k).15f The product was isolated by column chromatography
1
(hexane 98:2 ethyl acetate) as a light-yellow solid (50 mg, 75% yield); mp 166–168 ºC. H NMR (400
MHz, CDCl3): δ 7.61 (d, J = 7.4 Hz, 2H), 7.55 (d, J = 8.7 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.27 – 7.24 (m,
2H), 7.17 (d, J = 3.7 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 3.83 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
159.2, 143.6, 142.6, 134.4, 128.9, 127.3, 127.2, 126.9, 125.5, 123.9, 122.9, 114.3, 55.4.
2,5-Bis(4-methoxy-2-methylphenyl)thiophene (2l).5a The product was isolated by column chromatography
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(hexane 90:10 ethyl acetate) as a white solid (17 mg, 21% yield); mp 71–73 ºC. H NMR (400 MHz,
CDCl3): δ 7.38 (d, J = 8.4 Hz, 2H), 6.95 (s, 2H), 6.82 (d, J = 2.7 Hz, 2H), 6.78 (dd, J = 8.4, 2.7 Hz, 2H),
3.83 (s, 6H), 2.44 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 159.0, 142.2, 137.5, 131.4, 126.8, 126.0,
116.1, 111.2, 55.3, 21.5.
2,5-Bis(3,5-bis(trifluoromethyl)phenyl)thiophene (2m). The product was isolated by column
chromatography (hexane) as a light-yellow solid (76 mg, 60% yield); mp 163–165 ºC. 1H NMR (400 MHz,
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CDCl3): δ 8.04 (s, 4H), 7.82 (s, 2H), 7.49 (s, 2H). F{1H} NMR (376 MHz, CDCl3): δ –63.08. C{1H}
NMR (100 MHz, CDCl3): δ 142.1, 135.6, 132.6 (q, 2JC–F = 33.5 Hz), 126.4, 125.5, 123.1 (q, 1JC–F = 272.8
Hz), 121.4. HRMS (ESI) m/z: [M]+ calcd for C20H8F12S 508.0150; found 508.0150.
2,5-Di(cyclohex-1-enyl)thiophene (2n). The product was isolated by column chromatography (hexane) as
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a yellow solid (27 mg, 44% yield); mp 104–106 ºC. H NMR (400 MHz, CDCl3): δ 6.77 (s, 2H), 6.22 –
6.08 (m, 2H), 2.44 – 2.32 (m, 4H), 2.25 – 2.14 (m, 4H), 1.82 – 1.70 (m, 4H), 1.69 – 1.55 (m, 4H). 13C{1H}
NMR (100 MHz, CDCl3): δ 143.9, 131.2, 123.6, 121.2, 27.1, 25.6, 22.7, 22.1. HRMS (ESI) m/z: [M + H]+
calcd for C16H21S 245.1359; found 245.1361.
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2,5-Diheptylthiophene (2o).43 The product was isolated by column chromatography (hexane) as a brownish
oil (28 mg, 40% yield). 1H NMR (400 MHz, CDCl3): δ 6.54 (s, 2H), 2.73 (t, J = 7.6 Hz, 4H), 1.72 – 1.58
(m, 4H), 1.40 – 1.20 (m, 16H), 0.88 (t, J = 6.5 Hz, 6H). 13C{1H} NMR (100 MHz, CDCl3): δ 143.3, 123.2,
31.8, 31.7, 30.2, 29.1, 29.0, 22.6, 14.1.
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General Procedure for Deuterated Experiment A. In a dried schlenk tube under argon atmosphere,
DMSO (2 mL), CS2 (72 µL, 1.2 mmol, 4 equiv) and t-BuOK powder (135 mg, 1.2 mmol, 4 equiv) were
added. The mixture was stirred at room temperature for 15 minutes, and then became a dark red solution.
After this time, 1a (61 mg, 0.3 mmol) and D2O (24 µL, 1.2 mmol, 4 equiv) were added. The reaction was
stirred for 5 h at 50 ºC (temperature of the oil bath). Then, the reaction was cooled to room temperature,
and ethyl acetate (60 mL) was added. The mixture was washed with saturated aqueous NaCl solution (3x
30 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced
pressure. The crude was further purified by column chromatography on silica gel (hexane) to give the
desired product (57 mg, 80% yield).
General Procedure for Deuterated Experiment B. In a dried schlenk tube under argon atmosphere,
DMSO-d6 (2 mL), CS2 (72 µL, 1.2 mmol, 4 equiv) and t-BuOK powder (135 mg, 1.2 mmol, 4 equiv) were
added. The mixture was stirred at room temperature for 15 minutes, and then became a dark red solution.
After this time, 1a (61 mg, 0.3 mmol) and H2O (22 µL, 1.2 mmol, 4 equiv) were added. The reaction was
stirred for 5 h at 50 ºC (temperature of the oil bath). Then, the reaction was cooled to room temperature,
and ethyl acetate (60 mL) was added. The mixture was washed with saturated aqueous NaCl solution (3x
30 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced
pressure. The crude was further purified by column chromatography on silica gel (hexane) to give the
desired product (57 mg, 80% yield).
General Procedure for the Synthesis of 2-substituted benzo[b]thiophenes 5a-h. In a dried sealed
schlenk tube under argon atmosphere, DMSO (2 mL), CS2 (60 µL, 1 mmol, 4 equiv) and KOH powder (56
mg, 1.0 mmol, 4 equiv) were added. The mixture was stirred at room temperature for 15 minutes, and then
became a dark red solution. After this time, the corresponding 2-haloalkynylbenzene (0.25 mmol) and H2O
(9 µL, 0.5 mmol, 2 equiv) were added. Under argon atmosphere, the reaction mixture was stirred and heated
(using an oil bath) for 24 h at the temperature indicated on the scheme 6. After, the reaction was cooled to
room temperature, and ethyl acetate (60 mL) was added. The mixture was washed with saturated aqueous
NaCl solution (3x 30 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure. The crude was further purified by column chromatography on silica gel to give the
desired substituted benzo[b]thiophenes 5a-h.
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2-Phenylbenzo[b]thiophene (5a).44 The product was isolated by column chromatography (hexane) as a
white solid (49 mg, 93% yield); mp 177–179 ºC. 1H NMR (400 MHz, CDCl3): δ 7.83 (d, J = 7.7 Hz, 1H),
7.77 (d, J = 7.5 Hz, 1H), 7.72 (d, J = 7.5 Hz, 2H), 7.55 (s, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.39 – 7.28 (m,
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3H). C{1H} NMR (100 MHz, CDCl3): δ 144.2, 140.7, 139.5, 134.3, 128.9, 128.2, 126.5, 124.5, 124.3,
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123.5, 122.2, 119.4.
2-(p-Tolyl)benzo[b]thiophene (5b).44 The product was isolated by column chromatography (hexane) as a
white solid (43 mg, 76% yield); mp 169–171 ºC. 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J = 7.4 Hz, 1H),
7.75 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.49 (s, 1H), 7.36 – 7.27 (m, 2H), 7.22 (d, J = 8.1 Hz,
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2H), 2.38 (s, 3H). C{1H} NMR (100 MHz, CDCl3): δ 144.4, 140.7, 139.3, 138.3, 131.5, 129.6, 126.3,
124.4, 124.1, 123.4, 122.2, 118.8, 21.2.
2-(4-Fluorophenyl)benzo[b]thiophene (5c).18f The product was isolated by column chromatography
(hexane) as a white solid (35 mg, 61% yield); mp 175–177 ºC. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J =
7.9 Hz, 1H), 7.76 (d, J = 7.3 Hz, 1H), 7.71 – 7.65 (m, 2H), 7.46 (s, 1H), 7.39 – 7.28 (m, 2H), 7.12 (t, J =
8.6 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 162.7 (d, JC–F = 248.3 Hz), 143.0, 140.6, 139.4, 130.5
(d, JC–F = 3.4 Hz), 128.2 (d, JC–F = 8.1 Hz), 124.6, 124.4, 123.5, 122.2, 119.4 (d, JC–F = 1.1Hz), 115.9 (d,
JC–F = 21.8 Hz).
2-Butylbenzo[b]thiophene (5d).45 The product was isolated by column chromatography (hexane) as a
yellow oil (10 mg, 21% yield). 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 7.8 Hz,
1H), 7.34 – 7.21 (m, 2H), 6.99 (s, 1H), 2.90 (t, J = 7.5 Hz, 2H), 1.80 – 1.67 (m, 2H), 1.50 – 1.37 (m, 2H),
0.95 (t, J = 7.3 Hz, 3H). C{1H} NMR (100 MHz, CDCl3): δ 146.8, 140.2, 139.3, 123.9, 123.3, 122.6,
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122.1, 120.4, 33.2, 30.5, 22.2, 13.8.
2-(4-Chlorophenyl)benzo[b]thiophene (5e).18f The product was isolated by column chromatography
(hexane) as a white solid (25 mg, 41% yield); mp 196–198 ºC. 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J =
7.6 Hz, 1H), 7.76 (d, J = 7.2 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.51 (s, 1H), 7.38 (d, J = 8.5 Hz, 2H), 7.37
– 7.29 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 142.8, 140.5, 139.4, 134.0, 132.8, 129.1, 127.6, 124.6,
124.5, 123.6, 122.3, 119.8.
2-(Thiophen-2-yl)benzo[b]thiophene (5f).44 The product was isolated by column chromatography (hexane)
as a yellow solid (33 mg, 61% yield); mp 118–120 ºC. 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J = 7.7 Hz,
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1H), 7.72 (d, J = 7.3 Hz, 1H), 7.40 (s, 1H), 7.37 – 7.26 (m, 4H), 7.09 – 7.04 (m, 1H). 13C{1H} NMR (100
MHz, CDCl3): δ 140.3, 139.1, 137.4, 137.2, 127.9, 125.5, 125.0, 124.6, 124.4, 123.4, 122.1, 119.7.
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2-(5-Butylthiophen-2-yl)benzo[b]thiophene (5g). The product was isolated by column chromatography
(hexane) as a yellow solid (45 mg, 66% yield); mp 64–66 ºC. 1H NMR (400 MHz, CDCl3): δ 7.75 (d, J =
8.2 Hz, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.35 – 7.26 (m, 3H), 7.10 (d, J = 3.6 Hz, 1H), 6.72 (d, J = 3.6 Hz,
1H), 2.82 (t, J = 7.6 Hz, 2H), 1.75 – 1.62 (m, 2H), 1.50 – 1.33 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 146.6, 140.5, 138.9, 137.8, 134.7, 124.9, 124.8, 124.5, 124.2, 123.2, 122.0,
118.8, 33.7, 29.9, 22.1, 13.8. HRMS (ESI) m/z: [M + H]+ calcd for C16H17S2 273.0767; found 273.0772.
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2-(Benzo[b]thiophen-2-yl)pyridine (5h).46 The product was isolated by column chromatography (hexane
90:10 ethyl acetate) as a yellow solid (27 mg, 51% yield); mp 120–122 ºC. 1H NMR (400 MHz, CDCl3): δ
8.63 (ddd, J = 4.9, 1.7, 1.0 Hz, 1H), 7.90 – 7.85 (m, 1H), 7.83 (s, 1H), 7.82 – 7.78 (m, 2H), 7.72 (td, J =
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7.7, 1.7 Hz, 1H), 7.39 – 7.32 (m, 2H), 7.20 (ddd, J = 7.4, 4.9, 1.2 Hz, 1H). C{1H} NMR (100 MHz,
CDCl3): δ 152.5, 149.7, 144.8, 140.6, 140.4, 136.6, 125.0, 124.5, 124.1, 122.57, 122.56, 121.1, 119.6.
HRMS (ESI) m/z: [M + H]+ calcd for C13H10NS 212.0529; found 212.0528.
CONFLICTS OF INTEREST
There are no conflicts to declare.
SUPPORTING INFORMATION
The Supporting Information is available free of charge at (link).
1
Copies of H, 13C{1H} and 19F{1H} spectra of all the synthesized compounds; detailed experimental
procedures; additional reaction optimization studies (PDF)
ACKNOWLEDGEMENTS
We are grateful to Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) -
Finance Code 001, CNPq, INCT-CMN, FAPERGS.
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