One-pot synthesis of functionalized benzo[b]thiophenes and their hetero-fused analogues via intramolecular Cludeth C. Coper-catalyzed S-arylation of in situ generated enethiolates

Article abstract of DOI:10.1021/acs.joc.5b00032

An efficient one-pot synthesis of highly functionalized multisubstituted benzo[b]thiophenes and their hetero-fused analogues, such as thieno[2,3-b]thiophenes, indolo[2,3-b]thiophenes, and pyrazolo[3,2-c]thiophenes, has been reported. The overall strategy

Full text of DOI:10.1021/acs.joc.5b00032

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Note
One-Pot Synthesis of Functionalized Benzo[b]thiophenes
and Their Hetero- Fused Analogs via Intramolecular Copper
Catalyzed S-Arylation of In Situ Generated Enethiolates
Anand Acharya, Siripuram Vijay Kumar, Bonagiri Saraiah, and Hiriyakkanavar Ila
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00032 • Publication Date (Web): 06 Feb 2015
Downloaded from http://pubs.acs.org on February 10, 2015
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OneꢀPot Synthesis of Functionalized Benzo[b]thiophenes
and Their Heteroꢀ Fused Analogs via Intramolecular Copper
Catalyzed SꢀArylation of In Situ Generated Enethiolates
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Anand Acharya, S. Vijay Kumar, B. Saraiah and H. Ila*
New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur,
Bangalore 560064, India
E–mail: hila@jncasr.ac.in
CN
Br
NC
CN
R
CuI (10 mol%)
NaH / DMF
S
Ar/
Het
Ar/
Ar/
Het
R
S
Het
L-Proline (20 mol%)
90 °C / 3-6 h
S
Br
Na
R
C
or
N
SMe
25 examples
68-93%
Ph
C
S
R = aryl, (het)aryl, alkyl, SMe, alkoxy,
HN-alkyl, N-imidazolyl, PhNH
ABSTRACT: An efficient oneꢀpot synthesis of highly functionalized multisubstituted
benzo[b]thiophenes and their heteroꢀ fused analogs such as thieno[2,3ꢀb]thiophenes, indolo[2,3ꢀ
b]thiophenes and pyrazolo[3,2ꢀc]thiophenes has been reported. The overall strategy involves
sequential base mediated condensation 2ꢀbromoꢀhet(aryl)acetonitrile precursors with
(het)aryl/alkyl dithioesters or other thiocarbonyl species such as dimethyl trithiocarbonate, Sꢀ
methyl xanthates, methyl Nꢀimidazolyl dithioate, Nꢀalkyl dithiocarbamate and phenyl
isothiocyanate, followed by intramolecular copper catalyzed arylthiolation of in situ generated
enethiolates, furnishing a broad range of 2ꢀfunctionalized 3ꢀcyano benzo[b]ꢀ and /heteroꢀ fused
thiophenes in high yields.
Benzo[b]thiophene and its derivatives represent an important heterocyclic core, because
of their frequent occurrence in nature and wide range of biological activity displayed by these
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class of compounds.1 Several marketed drugs contain the benzothiophene core, such as
zileuton,1,2 a potent and selective inhibitor of 5ꢀlipoxygenase, whereas raloxifene and arzoxifene
are selective estrogen receptor modulators (SERM).1,3ꢀ4 Also, benzo[b]thiophene and its
condensed analogs are important structural component in development of optoelectronic
materials, including organic photovoltaics and field effect transistors.1b,5 Therefore research
directed towards concise new synthesis of multisubstituted benzo[b]thiophenes has been actively
pursued in recent years,1,6 and many efficient methods have been developed.
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Among recent syntheses, the most common approach for benzo[b]thiophenes involves
intramolecular 5ꢀendoꢀdig cyclization of oꢀalkynyl arylthioethers or their surrogates, employing
electrophilic reagents such as iodine, bromine, NBS, PhSCl or PhSeCl.5b,5eꢀf,6a7ꢀ9 The
methodology has also been extended to transition metal catalyzed cyclization of these analogs,
such as Pd,1b Cu10a or gold catalyzed anulations.10bꢀc 2ꢀSubstituted benzothiophenes have also
been accessed via tandem intramolecular palladium or copper catalyzed Sꢀvinylation and
intermolecular crossꢀcoupling reaction of oꢀ(gemdibromovinyl)thiophenols.10eꢀg The crucial bond
forming event in these reactions is intramolecular attack of nucleophilic sulfur atom on activated
CꢀC multiple bond, leading to the formation of S(1)ꢀC(2) bond of benzothiophene core. These
reactions, although selective and efficient, however, require prior synthesis of difficultly
accessible prefunctionalized thiophenol precursors.9 Recently, copper (or Pd) catalyzed double
thiolation of oꢀ(2ꢀhalovinyl)halobenzenes11a or 2ꢀbromoalkynylbenzenes11b with metal sulfides
or its surrogates11cꢀd leading to 2ꢀsubstituted benzo[b]thiophenes has also been reported.12 These
methods involve concomitant formation of S(1)ꢀC(7a) and S(1)ꢀC(2) bonds of
benzo[b]thiophenes. On the other hand, synthetic approaches to benzothiophenes involving S(1)ꢀ
C(7a) bond formation via intramolecular CꢀS couplingꢀcyclization of αꢀarylthioenol/enolate
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precursors is scarce in the literature. One of the oldest syntheses, which falls under this category,
involves iodine13 or chlorine14 mediated oxidative cyclization of βꢀarylꢀαꢀmercaptoacrylic acids
furnishing benzo[b]thiopheneꢀ2ꢀcarboxylic acids in good yields.15 Recently Willis and coꢀ
workers have described synthesis of 2,3ꢀannulated benzo[b]thiophenes in moderate to good
yields via palladium catalyzed intramolecular cyclization of oꢀ(haloaryl)substituted cyclic
thioketones.16a A palladium catalyzed intramolecular CꢀH thiolation approach for the direct
synthesis of 2,3ꢀdiarylbenzo[b]thiophenes via Pd chloride oxidative cyclization of 1,2,2ꢀ
triaryllethenethiols has been recently reported by Inamoto and coꢀworkers.17 However, the scope
of these reactions in terms of functional group/substituent diversity has not been much explored,
probably because of the limited accessibility and instability of the requisite thioketone (or
thioenol) precursors. During the course of our continued studies directed towards the
development of new and efficient methods for five and six membered heterocycles employing
novel organosulfur synthons,18 we have previously reported a novel approach to 2,3ꢀsubstituted
benzo[b]thiophenes 4 via intramolecular radical cyclization of 3ꢀ(methylthio)ꢀ3ꢀ(het)aryl/alkylꢀ
1ꢀ[2ꢀbromo(het)aryl]acrylonitriles 3 (Scheme 1).1a,19 These precursors 3 are prepared by base
induced condensation of the corresponding 2ꢀbromo(het)aryl acetonitriles 1 with (het)aryl
dithioesters 2 followed by in situ Sꢀmethylation of the resulting enethiolate intermediates
(Scheme 1).
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1. NaH / DMF,
S
CN
Br
CN
n-Bu3SnCl (20 mol %)
AIBN (10 mol %)
CN
2
(Het)Ar C SMe
(Het)Ar
(Het)Ar
SMe
NaCNBH3 (2 equiv)
tBuOH / ꢀ / 5-10 h
S
2. MeI / rt / 5-10 h
Br
X
X
X
3
4
1
Scheme 1. Intramolecular Radical Mediated Synthesis of Benzo[b]thiophenes
During the course of these studies, we conceived of a direct synthesis of
benzo[b]thiophenes by trapping the corresponding enethiolate intermediates 5 from 1 and 2 and
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subjecting them to copper (or palladium) metal catalyzed intramolecular CꢀS bond formation
cyclization in a cascade process (Scheme 2). We have successfully achieved this goal and report
in this paper an efficient one pot synthesis of multisubstituted benzo[b]thiophenes and their
heteroꢀfused analogs via intramolecular copper catalyzed CꢀS arylation of in situ generated
enethiolate salts 5 involving formation of C(2)ꢀC(3) and S(1)ꢀC(7a) bonds of benzothiophenes in
a tandem fashion.
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CN
Br
CN
Cu /Pd catalyzed
intramolecular
CN
Base
S
R
R
S
S
C-S bond
formation
M
Br
X
X
X
R C SMe
5
4
1
2
Scheme 2. Proposed Strategy for Synthesis of Benzo[b]thiophenes
Initially, 2ꢀbromoꢀ5ꢀmethoxyphenylacetonitrile (1a) and 4ꢀmethoxyphenyldithioester
(2a) were chosen as model substrates to examine the feasibility and efficiency of the proposed
tandem protocol. We first focused on optimization of reaction conditions for a two step process
via intramolecular Cu (or Pd) catalyzed cyclization of enethiol intermediate 5a, which was
obtained in 95% yield by condensation of 1a with 2a in the presence of base like sodium hydride
in DMF as solvent (Table 1). On the other hand, 5a was obtained in lower yields (20ꢀ30%) in the
presence of weaker bases like Cs2CO3, K2CO3 or K3PO4 under identical conditions. We first
attempted cyclization of 5a in the absence of any catalyst,20 which afforded benzo[b]thiophene
4a in 25ꢀ30% yields on prolonged heating (Table 1, entries 1ꢀ2). Intramolecular thiolationꢀcross
coupling of 5a to 4a was next examined under the influence of various copper catalysts, bases
and ligands with a view to explore the optimal reaction conditions (Table 1). Thus, our study
revealed that benzothiophene 4a was formed with practically all Cu catalysts in varying yields
o
on heating for prolonged time at 120 C (Table 1, entries 3ꢀ6), with CuI displaying best results
(entry 5). Screening of various bases and ligands (entries 7ꢀ14) revealed, that optimal results
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were obtained with 10 mol % of CuI, Lꢀproline (20 mol %) as ligand and NaH as base in DMF
5
6
o
as solvent, when the reaction was complete within 3 hr at 90 C, furnishing the benzothiophene
7
8
9
4a in 92% yield (entry 12). Decreasing the reaction temperature (entry 15), catalytic loading
(entry 16) or changing the CuI/ligand ratio (entries 17ꢀ18) required longer time for completion of
reaction without much affecting the yield of 4a (Table 1).
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Table 1. Optimization of Reaction Conditions for the Formation of 4a from 5a
CN
CN
CN
Reaction
NaH / DMF
0 °C→rt, 1 h
MeO
MeO
MeO
Ar
conditions
Ar
SH
S
S
Br
Br
5a, 95%
Ar C SMe
1a
4a
2a
2a, 4a, 5a, Ar = 4-OMeC6H4
entry
Cu catalyst
(10 mol %)
base
(1 equiv.)
ligand
(20 mol %)
temp (°C)
/time (h)
% yield
1a
2
110 °C /25h
120 °C /28h
25
30
ꢀ
ꢀ
NaH
ꢀ
NaH
ꢀ
CuCl
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
3
4
5
6
7
8
120 °C /18h
120 °C /18h
120 °C /14h
120 °C /16h
120 °C /11h
120 °C /10h
73
71
82
72
83
81
CuBr
CuI
ꢀ
ꢀ
Cu2O
ꢀ
K2CO3
Cs2CO3
CuI
CuI
K3PO4
NaH
CuI
CuI
CuI
CuI
CuI
CuI
ꢀ
ꢀ
ꢀ
9
120 °C /12h
120 °C /5h
120 °C /6h
90 °C /3h
90 °C /5h
90 °C /5h
79
90
84
92
85
85
10
11
12
13
KOtBu
NaH
LꢀProline
1,10ꢀphen
NaH
14
NaH
DMEDA
15
CuI
CuI
CuI
CuI
NaH
NaH
NaH
NaH
LꢀProline
LꢀProline
LꢀProline
LꢀProline
50 °C /8h
90 °C /7h
50 °C /10h
50 °C /8h
91
83
87
88
16b
17c
18d
a DMSO was used as solvent; b with 5 mol % of CuI ; c with 1:1 CuI/L-proline
ratio; d with 1:5 CuI/L-proline ratio
Having accomplished the optimal conditions for intramolecular cyclization of 5a to
benzothiophene 4a, we next aimed to combine synthesis of enethiol 5a, along with carbonꢀsulfur
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bond forming process in a one pot reaction. Thus in situ generated enethiolate 5a (from 1a and
dithioester 2a in the presence of sodium hydride and DMF) was subjected to intramolecular
arylthiolation by adding CuI (10 mol %) and Lꢀproline (20 mol %) to the reaction mixture and
further heating at 90 °C. Monitoring of the reaction mixture revealed that the reaction was
complete within 3 hr, providing benzothiophene 4a in comparable yield of 90% (Table 2, entry
1).
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With the optimized reaction conditions in hand, the generality and scope of the present
oneꢀpot protocol was explored and the results are summarized in Table 2. Thus aryl group of 1
bearing either the electron donating or withdrawing groups on phenyl ring has little effect on
cyclization reaction (entries 1ꢀ5). Similarly a range of (het)aryl dithioesters 2 bearing either
electron donating/withdrawing/sterically encumbering aryl or hetaryl groups are well tolerated,
yielding benzothiophenes 4a-f in good yields (Table 2, entries 1ꢀ6). Attempted cyclizationꢀ
coupling of 1b with 2ꢀhydroxyphenyl dithioester 2g under identical conditions, did not afford the
desired 2ꢀ(2ꢀhydroxyphenyl)benzothiophene 4g. However 4g could be obtained in good yield by
two step process via condensationꢀcyclization of 1b with 2ꢀ(4ꢀmethoxybenzyloxy)phenyl
dithioester 2h, furnishing the corresponding 2ꢀ[2ꢀ(4ꢀmethoxybenzyloxy)phenyl]benzothiophene
4h and its subsequent deprotection with trifluoroacetic acid (Table 2, entries 7ꢀ8 and also 17-
18). Similarly, using nꢀbutyl dithioester 2i, the corresponding 2ꢀ(nꢀbutyl)benzothiophene 4i was
obtained in 75% yield (entry 9).The reaction was found to be equally efficient for the synthesis
of heteroꢀfused thiophenes as shown in the entries 10ꢀ18 (Table 2). Thus 2,3ꢀsubstituted
thieno[2,3ꢀb]thiophenes 4j, 4n indolo[2,3ꢀb]thiophene 4k-l and pyrazolo[3,2ꢀc]thiophene 4m
could be readily accessed in good yields, by subjecting the corresponding 2ꢀbromo substituted
thienoꢀ, indoloꢀ, or pyrazoloꢀ acetonitriles 1d-f to two step, base mediated condensation ꢀ Cu
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catalyzed intramolecular thiolation process, with various dithioesters 2j-n under optimized
conditions (entries 10ꢀ14). The reaction could also be extended for the synthesis of 7ꢀ
azabenzo[b]thiophenes 4o-r by employing (2ꢀbromopyridyl)ꢀ3ꢀacetonitrile 1g and relevant
dithioesters (2o-p and 2h) as coupling partners (Table 2, entries 15ꢀ18). Further diversity at 2ꢀ
position of benzothiophene was introduced by employing a variety of thiocarbonyl substrates
such as dimethyl trithiocarbonate 2q, Oꢀalkyl Sꢀmethyl dithiocarbonate 2r-s, Nꢀimidazolyl
dithioate 2t and Nꢀalkyl Sꢀmethyl dithiocarbamate 2u, furnishing the corresponding 2ꢀ
(methylthio)ꢀ, 2ꢀ(alkoxy)ꢀ, 2ꢀ(Nꢀimidazolyl)ꢀ and 2ꢀ(Ar)alkylaminoꢀ benzo/hetero fused
thiophenes 4s-w respectively in high yields (entries 19ꢀ23). Similarly the 2ꢀ
(anilino)benzo[b]thiophene 4x or the indolofused analog 4y could also be synthesized in good
yields by using phenyl isothiocyanate as thiocarbonyl component (Table 2, entries 24ꢀ25).
Table 2. Syntheses of 2,3-Substituted Benzo[b]- and Hetero- Fused Thiophenes 4
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CN
CN
CuI (10 mol %)
CN
L-Proline (20 mol %)
S
NaH / DMF
R
Ar/
Het
Ar/
Het
Ar/
Het
+
R
S
R
SMe
90 °C / 3-6 h
Br
S
Br
5
Na
1
2
4
entry
1
2, R
product
yield (%)a
CN
Br
CN
MeO
MeO
1
90
MeO
OMe
S
4a
2a
1a
1a
CN
MeO
2
86
73
S
S
S
2b
2c
4b
CN
Br
CN
O
O
O
MeO
MeO
MeO
MeO
3
O
S
1b
4c
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CN
Br
CN
F
4
5
6
76
90
71
F
S
4d
CN
F
F
2d
2e
1c
1c
Me
Me
Me
N
N
10
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S
Me
F
4e
CN
1c
1b
S
OMe
F
MeO
CN
2f
4f
MeO
MeO
7
S
OR
RO
0b; 82c
68
2g, R = H
4g, , R = H
TFA
8
9
1b
1a
2h, R = PMB
4h, R = PMB
CN
MeO
75
S
2i
4i
NC
CN
10
11
75
N
N
S
S
S
Br
2j
4j
1d
NC
CN
Me
80
N
S
Me
N
S
S
N
N
Me
Br
Me
Me
Me
1e
2k
4k
CN
12
13
1e
84
87
N
Me
2l
N
S
N
Me
Me
4l
Ph
Ph
Br
N
N
S
N
N
N
Me
N
N
N
CN
Ph
Ph
Me
NC
2m
4m
CN
1f
14
15
1d
75
90
4
S
S
4n
2n
CN
Br
CN
N
Me
N
S
N
N
Me
1g
2o
4o
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CN
4
5
6
7
8
9
16
17
1g
81
N
S
N
N
2p
4p
CN
1g
S
10
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13
14
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N
OR
RO
2h, R = PMB
4q, R = PMB
68
79
TFA
4r, R = H
-
-
18
19
CN
Br
CN
88
SMe
SMe
S
2q
1h
1a
4s
CN
MeO
O
20
21
93
OnC4H11
S
2r
4t
CN
n-C8H17
O
1c
90
OnC8H17
S
4u
F
2s
CN
N
N
22
23
1d
1c
N
84
84
N
S
S
2t
4v
CN
H
MeO
MeO
N
Ar
N
F
S
H
2u
4w, Ar = 3,4-(OMe)2C6H3
CN
S
C
MeO
N
NH
24
25
1a
1e
80
78
S
2v
4x
CN
S
C
N
NH
N
Me
S
2v
4y
aReaction conditions: 1 (1.0 mmol), 2 (1.0 mmol) and NaH (2.0 mmol) in DMF (6 mL), stirred
for 1 h; CuI (10 mol%), L-proline (20 mol%) added and heated to 90 °C for 3-5 h; byield with
2g; cyield with 4h
In summary, we have developed an efficient and practical route to diversely
functionalized 2,3ꢀsubstituted benzo[b]thiophenes and hetero fused thiophenes from readily
available 2ꢀbromoꢀ(het)arylacetonitriles and (het)aryl/alkyldithioesters and other thiocarbonyl
precursors. The overall protocol involves a tandem base mediated condensation of
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(het)arylacetonitriles with dithioesters [intermolecular C(2)ꢀC(3) bond formation] followed by a
Cu catalyzed intramolecular arylthiolation of the in situ generated thioenolate intermediates
[S(1)ꢀC(7a) bond formation] in a oneꢀpot sequence. The new methodology allows direct access
to a broad range of benzo/hetero fused thiophenes with a variety of substitution patterns, making
it a useful process for structure activity relationship studies. The substrate scope is large and
many products have the potential for further synthetic transformations.
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Experimental Section
General Information. All reagents were purchased from commercial suppliers and used
without further purification. Solvents were dried according to the standard procedures. All the
reactions were monitored by thin layer chromatography using standard TLC Silica gel plates and
visualized with UV light. Column chromatography was performed using silica gel (100–200
mesh). Nuclear magnetic resonance spectra were recorded on (400 MHz) FT–NMR spectrometer
with CDCl3 (or) DMSO–d6 as solvent. Chemical shifts were reported in δ ppm using residual
1
solvent protons as internal standard (δ 7.26 for CDCl3 and δ 2.50 for DMSO–d6 in H–NMR, δ
77.16 for CDCl3 and δ 39.52 for DMSO–d6 in 13C–NMR). Coupling constants were reported as
J values in Hertz (Hz). Splitting patterns are designated as s (singlet), d (doublet), t (triplet), q
(quartet), quin (quintet), sex (sextet), dd (double doublet), dt (doublet of triplet), td (triplet of
doublet), ddd (doublet of doublet of doublet), m (multiplet) and br (broad). Infrared spectra of
neat samples were recorded in ATR (attenuated total reflectance) mode using FT–IR instrument
and HRMS on Q–TOF spectrometer. Melting points were recorded using an electrothermal
capillary melting point apparatus and are uncorrected.
All 2ꢀbromoꢀ(het)aryl acetonitriles 1a-h were prepared according to the reported
procedures.1a,19 All the known dithioesters 2a-e, 2i-m, 2o-p and the unknown dithioesters 2f-h,
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2n,21a dimethyl trithiocarbonate 2q,21b Oꢀalkyl Sꢀmethyl dithiocarbonates 2r-s,21c methyl Nꢀ
imidazolyl dithioate 2t,21d [Nꢀ(3,4ꢀdimethoxphenethyl)] Sꢀmethyl dithiocarbamate 2u21d and
phenyl isothiocyanate 2v21e were also prepared according to the literature procedure. The
spectral and analytical data of the new dithioesters 2f-h and 2n is given below.
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Methyl 2-methoxybenzodithioate (2f). Dark red liquid, (906 mg, 78%): Rf 0.86 (1:9
1
EtOAc/hexane); IR (neat, cm–1) 1592, 1483, 1250, 1040, 882; H NMR (400 MHz, CDCl3) δ
7.39 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.37ꢀ7.32 (m, 1H), 6.95 (dd, J = 7.6 Hz, 1.2 Hz, 1H), 6.94ꢀ
6.92 (m, 1H), 3.82 (s, 3H), 2.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 229.6, 154.8, 136.6,
131.3, 129.0, 120.4, 112.0, 56.1, 21.0; HRMS (ESI) m/z calcd for C9H11OS2 [M + H]+ 199.0251,
found 199.0248.
Methyl 2-hydroxybenzodithioate (2g). Red liquid, (944 mg, 71%): Rf 0.75 (2:8
EtOAc/hexane); IR (neat, cm–1) 3300ꢀ2450, 1607, 1459, 1198, 804; 1H NMR (400 MHz, CDCl3)
δ 12.15 (s, 1H), 8.11 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.42ꢀ7.38 (m, 1H), 7.05 (dd, J = 8.4 Hz, 1.2
13
Hz, 1H), 6.90ꢀ6.85 (m, 1H), 2.70 (s, 3H); C NMR (100 MHz, CDCl3) δ 226.9, 158.8, 135.1,
127.0, 126.5, 119.9, 119.1, 19.2; HRMS (ESI) m/z calcd for C8H9OS2 [M + H]+ 185.0095, found
185.0099.
Methyl 2-(4-methoxybenzyloxy)benzodithioate (2h). Red solid, (908 mg, 86%): mp 60ꢀ62 °C;
1
Rf 0.92 (1:9 EtOAc/hexane); IR (neat, cm–1) 1611, 1512, 1378, 1243, 1030, 749; H NMR (400
MHz, CDCl3) δ 7.41 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.31ꢀ7.27 (m, 3H), 6.96ꢀ6.92 (m, 2H), 6.86 (d,
13
J = 8.8 Hz, 2H), 5.05 (s, 2H), 3.77 (s, 3H), 2.72 (s, 3H); C NMR (100 MHz, CDCl3) δ 229.5,
159.4, 153.9, 137.2, 131.2, 129.0, 128.9, 128.8, 120.7, 114.0, 113.8, 70.7, 55.3, 21.0; HRMS
(ESI) m/z calcd for C16H17O2S2 [M + H]+ 305.0670, found 305.0668.
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Methyl octanedithioate (2n). Yellow liquid, (1.2 g, 95%): Rf 0.89 (hexane); IR (neat, cm–1)
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6
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2922, 2853, 1457, 1197, 954, 890; H NMR (400 MHz, CDCl3) δ 3.04 (t, J = 7.6 Hz, 2H), 2.61
7
8
9
(s, 3H), 1.83 (quin, J = 7.6 Hz, 2H), 1.37ꢀ1.28 (m, 8H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 240.3, 52.1, 31.8, 31.5, 29.1, 28.9, 22.7, 20.1, 14.2; HRMS (ESI) m/z calcd for
C9H19S2 [M + H]+ 191.0928, found 191.0919.
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Procedure
for
synthesis
of
2-(2-bromo-5-methoxyphenyl)-3-mercapto-3-(4-
methoxyphenyl)acrylonitrile (5a). A solution of 1a (226 mg, 1.0 mmol) in dry DMF (5 mL)
was added to a stirred suspension NaH (60% suspension in mineral oil) (80 mg, 2.0 mmol) in
DMF (5 mL) at 0 °C, After further stirring for 10 minutes, a solution of 4ꢀmethoxyphenyl
dithioester (2a) was added at 0 °C. The reaction mixture was stirred for 1 h at room temperature
(monitored by TLC). It was then diluted with sat. NH4Cl solution (25 mL), extracted with EtOAc
(3 × 25mL) and the combined organic layer was washed with water (3 × 25 mL), brine (2 × 25
mL), dried (Na2SO4) and concentrated under reduced pressure. The crude products were purified
by silica gel column chromatography using EtOAc/hexane as eluent to give pure 5a; brown
semiꢀsolid (158 mg, 95%): Rf 0.2 (1:4 EtOAc/hexane); IR (neat, cm–1) 2589, 2221, 1610, 1251,
841; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 9.2 Hz, 1H), 7.53 (d, J
= 9.2 Hz, 1H), 6.98ꢀ6.95 (m, 3H), 3.81 (s, 3H), 3.80 (s, 3H), 3.79 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 158.6, 135.4, 134.5, 129.9, 129.0, 119.8, 117.3, 117.0, 116.5, 114.5, 114.2, 113.8,
104.9, 55.7, 55.5; HRMS (ESI) m/z calcd for C17H15BrNO2S [M + H]+ 376.0007 and 377.9986,
found 376.0010 and 377.9990.
Procedure for copper catalyzed intramolecular cyclization of enethiol 5a to 5-methoxy-2-(4-
methoxyphenyl)benzo[b]thiophene-3-carbonitrile (4a). To a stirred solution of enethiol 5a
(188 mg, 0.5 mmol) in DMF (5 mL), CuI (9 mg, 0.05 mmol), Lꢀproline (12 mg, 1.0 mmol) and
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NaH (60% suspension in mineral oil) (18 mg, 0.5 mmol) were added and the reaction mixture
was heated at 90 °C with constant stirring for 3 h (monitored by TLC). It was then diluted with
sat. NH4Cl solution (25 mL), extracted with EtOAc (3 × 25mL) and the combined organic layer
was washed with water (3 × 25 mL), brine (2 × 25 mL), dried (Na2SO4) and concentrated under
reduced pressure. The crude products were purified by silica gel column chromatography using
EtOAc/hexane as eluent to give pure 4a; offꢀwhite solid (117 mg, 90%): mp 113ꢀ115 °C; Rf 0.6
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(1:9 EtOAc/hexane); IR (neat, cm–1) 2214, 1597, 1457, 1257, 1036, 823; H NMR (400 MHz,
CDCl3) δ 7.84 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.05 (dd, J
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= 8.8 Hz, 2.4 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 3.92 (s, 3H), 3.88 (s, 3H); C NMR (100 MHz,
CDCl3) δ 161.5, 158.9, 156.2, 140.8, 129.7, 129.3, 124.3, 123.1, 116.7, 115.8, 114.8, 104.0,
100.6, 55.8, 55.6; HRMS (ESI) m/z calcd for C17H14NO2S [M + H]+ 296.0745, found 296.0750.
General procedure for two step one-pot synthesis of substituted benzo[b]- and hetero-fused
thiophenes 4a-y. To a stirring suspension of NaH (60% suspension in mineral oil) (80 mg, 2.0
mmol) in 2 mL of DMF at 0 °C, corresponding 2ꢀbromo(het)arylacetonitrile (1a-h) (1.0 mmol)
in DMF (2 mL) was added drop wise. After further stirring for 10 minutes, a solution of either
respective dithioester (2a-p) or thioacarbonyl compound (2q-v) (1.0 mmol) in DMF (2 mL) was
added to the reaction mixture at 0 °C, followed by further stirring for 1 h at ambient temperature.
After complete consumption of starting materials (monitored by TLC), CuI (2 mg, 0.1 mmol)
and Lꢀproline (2.5 mg, 0.25 mmol) were added and the reaction mixture was heated at 90 °C
with continuous stirring (monitored by TLC). It was then diluted with sat. NH4Cl solution (25
mL), extracted with EtOAc (3 × 25mL) and the combined organic layer was washed with water
(3 × 25 mL), brine (2 × 25 mL), dried (Na2SO4) and concentrated under reduced pressure. The
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crude products were purified by silica gel column chromatography using EtOAc/hexane as
eluent.
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5-Methoxy-2-(thiophen-2-yl)benzo[b]thiophene-3-carbonitrile
(4b).
Obtained
from
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acetonitrile 1a and dithioester 2b, offꢀwhite solid (103 mg, 86%): mp 150ꢀ152 °C; Rf 0.7 (2:8
EtOAc/hexane); IR (neat, cm–1) 2212, 1601, 1456, 1211, 1028, 830; 1H NMR (400 MHz, CDCl3)
δ 7.75 (dd, J = 3.6 Hz, 1.2 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.50 (dd, J = 5.0 Hz, 1.2 Hz, 1H),
7.31 (d, J = 2.4 Hz, 1H), 7.17 (dd, J = 5.0 Hz, 3.6 Hz, 1H), 7.06 (dd, J = 8.8 Hz, 2.4 Hz, 1H),
3.92 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.2, 148.7, 140.4, 133.9, 132.5, 132.4, 129.0,
128.8, 128.6, 128.5, 123.1, 117.1, 104.2, 55.9; HRMS (ESI) m/z calcd for C14H10NOS2 [M + H]+
272.0204, found 272.0198.
2-(Benzo[d][1,3]dioxol-5-yl)-5,6-dimethoxybenzo[b]thiophene-3-carbonitrile (4c). Obtained
from acetonitrile 1b and dithioester 2c, offꢀwhite solid (96 mg, 73%): mp 188ꢀ190 °C; Rf 0.8 (1:9
EtOAc/hexane); IR (neat, cm–1) 2217, 1480, 1257, 1207, 1030, 796; 1H NMR (400 MHz, CDCl3)
δ 7.35 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.29 (s, 1H), 7.22 (s, 1H), 6.92 (d, J
= 8.0 Hz, 1H), 6.06 (s, 2H), 4.0 (s, 3H), 3.97 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 152.7,
149.8, 149.6, 149.4, 148.6, 133.1, 129.9, 125.9, 122.7, 115.8, 109.1, 108.3, 103.8, 103.5, 101.9,
101.0, 56.5, 56.4; HRMS (ESI) m/z calcd for C18H13NNaO4S [M + Na]+ 362.0463, found
362.0449.
6-Fluoro-2-(4-fluorophenyl)benzo[b]thiophene-3-carbonitrile
(4d).
Obtained
from
acetonitrile 1c and dithioester 2d, white solid (96 mg, 76%): mp 140ꢀ142 °C; Rf 0.8 (2:8
EtOAc/hexane); IR (Neat, cm–1) 2210, 1604, 1471, 1242, 834; 1H NMR (400 MHz, DMSO–d6) δ
7.91 (dd, J = 8.4 Hz, 5.2 Hz, 1H), 7.88ꢀ7.83 (m, 2H), 7.55 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.29 (td,
13
J = 8.4 Hz, 2.0 Hz, 1H), 7.25ꢀ7.20 (m, 2H); C NMR (100 MHz, CDCl3) δ 165.4, 162.9, 162.7,
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160.3, 153.68, 153.65, 138.4, 138.3, 135.6, 130.4, 130.3, 127.61, 127.58, 124.1, 124.0, 116.9,
116.7, 115.7, 115.5, 114.9, 109.1, 108.8, 102.0; HRMS (ESI) m/z calcd for C15H8F2NS [M + H]+
272.0346, found 272.0351.
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2-(4-(Dimethylamino)phenyl)-6-fluorobenzo[b]thiophene-3-carbonitrile (4e). Obtained from
acetonitrile 1c and dithioester 2e, pale yellow solid (125 mg, 90%): mp 167ꢀ169 °C; Rf 0.6 (2:8
1
EtOAc/hexane); IR (neat, cm–1) 2212, 1609, 1467, 1202, 813; H NMR (400 MHz, CDCl3) δ
7.83ꢀ7.79 (m, 3H), 7.46 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.21 (td, J = 9.2 Hz, 2.4 Hz, 1H), 6.76 (d, J
= 9.2 Hz, 2H), 3.06 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 162.2, 159.8, 156.22, 156.19, 151.8,
137.5, 137.4, 136.2, 129.2, 123.2, 123.1, 118.9, 116.0, 114.9, 114.7, 112.2, 108.8, 108.5, 98.1,
40.2; HRMS (ESI) m/z calcd for C17H14FN2S [M + H]+ 297.0862, found 297.0853.
6-Fluoro-2-(2-methoxyphenyl)benzo[b]thiophene-3-carbonitrile
(4f).
Obtained
from
acetonitrile 1c and dithioester 2f, white solid (94 mg, 71%): mp 110ꢀ112 °C; Rf 0.7 (2:8
1
EtOAc/hexane); IR (neat, cm–1) 2219, 1464, 1253, 1027, 746; H NMR (400 MHz, CDCl3) δ
7.90 (dd, J = 8.8 Hz, 4.8 Hz, 1H), 7.67 (dd, J = 7.6 Hz, 1.6 Hz, 1H), 7.52 (dd, J = 8.8 Hz, 2.4 Hz,
1H), 7.49ꢀ7.44 (m, 1H), 7.25 (td, J = 8.8 Hz, 2.4 Hz, 1H), 7.09 (td, J = 7.6 Hz, 1.6 Hz, 1H), 7.05
(d, J = 8.0 Hz, 1H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.4, 160.0, 156.6, 151.2,
151.1, 139.5, 139.4, 134.9, 132.0, 131.2, 123.8, 123.7, 121.2, 120.2, 115.1, 114.9, 114.8, 111.8,
108.6, 108.4, 104.4, 55.7; HRMS (ESI) m/z calcd for C16H11FNOS [M + H]+ 284.0545, found
284.0535.
2-(2-(4-Methoxybenzyloxy)phenyl)-5,6-dimethoxybenzo[b]thiophene-3-carbonitrile
(4h).
Obtained from acetonitrile 1b and dithioester 2h, offꢀwhite solid (115 mg, 68%): mp 165ꢀ167
1
°C; Rf 0.6 (1:1 EtOAc/hexane); IR (neat, cm–1) 2927, 2212, 1513, 1246, 1003, 757; H NMR
(400 MHz, CDCl3) δ 7.73 (dd, J = 7.2 Hz, 1.6 Hz, 1H), 7.42ꢀ7.38 (m, 1H), 7.34 (d, J = 8.4 Hz,
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2H), 7.32 (s, 1H), 7.22 (s, 1H), 7.11ꢀ7.07 (m, 2H), 6.87 (d, J = 8.4 Hz, 2H), 5.13 (s, 2H), 4.00 (s,
3H), 3.96 (s, 3H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.5, 155.8, 149.44, 149.40,
149.1, 132.2, 131.6, 131.4, 131.3, 129.3, 128.5, 121.4, 121.2, 115.8, 114.1, 113.4, 104.0, 103.5,
103.3, 70.8, 56.41, 56.37, 55.4; HRMS (ESI) m/z calcd for C25H22NO4S [M + H]+ 432.1270,
found 432.1258.
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Deprotection
of
4h
with
TFA:
Synthesis
of
2-(2-Hydroxyphenyl)-5,6-
dimethoxybenzo[b]thiophene-3-carbonitrile (4g). 2ꢀ(2ꢀ(4ꢀMethoxybenzyloxy)phenyl)ꢀ5,6ꢀ
dimethoxybenzo[b]thiopheneꢀ3ꢀcarbonitrile (4h) (100 mg, 0.2 mmol) was dissolved in
trifluoroacetic acid (5 mL) and refluxed for 5 h (monitored by TLC). Reaction mixture was
poured in ice cold water, extracted with DCM (3 × 25 mL and the combined organic layer was
washed with water (3 × 25 mL), brine (2 × 25 mL), dried (Na2SO4) and concentrated under
reduced pressure. The crude products was purified by silica gel column chromatography using
EtOAc/hexane as eluent to give pure 4g; yellow solid (60 mg, 82%): mp 152–154 °C; Rf 0.2 (8:2
1
EtOAc/hexane); IR (neat, cm–1) 3480ꢀ2740, 2219, 1609, 1467, 1202, 813; H NMR (400 MHz,
DMSO–d6) δ 9.07 (br s, 1H), 8.25 (s, 1H), 7.75 (d, J = 4.8 Hz, 2H), 7.53ꢀ7.49 (m, 1H), 7.36ꢀ7.30
(m, 2H), 3.88 (s, 3H), 3.87 (s, 3H); 13C NMR (100 MHz, DMSO–d6) δ 152.6, 150.5, 149.0,
148.6, 130.6, 130.3, 129.1, 125.0, 124.0, 123.7, 119.4, 117.0, 115.6, 106.5, 104.9, 55.8, 55.5;
HRMS (ESI) m/z calcd for C17H14NO3S [M + H]+ 312.0694, found 312.0690.
2-Butyl-5-methoxybenzo[b]thiophene-3-carbonitrile (4i). Obtained from acetonitrile 1a and
dithioester 2i, yellow liquid (81 mg, 75%): Rf 0.5 (hexane); IR (neat, cm–1) 2927, 2218, 1601,
1
1459, 1224, 835; H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 9.2 Hz, 1H), 7.26 (d, J = 2.4 Hz,
1H), 7.02 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 3.90 (s, 3H), 3.11 (t, J = 7.6 Hz, 2H), 1.78 (quin, J = 7.2
Hz, 2H), 1.45 (sex, J = 7.2 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO–d6) δ
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(ESI) m/z calcd for C14H16NOS [M + H]+ 246.0953, found 246.0948.
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2-(4-(Piperidin-1-yl)phenyl)thieno[2,3-b]thiophene-3-carbonitrile (4j). Obtained from
acetonitrile 1d and dithioester 2j, brown solid (120 mg, 75%): mp 108ꢀ110 °C; Rf 0.6 (3:7
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EtOAc/hexane); IR (neat, cm–1) 2932, 2217, 1599, 1235, 764; H NMR (400 MHz, CDCl3) δ
7.69 (d, J = 9.2 Hz, 2H), 7.44 (d, J = 5.2 Hz, 1H), 7.32 (d, J = 5.2 Hz, 1H), 6.96 (d, J = 9.2 Hz,
2H), 3.30 (t, J = 5.6 Hz, 4H), 1.72ꢀ1.68 (m, 4H), 1.66 (1.62 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 158.5, 152.7, 146.6, 133.8, 129.3, 128.8, 121.5, 119.2, 116.1, 115.4, 96.8, 49.3, 25.6,
24.5; HRMS (ESI) m/z calcd for C18H17N2S2 [M + H]+ 325.0833, found 325.0828.
2-(5-(Dimethylamino)thiophen-2-yl)-8-methyl-8H-thieno[2,3-b]indole-3-carbonitrile (4k).
Obtained from acetonitrile 1e and dithioester 2k, orange solid (110 mg, 80%): mp 154ꢀ156 °C;
Rf 0.3 (1:1 EtOAc/hexane); IR (neat, cm–1) 2196, 1549, 1492, 1408, 1055, 735; H NMR (400
1
MHz, DMSO–d6) δ 7.77 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.33 (td, J = 8.0 Hz, 1.0
Hz, 1H), 7.29 (d, J = 4.4 Hz, 1H), 7.22 (td, J = 8.0 Hz, 1.0 Hz, 1H), 5.98 (d, J = 4.4 Hz, 1H),
13
3.86 (s, 3H), 2.97 (s, 6H); C NMR (100 MHz, DMSO–d6) δ 160.1, 141.4, 140.8, 138.2, 127.7,
122.8, 120.0, 119.8 ,119.6, 117.5, 116.3, 116.2, 110.4, 102.5, 90.8; HRMS (ESI) m/z calcd for
C18H16N3S2 [M + H]+ 338.0786, found 338.0782.
8-Methyl-2-(1-methyl-1H-pyrrol-2-yl)-8H-thieno[2,3-b]indole-3-carbonitrile (4l). Obtained
from acetonitrile 1e and dithioester 2l, offꢀwhite solid (98 mg, 84%): mp 191ꢀ193 °C; Rf 0.5 (6:4
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EtOAc/hexane); IR (neat, cm–1) 2214, 1489, 1302, 1054, 749; H NMR (400 MHz, CDCl3) δ
8.07 (d, J = 8.0 Hz, 1H), 7.40ꢀ7.39 (m, 2H), 7.31ꢀ7.27 (m, 1H), 6.83 (dd, J = 2.4 Hz, 1.6 Hz,
1H), 6.55 (dd, J = 3.6 Hz, 1.6 Hz, 1H), 6.26 (dd, J = 3.6 Hz, 2.4 Hz, 1H), 3.88 (s, 3H), 3.79 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 142.1, 141.9, 135.8, 125.9, 124.0, 123.6, 121.5, 120.8,
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120.5, 119.4, 115.8, 113.5, 109.5, 108.9, 100.4, 35.3, 32.5; HRMS (ESI) m/z calcd for
C17H14N3S [M + H]+ 292.0908, found 292.0897.
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5-(1-Methyl-1H-imidazol-2-yl)-1,3-diphenyl-1H-thieno[3,2-c]pyrazole-6-carbonitrile (4m).
Obtained from acetonitrile 1f and dithioester 2m, offꢀwhite solid (98 mg, 87%): mp 259ꢀ261 °C;
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Rf 0.6 (4:6 EtOAc/hexane); IR (Neat, cm–1) 2223, 1518, 1498, 1277, 909, 758; H NMR (400
MHz, CDCl3) δ 7.96ꢀ7.94 (m, 2H), 7.79ꢀ7.77 (m, 2H), 7.59 (t, J = 8.0 Hz, 2H), 7.54ꢀ7.41 (m,
4H), 7.29 (s, 1H), 7.15 (s, 1H), 3.93 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 149.1, 144.2, 143.9,
138.6, 131.1, 131.0, 129.5, 129.2, 129.1, 128.7, 126.2, 124.1, 120.5, 113.2, 94.2, 35.2; HRMS
(ESI) m/z calcd for C22H16N5S [M + H]+ 382.1126, found 382.1121.
2-Heptylthieno[2,3-b]thiophene-3-carbonitrile (4n). Obtained from acetonitrile 1e and
dithioester 2n, pale yellow liquid (91 mg, 70%): Rf 0.9 (hexane); IR (neat, cm–1) 2205, 1612,
1
1460, 1201, 840; H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 5.2 Hz, 1H), 7.27 (d, J = 5.2 Hz,
1H), 3.07 (t, J = 7.6 Hz, 2H), 1.77 (p, J = 7.6 Hz, 2H), 1.42ꢀ1.26 (m, 8H), 0.89 (t, J = 7.2 Hz,
13
3H); C NMR (100 MHz, DMSO–d6) δ 161.6, 144.9, 134.5, 129.5, 118.8, 114.6, 101.4, 31.8,
31.6, 30.9, 29.05, 29.01, 22.7, 14.2; HRMS (ESI) m/z calcd for C14H18NS2 [M + H]+ 264.0881,
found 264.0867.
2-(1-Methyl-1H-indol-3-yl)thieno[2,3-b]pyridine-3-carbonitrile
(4o).
Obtained
from
acetonitrile 1g and dithioester 2o, brown solid (132 mg, 90%): mp 180ꢀ182 °C; Rf 0.3 (1:1
EtOAc/hexane); IR (neat, cm–1) 2204, 1524, 1378, 1233, 750; 1H NMR (400 MHz, DMSO–d6) δ
8.63 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 8.31 (s, 1H), 8.21 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 8.03ꢀ8.01 (m,
1H), 7.66ꢀ7.64 (m, 1H), 7.61 (dd, J = 8.0 Hz, 4.8 Hz, 1H), 7.38 (td, J = 8.0 Hz, 1.6 Hz, 1H), 7.32
(td, J = 6.8 Hz, 1.2 Hz, 1H), 3.96 (s, 3H); 13C NMR (100 MHz, DMSO–d6) δ 157.0, 149.5,
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147.2, 137.0, 131.8, 131.4, 128.8, 124.7, 123.1, 121.6, 119.4, 115.1, 111.2, 105.8, 94.7, 33.2;
HRMS (ESI) m/z calcd for C17H12N3S [M + H]+ 290.0752, found 290.0750.
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2-(Pyridin-3-yl)thieno[2,3-b]pyridine-3-carbonitrile (4p). Obtained from acetonitrile 1g and
dithioester 1g, grey solid (97 mg, 81%): mp 182ꢀ184 °C; Rf 0.32 (4:6 EtOAc/hexane); IR (neat,
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cm–1) 2218, 1533, 1385, 1267, 798, 746; H NMR (400 MHz, CDCl3) δ 9.12 (br s, 1H), 8.80 (br
s, 1H), 8.70 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 8.26 (dd, J = 8.0 Hz, 1.6 Hz, 2H), 7.52 (dd, J = 8.0 Hz,
4.8 Hz, 2H); 13C NMR (100 MHz, DMSO–d6) δ 158.3, 151.8, 151.0, 149.1, 148.4, 136.0, 131.9,
130.8, 122.1, 113.7, 101.1; HRMS (ESI) m/z calcd for C13H8N3S [M + H]+ 238.0439, found
238.0439.
2-(2-(4-Methoxyphenethyl)phenyl)thieno[2,3-b]pyridine-3-carbonitrile (4q). Obtained from
acetonitrile 1g and dithioester 2h, pale brown solid (128 mg, 68%): mp 112ꢀ114 °C; Rf 0.4 (1:1
EtOAc/hexane); IR (neat, cm–1) 2219, 1514, 1242, 984, 748; 1H NMR (400 MHz, CDCl3) δ 8.63
(dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.20 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.76 (dd, J = 8.0 Hz, 1.6 Hz, 1H),
7.50ꢀ7.45 (m, 1H), 7.44 (dd, J = 8.0 Hz, 4.45 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.0
Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.15 (s, 2H), 3.79 (s, 3H); 13C NMR (100 MHz, DMSO–d6) δ
160.1, 160.0, 156.0, 152.2, 148.0, 132.4, 132.1, 131.4, 130.0, 129.5, 128.1, 121.5, 120.8, 114.6,
114.2, 113.4, 102.2, 71.0, 55.4; HRMS (ESI) m/z calcd for C22H17N2O2S [M + H]+ 373.1011,
found 373.0985..
2-(2-Hydroxyphenyl)thieno[2,3-b]pyridine-3-carbonitrile
(4r).
Obtained
from
benzothiophene 4q by treatment with TFA as for 4g, brown solid (55 mg, 79%): mp 265ꢀ267 °C;
Rf 0.2 (9:1 EtOAc/hexane); IR (neat, cm–1) 3490ꢀ2850, 2212, 1609, 1459, 1241, 831; H NMR
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(400 MHz, DMSO–d6) δ 8.77 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 8.74 (d, J = 3.6 Hz, 1H), 8.03 (d, J =
8.0 Hz, 1H), 7.73 (t, J = 7.2 Hz, 1H), 7.69 (dd, J = 8.0 Hz, 4.8 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H),
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7.50 (t, J = 7.2 Hz, 1H), ; C NMR (100 MHz, DMSO–d6) δ 159.3, 155.5, 151.3, 150.0, 148.5,
132.5, 131.7, 129.5, 125.2, 125.0, 121.8, 117.2, 116.1, 115.9; HRMS (ESI) m/z calcd for
C14H9N2OS [M + H]+ 253.0436, found 253.0447.
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2-(Methylthio)benzo[b]thiophene-3-carbonitrile (4s). Obtained from acetonitrile 1h and
trithiocarbonate 2q, offꢀwhite solid (92 mg, 88%): mp 73ꢀ75 °C; Rf 0.7 (1:9 EtOAc/hexane); IR
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(neat, cm–1) 2922, 2852, 2210, 1420, 744; H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz,
1H), 7.74 (d, J = 8.0 Hz, 1H), 7.46 (td, J = 7.2 Hz, 1.2 Hz, 1H), 7.40ꢀ7.36 (m, 1H), 2.73 (s, 3H);
13C NMR (100 MHz, DMSO–d6) δ 154.5, 138.5, 137.8, 126.3, 125.5, 122.0, 121.6, 113.8, 105.2,
19.1; HRMS (ESI) m/z calcd for C10H8NS2 [M + H]+ 206.0098, found 206.0084.
2-(n-Butoxy)-5-methoxybenzo[b]thiophene-3-carbonitrile (4t). Obtained from acetonitrile 1a
and xanthate 2r, white waxy solid (133 mg, 93%): Rf 0.8 (2:8 EtOAc/hexane); IR (neat, cm–1)
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2921, 2932, 2213, 1539, 1464, 1278, 1034; H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.8 Hz,
1H), 7.13 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 8.8 Hz, 1H), 4.31 (t, J = 6.8 Hz, 2H), 3.86 (s, 3H),
1.87 (quin, J = 6.4 Hz, 2H), 1.53 (sex, J = 7.2 Hz, 2H), 1.00 (t, J = 7.6 Hz, 3H)13C NMR (100
MHz, CDCl3) δ 175.2, 159.1, 136.9, 123.3, 120.7, 114.3, 113.9, 103.8, 86.2, 76.0, 55.7, 31.2,
19.0, 13.8; HRMS (ESI) m/z calcd for C14H16NO2S [M + H]+ 262.0902, found 262.0913.
6-Fluoro-2-(octyloxy)benzo[b]thiophene-3-carbonitrile (4u). Obtained from acetonitrile 1c
and xanthate 2s, white solid (128 mg, 90%): Rf 0.8 (2:8 EtOAc/hexane); IR (neat, cm–1) 2925,
1
2215, 1542, 1470, 1238, 818; H NMR (400 MHz, CDCl3) δ 7.63 (dd, J = 8.8 Hz, 4.8 Hz 1H),
7.35 (dd, J = 4.8 Hz, 2.4 Hz, 1H), 7.18 (td, J = 8.8 Hz, 2.4 Hz, 1H), 4.34 (t, J = 6.8 Hz, 2H), 1.90
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(p, J = 6.8 Hz, 2H), 1.49 (p, J = 7.6 Hz, 2H), 1.33ꢀ1.29 (m, 8H), 0.89 (t, J = 6.8 Hz, 3H);; C
NMR (100 MHz, CDCl3) δ 173.5, 173.5, 161.5, 159.0, 131.87, 131.85, 129.9, 129.8, 122.3,
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122.2, 115.1, 114.9, 113.5, 109.3, 109.0, 85.7, 76.59, 31.8, 29.24, 29.21, 25.7, 22.7, 14.2; HRMS
(ESI) m/z calcd for C17H21FNOS [M + H]+ 306.1328, found 306.1330.
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2-(1H-Imidazol-1-yl)thieno[2,3-b]thiophene-3-carbonitrile (4v). Obtained from acetonitrile 1e
and carbamate 2t, brown solid (96 mg, 84%): mp 110ꢀ112 °C; Rf 0.8 (3:7 EtOAc/hexane); IR
(neat, cm–1) 2218, 1543, 1308, 1079, 749; 1H NMR (400 MHz, CDCl3) δ 8.24 (br s, 1H), 7.88 (d,
J = 5.2 Hz, 1H), 7.75 (br s, 1H), 7.48 (d, J = 5.2 Hz, 1H), 7.24 (br s, 1H) ; 13C NMR (100 MHz,
CDCl3) δ 149.2, 140.9, 140.0, 132.9, 132.3, 122.1, 118.6, 116.7, 113.0, 96.1; HRMS (ESI) m/z
calcd for C10H6N3S2 [M + H]+ 232.0003, found 231.9997.
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2-(3,4-Dimethoxyphenethylamino)-6-fluorobenzo[b]thiophene-3-carbonitrile (4w). Obtained
from acetonitrile 1b and carbamate 2v, offꢀwhite solid (140 mg, 84%): mp 161ꢀ163 °C; Rf 0.3
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(3:7 EtOAc/hexane); IR (neat, cm–1) 3309, 2202, 1560, 1468, 1259, 1235, 810; H NMR (400
MHz, DMSO–d6) δ 8.39 (t, J = 5.6 Hz, 1H), 7.70 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.31 (dd, J = 7.2
Hz, 5.2 Hz, 1H), 7.20 (td, J = 8.8 Hz, 2.4 Hz, 1H), 6.91 (d, J = 1.6 Hz, 1H), 6.89 (d, J = 8.0 Hz,
1H), 6.80 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 3.76 (s, 3H), 3.73 (s, 3H), 3.57 (q, J = 6.4 Hz, 2H), 2.89
13
(t, J = 6.4 Hz, 2H); C NMR (100 MHz, CDCl3) δ 164.5, 160.5, 158.1, 149.5, 148.4, 134.00,
133.99, 130.0, 129.4, 129.3, 126.8, 120.9, 120.3, 120.2, 115.6, 114.6, 114.3, 112.1, 111.9, 109.0,
109.7, 56.1, 49.2, 35.5; HRMS (ESI) m/z calcd for C19H18FN2O2S [M + H]+ 357.1073, found
357.1059.
5-Methoxy-2-(phenylamino)benzo[b]thiophene-3-carbonitrile
(4x).
Obtained
from
acetonitrile 1a and isothiocyanate 2u, pale orange solid (100 mg, 80%): mp 181ꢀ183 °C; Rf 0.5
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(3:7 EtOAc/hexane); IR (Neat, cm–1) 3251, 2198, 1545, 1451, 1293, 758; H NMR (400 MHz,
CDCl3) δ 7.43ꢀ7.39 (m, 3H), 7.35ꢀ7.33 (m, 2H), 7.27 (br s, 1H), 7.22ꢀ7.18 (m, 1H), 7.08 (d, J =
2.4 Hz, 1H), 6.84 (dd, J = 4.8 Hz, 2.4 Hz, 1H), 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
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161.6, 159.1, 140.1, 137.9, 129.9, 125.1, 122.8, 120.9, 120.2, 115.5, 113.1, 103.1, 84.0, 55.8;
HRMS (ESI) m/z calcd for C16H13N2OS [M + H]+ 281.0749, found 281.0745.
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8-Methyl-2-(phenylamino)-8H-thieno[2,3-b]indole-3-carbonitrile (4y). Obtained from
acetonitrile 1e and isothiocyanate 2u, brown solid (95 mg, 78%): mp 193ꢀ195 °C; Rf 0.4 (1:1
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EtOAc/hexane); IR (neat, cm–1) 3361, 2224, 1600, 1497, 1276, 745; H NMR (400 MHz,
DMSO–d6) δ 9.28 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.34ꢀ7.27 (m, 3H),
7.24ꢀ7.20 (m, 1H), 7.10ꢀ7.08 (m, 2H), 6.31 (t, J = 8.0 Hz, 1H), 3.86 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 149.6, 143.7, 141.1, 135.3, 129.7, 122.9, 122.2, 121.0, 120.3, 119.2, 116.3,
116.1, 115.0, 109.5, 92.8, 32.4; HRMS (ESI) m/z calcd for C18H14N3S [M + H]+ 304.0908, found
304.0902.
Supporting information. 30 figures showing scanned copies of H NMR and 13C NMR spectra
1
for compounds 2f-h, 2n, 5a and 4a-y. This material is available free of charge via the internet at
http://pubs.acs.org.
Acknowledgements. We thank Professor C. N. R. Rao, FRS, for encouragement and support of
our research; JNCASR, and the Council of Scientific and Industrial Research (CSIR, New Delhi)
for financial assistance; and CSIR–SRF (to A.A., B.S. and S.V.K) and Indian National Science
Academy, New Delhi, for INSA Senior Scientist position (to H.I.).
References
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G.; Carfagna, C. J. Org. Chem. 2011, 76, 8277 and references cited therein.
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D. P.; Hering, T.; Konig, B. Org. Lett. 2012, 14, 5334 and references cited therein. (d)
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Yamamoto, T.; Doi, I.; Miyazaki, E.; Osaka, I.; Takimiya, K. J. Am. Chem. Soc. 2013,
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