A novel radical cyclization approach to thieno-fused heterocycles

Article abstract of DOI:10.1002/ejoc.201100516

An efficient synthesis of novel aryl/heteroaryl-substituted thieno-fused heterocycles, that is, thieno[2,3-b]thiophenes, thieno[2,3-b]indoles, and pyrazolo[3,2-c]thiophenes, involving radical-mediated cyclization of 2-(2-bromoheteroaryl)-3-methylthio-3-ar

Full text of DOI:10.1002/ejoc.201100516

FULL PAPER
DOI: 10.1002/ejoc.201100516
A Novel Radical Cyclization Approach to Thieno-Fused Heterocycles
Prabal P. Singh,[a] Ashok K. Yadav,[a] Hiriyakkanavar Ila,*[b] and
Hiriyakkanavar Junjappa[c]
Dedicated to Professor Carmen Nájera on the occasion of her 60th birthday
Keywords: Sulfur heterocycles / Radical reactions / Cyclization / Fused-ring systems
An efficient synthesis of novel aryl/heteroaryl-substituted
thieno-fused heterocycles, that is, thieno[2,3-b]thiophenes,
thieno[2,3-b]indoles, and pyrazolo[3,2-c]thiophenes, involv-
ing radical-mediated cyclization of 2-(2-bromoheteroaryl)-
3-methylthio-3-aryl/heteroaryl acrylonitriles has been re-
ported.
phenes such as thieno[3,2-b]pyrroles,[9a,9b] thieno[3,2-d]-
imidazole, and thieno[2,3-d]imidazoles[9b] have been shown
to be potential anti-inflammatory agents[9a] and are useful
in the treatment of hepatitis C infection.[9a–9c] A thieno[3,2-
c]pyrazole derivative A02011–1 (4) has been found to be a
potent adenyl cyclase activator exhibiting an antiprolifera-
tive effect in rat vascular smooth muscle cells.[9d]
Introduction
Condensed thiophenes, especially heterocyclo-fused sys-
tems, have attracted considerable attention because several
of these compounds display exceptional optoelectronic
properties as well as a range of biological activities, thus
finding applications as organic functional materials and as
pharmaceuticals.[1–5] Thus, fused thienothiophenes such as
thieno[2,3-b]thiophene (1a), thieno[3,2-b]thiophene (1b),
and dithienothiophenes have been widely investigated as
key components in several molecular structures for a variety
of applications such as charge conducting materials,[2] or-
ganic field-effect transistors,[3] organic luminescence de-
vices, nonlinear optics,[4] and as porous hydrogen storage
hosts.[5] On the other hand, heterocyclo-fused thiophenes
such as thieno[2,3-b]indole (2) have attracted great deal of
interest due to its presence in natural products, and thieno-
indolin (3, Figure 1) isolated from the culture broth of
Streptomyces albogriseolus (MJ 286–76F7) displays both
growth promoting and inhibiting activities in rice seed-
lings.[6] Also, a number of thieno[2,3-b]indole derivatives are
shown to display antifungal activity[7] and are useful in the
treatment of central nervous system diseases such as epi-
lepsy, senile dementia, Parkinson’s disease, brain ischemia,
and so on.[8] Some of the thieno[3,2-b]indole derivatives
have also been found to be novel conducting polymers.
Similarly, other five-membered heterocyclo-fused thio-
Figure 1. Important thieno-fused heterocycles.
[a] Department of Chemistry, Indian Institute of Technology,
Kanpur 208016, India
A number of approaches have been reported in the litera-
ture for the synthesis of heterocyclo-fused thiophenes. Thus,
symmetrically substituted thieno[2,3-b]thiophenes are usu-
ally synthesized by intramolecular cyclocondensation of in
situ generated polarized ketene dithioacetals obtained by
dialkylation of dithioate salts with activated halomethylene
compounds involving construction of both thiophene rings
in a one-pot reaction.[10] A similar general approach to
[b] New Chemistry Unit,
Jawaharlal Nehru Centre for Advanced Scientific Research,
Jakkur, Bangalore 560064, India
Fax: +91-80-22082766
E-mail: hila@jncasr.ac.in
[c] Reva Institute of Science and Management,
Kattigenahalli, Yelahanka, Bangalore 5600064, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100516.
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P. P. Singh, A. K. Yadav, H. Ila, H. Junjappa
FULL PAPER
these heterocycles involves construction of a thiophene ring viously developed methodology from our laboratory by
on vicinally substituted 2-formyl (or acyl)-3-thiomethylene- base-induced condensation of the corresponding 2-bromo-
thiophene derivatives through base-induced intramolecular 3-thienylacetonitrile, 2-bromo-1-N-methyl-3-indolylaceton-
cyclocondensation.[11] This methodology or its variants has itrile, and 1,3-diphenyl-4-bromo-5-pyrazolylacetonitrile,
also been employed for the synthesis of other thieno-fused respectively, with either aryl/heteroaryl dithioesters (or car-
heterocycles such as thieno[2,3-c]- and thieno[3,2-c]pyr- bon disulfide) followed by in situ S-methylation of the re-
azoles,[12] thieno[2,3-b]indole derivatives,[8,13,14] as well as in sulting enethioates (Scheme 2).[22b] The structures of the
total synthesis of thienoindolin alkaloids by Bergman and known (i.e., 9b, 9c, 11b–e, 13a, and 13c) and the unknown
co-workers.[15] Other preparative methods for aryl/hetero- (i.e., 8, 9a, 9d, 9e, 10, 11a, 12, 13b, 13d, 13e) precursors were
aryl-substituted thienothiophenes utilize palladium-cata- established with the help of spectral and analytical data.
lyzed cross-coupling or selective metalation reac- The 1H and 13C NMR spectra of these compounds showed
tions[1c,11a–11d,16] including direct C–H arylation of thieno- them to be inseparable mixture of (E)/(Z) isomers, which
[2,3-b]thiophenes[17] and intramolecular cyclization of bis- also undergo thermal (Z)/(E) isomerization as reported in
acetylene dithioate salts obtained by treatment of metalated our previous paper.[22d]
bisacetylenes with carbon disulfide.[18] Thieno[2,3-b]indole
and its derivatives have also been obtained by nitrene-medi-
ated Cadogan cyclization of 3-(o-nitrophenyl)thiophene,[19]
AlCl3-induced electrophilic recyclization of 2-(2-furyl)aryl-
isothiocyanates,[20] and tandem sigmatropic rearrangement
of 2-(2Ј-butynylthio)indole sulfoxide derivative.[21a–21c]
However, most of these methods suffer from some draw-
backs and are limited in scope and generality. Therefore
more flexible and efficient general methods for the prepara-
tion of thieno-fused heterocycles are desirable in view of
their applications in materials science as well as pharmaceu-
ticals.
Scheme 2. Synthesis of 2-(bromoaryl/heteroaryl)-3-(methylthio)-3-
aryl/heteroarylacrylonitriles.
A detailed investigation on the radical cyclization of sub-
strate 8 with various reagents under different reaction con-
ditions revealed that the best yield of 14 (Table 1, Entry 1)
Our own interest in the synthesis of thienoheterocycles
derives from our continued research program based on the
development of new synthetic methods for five- and six-
membered heterocycles by employing polarized ketene di-
thioacetals and other novel organosulfur precursors.[22]
During the course of these studies, we recently reported a
novel efficient approach for the synthesis of substituted 2-
aryl/heteroaryl-3-cyano benzo[b]thiophenes through radi-
cal-mediated cyclization of 2-(o-bromoaryl)-3-aryl/het-
eroaryl/methylthioacrylonitriles (Scheme 1).[22d] The effi-
ciency of this method along with the high yields of the
product benzo[b]thiophenes prompted us to apply this radi-
cal cyclization protocol for the synthesis of novel thieno-
fused heterocycles such as thieno[2,3-b]thiophenes, thi-
eno[2,3-b]indoles, and pyrazolo[3,2-c]thiophenes from the
appropriately substituted precursors. We have successively
achieved this goal, and the results of these studies are pre-
sented in this paper.
Table 1. Synthesis of substituted thieno[2,3-b]thiophenes 14 and 15.
Scheme 1. Synthesis of substituted benzo[b]thiophenes by radical
cyclization.
Results and Discussion
Desired acrylonitriles 9, 11, and 13 and related ketene
dithioacetals 8, 10, and 12 were prepared according to pre-
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A Novel Radical Cyclization Approach to Thieno-Fused Heterocycles
was obtained under catalytic tin hydride conditions by
The radical cyclization protocol was found to be equally
using 20 mol-% of tributyltin chloride in the presence of facile for the construction of the thieno[2,3-b]indole ring
NaCNBH3 and AIBN (10 mol-%) in refluxing tert-butyl system from the corresponding precursors 10 and 11a–e, as
alcohol as reported in our previous paper.[22d] These opti- shown in Scheme 4 and Table 2. Interestingly, treatment of
mized reaction conditions were applied throughout our ketene dithioacetal 10 with nBu3SnCl/NaCNBH3 under
studies of radical cyclization of various 2,3-aryl/heteroaryl- previously reported reaction conditions yielded exclusively
substituted 3-(methylthio)acrylonitriles 8–13. Thus, ketene 16a (69%), which is apparently formed by further reductive
dithioacetal 8 and acrylonitriles 9a–e underwent smooth dethiomethylation of the corresponding 2-(methylthio) de-
radical cyclization under these conditions to furnish thio- rivative 16b under these conditions (Table 2, Entry 1). On
phenes 14 and 15a–e in overall high yields (Scheme 3; the other hand, novel thieno[2,3-b]indole-3-carbonitriles
Table 1, Entries 2–6), and no trace of the formation of de- 17a–e bearing an aryl or heteroaryl group in the 2-position
brominated products was observed in these reactions.
could be synthesized in excellent yields by exposing 11a–e
to nBu3SnCl/NaCNBH3 under optimized reaction condi-
tions (Table 2, Entries 2–6).
Scheme 3. Synthesis of substituted thieno[2,3-b]thiophenes 14 and
15.
Table 2. Synthesis of 2,3-substituted thieno[2,3-b]indoles 16 and 17.
Scheme 4. Synthesis of 2,3-substituted thieno[2,3-b]indoles 16 and
17.
Table 3. Synthesis of 5,6-substituted thieno[3,2-c]pyrazoles 18 and
19.
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P. P. Singh, A. K. Yadav, H. Ila, H. Junjappa
FULL PAPER
vents. Wherever appropriate, all reagents were purified prior to use
according to the appropriate guidelines.[23] 1H NMR (300, 400, or
500 MHz) and 13C NMR (75, 100, or 125 MHz) spectra were re-
corded with a Jeol JNM-LA 400 FT NMR or a Jeol JNM-LA 500
FT NMR spectrometer with CDCl3 as the solvent. Tetramethylsil-
ane was used as an internal reference. Melting points were recorded
with a Mel-Temp melting point apparatus (capillary method). IR
spectra were recorded with a Perkin–Elmer 1320 spectrophotome-
ter. The FAB mass spectra were recorded with a JEOL SX 102/
DA-6000 Mass Spectrometer/Data system. HRMS (ESI) data were
recorded with a Waters Micromass Q-TOF Premier Mass Spec-
trometer and a Bruker Daltonics APEXII FTICR spectrometer.
Chromatographic purification was conducted by column
chromatography on 100–200 mesh size silica gel obtained from
Acme Synthetic Chemicals (India).
The scope and generality of this efficient radical-medi-
ated thiophene annulation protocol was further evident by
extending the methodology for the synthesis of tetrasubsti-
tuted thieno[3,2-c]pyrazoles 18 and 19a–e as depicted in
Scheme 5. Thus, a number of 1,3-diphenyl-6-cyano-5-meth-
ylthio- (18), 5-aryl-/5-heteroarylthieno[3,2-c]pyrazoles 19a–
e were obtained in excellent yields when acrylonitrile pre-
cursors 12 and 13a–e were subjected to radical cyclization
under identical conditions (Table 3, Entries 1–6).
General Procedure for the Preparation of 2-(2-Bromoheteroaryl)-
3-aryl/heteroaryl-3-(methylthio)-2-propenenitriles (9, 1,1 and
13):[22b,22d,22e] To a stirred suspension of NaH (0.44 g, 11 mmol,
60%) in dry THF or DMF (25 mL) under a N2 atmosphere was
added a solution of the corresponding 2,4-bromoheteroarylaceton-
itrile (5.0 mmol) in dry THF or DMF (50 mL) dropwise at 0 °C.
The reaction mixture was stirred at room temperature for 1 h and
a solution of the corresponding dithioester (5.0 mmol) in dry THF
or DMF (15 mL) was added dropwise over a period of 15–20 min
at 0 °C. The reaction mixture was further stirred for 3 h at room
temperature and MeI (0.46 mL, 7.5 mmol) was then added drop-
Scheme 5. Synthesis of 5,6-substituted thieno[3,2-c]pyrazoles 18
and 19.
A probable mechanism for the formation of thieno-fused
heterocycles 14–19 from acrylonitrile precursors 8–13 is
shown in Scheme 6. Thus, carbon-centered heterocyclic
radical intermediate 20 (formed through abstraction of a
bromine radical by a tributyltin radical) undergoes intramo-
lecular addition to the favorably located methylthio group
to give fused five-membered radical intermediate 21, which wise at 0 °C. The mixture was further stirred for 3 h and then
poured into ice-cold water. The aqueous layer was extracted with
CH2Cl2 (3ϫ50 mL). The combined organic extract was washed
with H2O (3ϫ50 mL) and brine (50 mL) and dried with Na2SO4.
The solvent was removed under reduced pressure to give crude ad-
ducts 9, 11, and 13, which were purified by column chromatog-
raphy (hexane/EtOAc).
undergoes homolytic C–S bond cleavage to furnish thieno-
fused heterocycles 14–19 in good yields (Scheme 6).
2-(2-Bromo-3-thienyl)-3-(1-N-methyl-2-pyrrolyl)-3-methylthio-2-prop-
enenitrile (9d): Obtained as a 1:1 inseparable mixture of geometrical
isomers; yield: 72% (1.22 g); viscous liquid; Rf = 0.46 (hexane/
1
EtOAc, 9:1). IR (KBr): ν = 3090, 2925, 2204, 1556, 1500 cm–1. H
˜
NMR (400 MHz, CDCl3, 25 °C): δ = 7.32 (d, J = 5.6, 0.5 Hz, 0.5
H, HetArH), 7.02–7.03 (m, 1 H, HetArH), 6.79 (dd, J = 2.2,
2.2 Hz, 0.5 H, HetArH), 6.61 (dd, J = 2.2, 2.2 Hz, 0.5 H, HetArH),
6.44 (dd, J = 3.6, 1.7 Hz, 0.5 H, HetArH), 6.25 (d, J = 5.6 Hz, 0.5
H, HetArH), 6.21–6.19 (m, 1 H, HetArH), 6.10 (dd, J = 3.7,
2.7 Hz, 0.5 H, HetArH), 3.63 (s, 1.5 H, NMe), 3.17 (s, 1.5 H,
NMe), 2.05 (s, 1.5 H, SMe), 1.79 (s, 1.5 H, SMe) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 155.1, 152.5, 133.5, 128.5, 128.3,
126.7, 126.1, 125.8, 125.4, 117.0, 116.5, 114.6, 113.8, 113.6, 112.1,
108.7, 102.4, 101.8, 34.4, 34.3, 16.5, 15.9 ppm. HRMS (ESI): calcd.
for C13H12N2S2 [M + H]+ 338.9625; found 338.9623.
Scheme 6. Mechanism for the formation of 14–19 from 8–13.
Conclusions
In summary, we have reported an efficient, general, high-
yielding synthesis of novel aryl/heteroaryl-substituted thi-
eno-fused heterocyclic motifs by a radical cyclization pro-
cess involving unusual intramolecular addition of a carbon-
centered radical to a neighboring sulfide as the key step.
The methodology utilizes readily accessible precursors and
proceeds under simple and mild reaction conditions with-
out formation of any side products. The broad scope of the
reaction for the synthesis of other thieno-fused heterocycles
is currently under investigation.
General Procedure for the Radical Cyclization of 2-(2-Bromo-3-
thienyl)-/2-(2-Bromo-1-N-methyl-3-indolyl)-/2-(4-Bromo-1,3-diphen-
yl-1H-5-pyrazolyl)-3-aryl/heteroaryl/methylthio-3-(methylthio)-2-
propenenitriles (8, 9a–e, 10, 11a–e, 12, and 13a–e):[22d] To a solution
of the appropriate propenenitrile 8–13 (2.5 mmol), AIBN
(10 mmol-%), and NaCNBH3 (5.0 mmol) in degassed tBuOH
(25 mL) was added nBu3SnCl (20 mmol-%), and the reaction mix-
ture was heated at reflux for 5–8 h. It was then cooled to room
temperature and the solvent was evaporated followed by the ad-
dition of water (25 mL). It was extracted with ethyl acetate
(3ϫ25 mL), the combined organic extracts were washed with H2O
(2ϫ50 mL) and brine (50 mL), dried (Na2SO4), and evaporated
under reduced pressure to afford the crude product, which was
purified by column chromatography over silica gel (EtOAc/hexane)
to give pure thieno-fused heterocycles 14–19.
Experimental Section
General: Unless otherwise noted, all reactions were carried out in
oven-dried glassware under an N2 atmosphere in anhydrous sol-
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A Novel Radical Cyclization Approach to Thieno-Fused Heterocycles
2-Methylthiothieno[2,3-b]thiophene-3-carbonitrile (14): Yield: 76%
(0.40 g); colorless liquid; Rf = 0.58 (hexane/EtOAc, 9:1). IR (KBr):
˜
9:1). IR (KBr): ν = 2937, 2218, 1497, 1325 cm–1 1H NMR
.
˜
(300 MHz, CDCl3, 25 °C): δ = 8.01 (d, J = 7.8 Hz, 1 H, ArH), 7.44
(s, 1 H, HetArH), 7.37–7.23 (m, 3 H, ArH), 3.81 (s, 3 H, NMe)
ν = 3102, 2923, 2223, 1506, 1461, 1429, 1374, 1262 cm–1. 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 7.45 (d, J = 5.2 Hz, 1 H, HetArH), ppm. 13C NMR (75 MHz, CDCl3, 25 °C): δ = 168.8, 143.3, 142.3,
7.23 (d, J = 5.2 Hz, 1 H, HetArH), 2.62 (s, 3 H, SMe) ppm. 13C 126.1, 123.4, 121.2, 120.2, 119.2, 115.3, 109.3, 102.1, 32.2 ppm.
NMR (100 MHz, CDCl3, 25 °C): δ = 152.2, 144.9, 136.6, 129.8, HRMS (ESI): calcd. for C12H9N2S [M + H]+ 213.0486; found
118.5, 113.6, 106.4, 21.2 ppm. HRMS (ESI): calcd. for C8H5NS3
213.0485.
[M + H]+ 211.9662; found 211.9666.
8-Methyl-2-(3,4,5-trimethoxyphenyl)-8H-thieno[2,3-b]indole-3-
carbonitrile (17a): Yield: 73 % (0.69 g); yellow solid; m.p. 170–
2-(3,4,5-Trimethoxyphenyl)thieno[2,3-b]thiophene-3-carbonitrile
(15a): Yield: 89% (0.74 g); white solid; m.p. 136–137 °C; Rf = 0.51
171 °C; R = 0.50 (hexane/EtOAc, 9:1). IR (KBr): ν = 2932, 2831,
˜
f
2214, 1581, 1490, 1328, 1258, 1133 cm–1 1H NMR (400 MHz,
.
(hexane/EtOAc, 9:1). IR (KBr): ν = 3096, 2937, 2217, 1584, 1501,
˜
1413, 1331, 1247 cm–1. 1H NMR (500 MHz, CDCl3, 25 °C): δ =
7.48 (d, J = 5.4 Hz, 1 H, HetArH), 7.35 (d, J = 5.4 Hz, 1 H, Het-
ArH), 6.99 (s, 2 H, ArH), 3.93 (s, 6 H, 2 OMe), 3.90 (s, 3 H, OMe)
ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ = 157.2, 153.6, 146.3,
139.6, 135.0, 129.8, 127.2, 119.1, 115.4, 105.0, 98.7, 61.0, 56.3 ppm.
HRMS (ESI): calcd. for C16H14NS2O3 [M + H]+ 332.0333; found
332.0334.
CDCl3, 25 °C): δ = 8.08 (d, J = 7.8 Hz, 1 H, ArH), 7.38 (d, J =
6.2 Hz, 2 H, ArH), 7.30–7.26 (m, 1 H, ArH), 7.02 (s, 2 H, ArH),
3.96 (s, 6 H, 2 OMe), 3.91 (s, 3 H, OMe), 3.86 (s, 3 H, NMe) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 153.6, 145.1, 141.7, 141.0,
138.9, 128.0, 123.4, 122.4, 120.7, 120.4, 119.1, 116.1, 109.3, 104.6,
9 7 . 0 , 6 1 . 0 , 5 6 . 2 , 3 2 . 2 p p m . H R M S ( E S I ) : c a l c d . fo r
C21H19N2SO3[M + H]+ 379.1116; found 379.1137.
2-(2-Thienyl)thieno[2,3-b]thiophene-3-carbonitrile (15b): Yield: 70%
(0.43 g); white solid; m.p. 97–98 °C; Rf = 0.81 (hexane/EtOAc, 9:1).
8-Methyl-2-(2-thienyl)-8H-thieno[2,3-b]indole-3-carbonitrile (17b):
Yield: 75% (0.55 g); white solid; m.p. 139–140 °C; Rf = 0.38 (hex-
IR (KBr): ν = 3100, 2924, 2215, 1247, 1087 cm–1 1H NMR
.
˜
ane/EtOAc, 9:1). IR (KBr): ν = 3098, 3084, 2928, 2209, 1493, 1461,
˜
1410, 1324, 1052 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
7.97 (d, J = 7.6 Hz, 1 H, ArH), 7.50 (dd, J = 3.6, 1.2 Hz, 1 H,
HetArH), 7.34–7.20 (m, 4 H, ArH/ArHetArH), 7.08 (dd, J = 5.0,
1.2 Hz, 1 H, HetArH), 3.75 (s, 3 H, NMe) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 141.7, 140.5, 138.1, 134.5, 128.1,
126.3, 126.1, 123.4, 121.7, 120.5, 120.4, 119.1, 115.7, 109.3, 96.6,
32.2 ppm. HRMS (ESI): calcd. for C16H11N2S2 [M + H]+ 295.0364;
found 295.0389.
(400 MHz, CDCl3, 25 °C): δ = 7.58 (dd, J = 5.0, 1.0 Hz, 1 H, Het-
ArH), 7.45 (d, J = 5.0 Hz, 1 H, HetArH), 7.43 (dd, J = 5.0, 1.0 Hz,
1 H, HetArH), 7.31 (d, J = 5.0 Hz, 1 H, HetArH), 7.12 (dd, J = 5.0,
3.9 Hz, 1 H, HetArH) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ
= 149.8, 146.1, 134.7, 133.6, 130.1, 128.0, 127.5, 119.1, 115.1,
98.1 ppm. HRMS (ESI): calcd. for C11H6NS3 [M + H]+ 247.9662;
found 247.9665.
2-(2-Furyl)thieno[2,3-b]thiophene-3-carbonitrile (15c): Yield: 65%
(0.37 g); white solid; m.p. 115–116 °C; Rf = 0.78 (hexane/EtOAc,
8-Methyl-2-(2-furyl)-8H-thieno[2,3-b]indole-3-carbonitrile (17c):
Yield: 72% (0.50 g); yellow solid; m.p. 111–112 °C; Rf = 0.41 (hex-
9:1). IR (KBr): ν = 3108, 2924, 2216, 1607, 1388, 1287, 1255,
˜
1075 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.51 (d, J =
1.7 Hz, 1 H, HetArH), 7.45 (d, J = 5.4 Hz, 1 H, HetArH), 7.30 (d,
J = 5.4 Hz, 1 H, HetArH), 7.16 (d, J = 3.6 Hz, 1 H, HetArH), 6.57
(dd, J = 3.6, 1.7 Hz, 1 H, HetArH) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 146.4, 145.6, 145.5, 143.3, 134.8, 130.1, 118.8,
114.8, 112.5, 109.7, 95.8 ppm. HRMS (ESI): calcd. for C11H6NOS2
[M + H]+ 231.9891; found 231.9893.
ane/EtOAc, 9:1). IR (KBr): ν = 2924, 2214, 1496, 1459 cm–1. 1H
˜
NMR (400 MHz, CDCl3 25 °C): δ = 8.02 (d, J = 7.8 Hz, 1 H,
ArH), 7.47 (d, J = 1.7 Hz, 1 H, HetArH), 7.36–7.35 (m, 2 H, ArH),
7.28–7.24 (m, 1 H, ArH), 7.09 (d, J = 3.5 Hz, 1 H, HetArH), 6.56
(dd, J = 3.5, 1.7 Hz, 1 H, HetArH), 3.84 (s, 3 H, NMe) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 142.3, 142.2, 138.1, 134.5,
133.1, 128.0, 125.5, 123.5, 120.5, 119.3, 115.5, 112.5, 109.4, 108.2,
96.6, 32.3 ppm. HRMS (ESI): calcd. for C16H10N2OSNa
[M + Na]+ 301.0411; found 301.0418.
2-(1-N-Methyl-2-pyrrolyl)thieno[2,3-b]thiophene-3-carbonitrile
(15d): Yield: 84% (0.51 g); white solid; m.p. 88–89 °C; Rf = 0.67
(hexane/EtOAc, 9:1). IR (KBr): ν = 3096, 2953, 2216, 1554, 1488,
˜
8-Methyl-2-(1-N-methyl-2-pyrrolyl)-8H-thieno[2,3-b]indole-3-
carbonitrile (17d): Yield: 74% (0.54 g); m.p. 167–168 °C; Rf = 0.42
1
1457, 1304 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 7.46 (d,
J = 5.2 Hz, 1 H, HetArH), 7.34 (d, J = 5.2 Hz, 1 H, HetArH), 6.82
(dd, J = 2.4, 2.2 Hz, 1 H, HetArH), 6.58 (dd, J = 3.6, 1.8 Hz, 1 H,
HetArH), 6.23 (dd, J = 3.6, 2.7 Hz, 1 H, HetArH), 3.77 (s, 3 H,
NMe) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 147.8, 145.5,
135.5, 129.7, 126.6, 123.6, 119.0, 115.1, 113.8, 109.0, 100.8,
35.4 ppm. HRMS (ESI): calcd. for C12H9N2S2 [M + H]+ 245.0207;
found 245.0209.
(hexane/EtOAc, 9:1). IR (KBr): ν = 2925, 2854, 2214, 1491, 1460,
˜
1403, 1331, 1302 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
8.08 (d, J = 7.8 Hz, 1 H, ArH), 7.40–7.38 (m, 2 H, ArH), 7.30–
7.25 (m, 1 H, ArH), 6.83 (dd, J = 2.7, 1.8 Hz, 1 H, HetArH), 6.25
(dd, J = 3.8, 2.7 Hz, 1 H, HetArH), 5.68 (dd, J = 3.8, 1.8 Hz, 1 H,
HetArH), 3.87 (s, 3 H, NCH3), 3.78 (s, 3 H, NCH3) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 141.8, 141.7, 135.6, 125.7,
123.8, 123.4, 121.3, 120.6, 120.3, 119.2, 115.7, 113.3, 109.3, 108.7,
100.2, 35.1, 32.3 ppm. HRMS (ESI): calcd. for C17H13N3S [M +
H]+ 292.0907; found 292.0907.
2-(1-N-Methyl-3-indolyl)thieno[2,3-b]thiophene-3-carbonitrile (15e):
Yield: 80% (0.58 g); white solid; m.p. 139–140 °C; Rf = 0.48 (hex-
ane/EtOAc, 9:1). IR (KBr): ν = 3123, 3050, 2908, 2210, 1534, 1227,
˜
1163 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 8.01 (d, J =
7.8 Hz, 1 H, ArH), 7.80 (s, 1 H, HetArH), 7.46 (d, J = 5.4 Hz, 1
H, HetArH), 7.41 (d, J = 7.8 Hz, 1 H, ArH), 7.37–5.25 (m, 3 H,
ArH), 3.89 (s, 3 H, NMe) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 152.1, 145.4, 137.0, 133.4, 129.2, 129.0, 125.5, 123.0,
121.2, 119.9, 118.7, 116.5, 110.0, 107.7, 95.8, 33.2 ppm. HRMS
(ESI): calcd. for C16H10N2S2 [M]+ 294.0285; found 294.0282.
8-Methyl-2-(3-pyridyl)-8H-thieno[2,3-b]indole-3-carbonitrile (17e):
Yield: 72% (0.52 g); white solid; m.p. 191–192 °C; Rf = 0.47 (hex-
ane/EtOAc, 9:1). IR (KBr): ν = 2921, 2219, 1495, 1469, 1410, 1327,
˜
1
1089 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 8.60 (br. s, 1
H, HetArH), 8.28 (br. s, 1 H, HetArH), 7.87 (d, J = 8.0 Hz, 1 H,
ArH), 7.70 (d, J = 7.6 Hz, 1 H, HetArH), 7.10 (dd, J = 7.6, 1.0 Hz,
1 H, HetArH), 7.06–7.01 (m, 1 H, ArH), 6.96–6.90 (m, 2 H, ArH),
3.51 (s, 3 H, NCH3) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ
= 149.0, 147.0, 142.1, 142.0, 139.5, 134.7, 129.2, 124.0, 123.9, 122.8,
8-Methyl-8H-thieno[2,3-b]indole-3-carbonitrile (16a): Yield: 69%
(0.37 g); white solid; m.p. 118–120 °C; Rf = 0.42 (hexane/EtOAc,
Eur. J. Org. Chem. 2011, 4001–4007
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4005

P. P. Singh, A. K. Yadav, H. Ila, H. Junjappa
FULL PAPER
120.7, 120.5, 119.3, 115.3, 109.5, 98.9, 32.4 ppm. HRMS (ESI):
calcd. for C17H12N3S [M + H]+ 290.0752; found 290.0750.
ArH), 7.70 (d, J = 8.0 Hz, 2 H, ArH), 7.59–7.33 (m, 9 H, ArH),
3.88 (s, 3 H, NCH3) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ
= 157.3, 144.6, 143.7, 138.9, 137.2, 131.5, 130.1, 129.3, 129.1, 128.7,
128.2, 126.1, 125.6, 124.1, 123.4, 121.7, 120.3, 117.4, 115.5, 110.3,
108.0, 87.1, 33.6 ppm. HRMS (ESI): calcd. for C27H19N4S [M +
H]+ 431.1330; found 431.1358.
1,3-Diphenyl-5-(methylthio)-1H-thieno[3,2-c]pyrazole-6-carbonitrile
(18): Yield: 62% (0.54 g); white solid; m.p. 221–222 °C; Rf = 0.65
(hexane/EtOAc, 9:1). IR (KBr): ν = 2923, 2853, 2218, 1598, 1502,
˜
1
1457, 1371, 1183, 1026 cm–1. H NMR (500 MHz, CDCl3, 25 °C):
Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedure of 8, 10, and 12; characteriza-
tion data of 8, 9a, 9e, 10, 11a, 12, 13b, 13d, and 13e; and copies of
δ = 8.21 (d, J = 8.0 Hz, 2 H, ArH), 7.52–7.37 (m, 8 H, ArH), 2.49
(s, 3 H, SCH3) ppm. 13C NMR (125 MHz, CDCl3, 25 °C): δ =
166.3, 153.2, 140.6, 136.7, 133.4, 130.3, 129.7, 129.5, 129.4, 126.8,
125.3, 117.6, 108.3, 101.1, 19.6 ppm. HRMS (ESI): calcd. for
C19H13N3S2 [M]+ 347.055; found 347.054.
1
the H NMR and 13C NMR spectra of 14, 15a–e, 16a, 17a–e, 18,
and 19a–e.
1,3-Diphenyl-5-(4-methoxyphenyl)-1H-thieno[3,2-c]pyrazole-6-
carbonitrile (19a): Yield: 76 % (0.77 g); white solid; m.p. 214–
Acknowledgments
215 °C; R = 0.32 (hexane/EtOAc, 9:1). IR (KBr): ν = 2923, 2851,
˜
f
2219, 1606, 1522, 1497, 1458, 1262, 1173, 1032 cm–1 1H NMR
.
We are thankful to the Council of Scientific and Industrial Re-
search (CSIR), New Delhi, for financial support. H.I. thanks In-
dian National Science Academy, New Delhi for an INSA Senior
Scientist position at JNCASR, Bangalore.
(500 MHz, CDCl3, 25 °C): δ = 7.94 (d, J = 7.9 Hz, 2 H, ArH), 7.77
(dd, J = 8.5 Hz, 4H ArH), 7.57 (dd, J = 7.9 Hz, 2 H, ArH), 7.48
(dd, J = 7.5 Hz, 2 H, ArH), 7.46–7.39 (m, 2 H, ArH), 7.03 (dd, J
= 8.5, 1.5 Hz, 2H. ArH), 3.87 (s, 3 H, OMe) ppm. 13C NMR
(125 MHz, CDCl3): δ = 162.4, 161.7, 145.1, 143.7, 138.7, 131.3,
129.7, 129.3, 129.1, 128.8, 128.4, 126.0, 124.5, 124.2, 118.1, 114.9,
114.2, 90.1, 55.6 ppm. HRMS (ESI): calcd. for C25H18N3SO [M +
H]+ 408.1171; found 408.1177.
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1,3-Diphenyl-5-(2-thienyl)-1H-thieno[3,2-c]pyrazole-6-carbonitrile
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(hexane/EtOAc, 6:1). IR (KBr): ν = 3073, 2925, 2219, 1594, 1554,
˜
1496, 1453, 1435 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
7.93 (d, J = 7.5 Hz, 2 H, ArH), 7.77–7.75 (m, 3 H, ArH), 7.60 (d,
J = 8.0 Hz, 2 H, ArH), 7.54–7.42 (m, 5 H, ArH/HetArH), 7.19 (dd,
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25 °C): δ = 154.8, 145.1, 144.0, 138.8, 134.1, 131.4, 129.6, 129.3,
129.1, 128.9, 128.8, 126.3, 124.4, 117.7, 114.1, 101.0, 90.1 ppm.
MS: m/z (%) = 383 (75) [M]+, 384 (100) [M + H]+. HRMS (ESI):
calcd. for C22H13N3S2 [M]+ 383.0551; found 383.0554.
1,3-Diphenyl-5-(2-furyl)-1H-thieno[3,2-c]pyrazole-6-carbonitrile
(19c): Yield: 73% (0.67 g); white solid; m.p. 231–232 °C; Rf = 0.45
(hexane/EtOAc, 6:1). IR (KBr): ν = 2923, 2853, 2218, 1598, 1502,
˜
1457 cm–1. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 7.93 (d, J =
8.5 Hz, 2 H, ArH); 7.75 (d, J = 8.5 Hz, 2 H, ArH), 7.59–7.57 (m,
3 H, ArH), 7.51–7.48 (m, 3 H, ArH), 7.47–7.40 (m, 2 H, HetArH),
6.32 (d, J = 3.4 Hz, 1 H, HetArH) ppm. 13C NMR (125 MHz,
CDCl3, 25 °C): δ = 150.0, 146.5, 144.6, 144.2, 143.8, 138.6, 131.1,
129.4, 129.1, 128.9, 128.5, 126.0, 124.0, 118.0, 113.8, 113.1, 111.8,
87.4 ppm. HRMS (ESI): calcd. for C22H14N3SO [M + H]+
368.0858; found 368.0858.
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6-carbonitrile (19d): Yield: 71 % (0.85 g); white solid; m.p. 214–
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˜
f
1598, 1502, 1457, 1371, 1183, 1026 cm–1 1H NMR (500 MHz,
.
CDCl3, 25 °C): δ = 7.93 (d, J = 8.0 Hz, 2 H, ArH), 7.76 (d, J =
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[M + H]+ 382.1126; found 382.1123.
1,3-Diphenyl-5-(1-N-methyindol-3-yl)-1H-thieno[3,2-c]pyrazole-6-
carbonitrile (19e): Yield: 74% (0.80 g); white solid; m.p. 219–
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˜
f
1598, 1527, 1458, 1377, 1259 cm–1. 1H NMR (400 MHz, CDCl3,
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4006
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4001–4007

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Received: April 12, 2011
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Published Online: May 27, 2011
Eur. J. Org. Chem. 2011, 4001–4007
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4007