α-Oxoketene dithioacetals mediated benzoannelation of aromatic heterocycles: An efficient regiocontrolled synthesis of highly substituted and polycyclic benzo[b]thiophenes

Article abstract of DOI:10.1016/S0040-4020(00)00722-5

An efficient regiocontrolled synthesis of highly substituted and complex polycyclic benzo[b]thiophenes has been developed via our benzoannelation strategy involving conjugate addition-displacement on a variety of α-oxoketene dithioacetals by carbanions derived from 2- and 3-cyanomethylthiophenes followed by acid induced cyclization of the resulting conjugate adducts. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00722-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8153±8160
a-Oxoketene Dithioacetals Mediated Benzoannelation of
Aromatic Heterocycles: an Ef®cient Regiocontrolled Synthesis of
Highly Substituted and Polycyclic Benzo[b]thiophenes
*
J. R. Suresh, Okram Barun, H. Ila and H. Junjappa
*
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
Received 26 May 2000; revised 26 July 2000; accepted 10 August 2000
AbstractÐAn ef®cient regiocontrolled synthesis of highly substituted and complex polycyclic benzo[b]thiophenes has been developed via
our benzoannelation strategy involving conjugate addition±displacement on a variety of a-oxoketene dithioacetals by carbanions derived
from 2- and 3-cyanomethylthiophenes followed by acid induced cyclization of the resulting conjugate adducts. q 2000 Elsevier Science Ltd.
All rights reserved.
Introduction
of 2-(benzotriazol-1-ylmethyl)thiophenes with a, b-unsatu-
rated ketones and aldehydes.27 Beside these strategies,
benzoannelation has been achieved by palladium catalysed
cross coupling of 2-stannylthiophenes with chlorocyclo-
butenone,28 photochemical addition of thienyl ketene
(generated photochemically from a-diazoketone) with an
acetylene derivative29 and cycloaddition of thiophene±
carbene chromium complex with alkynes.30 However, all
these methods suffer from limitations like the dif®culty in
availability of annelation components with suitable substi-
tution pattern, regiochemical control of cycloaddition via
thieno o-xylene and ¯exibility of substituent introduction
into the benzene ring. Besides, none of these methods can
be extrapolated for the general synthesis of more complex
polycyclic benzo[b]thiophenes.
The chemistry of benzo[b]thiophenes received its early
stimulus from the discovery of thioindigo dyes introduced
in 1906.1 They are also found to be clinically useful as
antihistamines, cardiac drugs possessing vasopressure
activity and their biosteric relationship with indoles has
yielded many benzothiophenes with interesting pharmaco-
logical properties.2 Thus the benzothiophene ring system
may replace benzene, naphthalene or indole rings to
produce biologically active molecules with different physio-
logical disposition, metabolism and lower toxicity.3
Benzothiophenes are generally synthesised by the con-
struction of a thiophene component onto a thiophenol
precursor.4±6 Subsequently a number of approaches for
benzo[b]thiophene synthesis involving annelation of a
benzene ring on a preformed thiophene moiety were
developed.7±30 Various approaches for benzologation of
thiophene described in the literature involve: (a) side
chain elaboration of substituted thiophenes either through
the Stobbe cyclization or via acid catalysed cyclization of a
b-ketosulfoxide;7±13 (b) Michael addition and intramolecu-
lar cyclization of ortho substituted thiophenes bearing
electrophilic and potentially nucleophilic carbon sub-
stituents;14 (c) Diels±Alder reaction of vinyl thio-
phenes;15±17 (d) [412] cycloaddition of thieno-2,3-o-
xylylenes and their heterocyclic analogs such as
thieno[2,3-c]furan, thieno[2,3-c]pyrrole and thieno[2,3-c]
pyranone;18±25 (e) Pd catalysed cyclocarbonylation of 2-
and 3-thienyl allylic acetates;26 (f) [313] benzannulation
We have recently reported benzoannelation of 2-methyl-,
3-cyanomethylindole and 2-cyanomethylpyrrole to the
corresponding regiospeci®cally substituted carbazoles31,32
and indoles33 utilising a-oxoketene dithioacetals34 as
3-carbon components in a [313] annelation process.
These reactions were also found to be ef®cient for the
synthesis of more complex annulated carbazoles and indoles
with diverse structural frameworks. Also, we have further
shown that depending on the nature of the (indolyl)methyl
carbanion the regiochemistry of the reaction (1,4- vs 1,2-
addition) can be manipulated leading to either linearly31 or
angularly32 substituted and annulated carbazoles. Alterna-
tively, the novel oxoketene dithioacetals derived from
heterocyclic ketones (i.e. 3-oxoindole35 or 4-quinolone36)
could be subjected to benzo-, naphtho- or heteroaromatic
annelation with either allyl, benzyl or heteroallyl anions
following a similar protocol to ef®ciently synthesise a
variety of polyheterocyclic ring systems. These studies
have clearly demonstrated that the oxoketene dithioacetal
Keywords: a-oxoketene dithioacetals; aromatic annelation; benzo[b]thio-
phenes.
* Corresponding authors. Fax: 191-0512-597436; e-mail: hila@iitk.ac.in
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00722-5

8154
J. R. Suresh et al. / Tetrahedron 56 (2000) 8153±8160
Scheme 1.
Table 1. Synthesis of 4,5,6,7-substituted benzo[b]thiophenes

J. R. Suresh et al. / Tetrahedron 56 (2000) 8153±8160
8155
Table 2. Synthesis of annelated benzo[b]thiophenes
mediated aromatic annelation process is a powerful method
for the construction of complex heteroaromatics that
provides special opportunity for the introduction of sub-
stituents into the benzene moiety of heteroaromatics without
relying on electrophilic substitution. In continuation of these
studies we now wish to report further work designed to
extend the utility of our aromatic annelation process for a
new highly regiospeci®c synthesis of polysubstituted and
annelated benzo[b]thiophenes. The results of these studies
are described herein.
methylthiophenes as anionic components in the benzo-
annelation process. Thus in a typical experiment, the
oxoketene dithioacetal 1a was reacted with thiophene-2-
acetonitrile 2 in the presence of sodium hydride in DMF/
benzene at 08C to give the adduct 4a (R1ˆMe, R2ˆH) in
88% yield. The adduct 4a underwent smooth cycloaromati-
zation in the presence of p-toluenesulfonic acid in re¯uxing
benzene to furnish 7-cyano-4-methyl-6-(methylthio)-
benzo[b]thiophene 5a exclusively in 70% yield (Scheme
1, Table 1). The reaction sequence could be extended to
the synthesis of other substituted benzo[b]thiophenes, i.e.
4-isopropyl- (5b), 4-phenyl- (5c) and the 4,5,6,7-tetra-
substituted derivatives (5e) in excellent yields with high
regiocontrol of substituent positions. Following a similar
protocol, the regioisomeric polysubstituted benzo[b]thio-
phenes 7a±e could be readily prepared in high yields via
benzoannelation of thiophene-3-acetonitrile with appro-
priate oxoketene dithioacetals (Scheme 1, Table 1). All
these benzothiophenes are novel and their structures are
fully supported by their NMR spectral and analytical data.
Results and Discussion
Side chain metallation of methyl substituted thiophene
derivatives is normally dif®cult to achieve because ring
metallation is predominant in these reactions. Several
substituents are conceivable to stabilise the negative charge
in the conjugate base of methylthiophene precursors
required for the Michael addition±elimination process
with oxoketene dithioacetals. Previous work in our group
on the synthesis of carbazoles32 and indoles33 has shown that
the cyano group is especially useful for this purpose. We
therefore selected commercially available 2- and 3-cyano-
In an extension of this methodology, we next turned our
attention to the synthesis of [e]- and [g]- annelated
benzo[b]thiophenes by employing oxoketene dithioacetals

8156
J. R. Suresh et al. / Tetrahedron 56 (2000) 8153±8160
1f±i derived from cyclic ketones. Table 2 delineates the
versatility of this aromatic annelation strategy for the
regiospeci®c construction of wide range of complex poly-
cyclic benzo[b]thiophene systems 5f±i and 7f±i in high
yields from readily accessible precursors. The methodology
provides an easy general entry into these class of
compounds which is far superior to the previously reported
multistep preparation of the related systems.23,37
(methylthio)benzothiophenes 7c, 7f and 5d with W2
Raney Ni under controlled conditions. As a representative
example the nitrile group in 5c and 7c could be removed by
re¯uxing them with a mixture of sulfuric and acetic acids in
water to provide the corresponding cyanide free
benzo[b]thiophenes 20c and 21c in good yields.
In a further extension of these studies, benzoannelation of 2
and 3 with a few representative N,S- and O,S-acetals was
examined following a similar strategy with a view to extend
the scope of this methodology for regiospeci®c introduction
of an amino or alkoxy substituent in the benzene ring of
benzo[b]thiophene. Thus the 5- and 6-cycloamino and the
corresponding 5- and 6-methoxy benzo[b]thiophenes were
smoothly obtained in high yields from the respective N,S-
and O,S-acetals and 2- and 3-cyanomethylthiophenes under
the described reaction conditions (Scheme 2, Table 3).
Attempts were made to selectively dethiomethylate the
benzo[b]thiophenes without affecting the thiophene ring.
However, these reactions did not meet with any success
and desulfurization with W2 or deactivated Raney Ni or
with nickel boride (NiCl2±NaBH4) yielded only inseparable
product mixtures in most of the cases except isolation of
17c, 18f and 19d on treatment of the corresponding
Scheme 2.
Table 3.

J. R. Suresh et al. / Tetrahedron 56 (2000) 8153±8160
8157
In conclusion, we have demonstrated that the a-oxoketene
dithioacetal mediated conjugate addition±cyclization
benzoannelation sequence can be used to ef®ciently synthe-
sise a variety of regioisomeric polysubstituted benzo[b]thio-
phenes from readily available precursors. The methodology
could be easily adapted for regiocontrolled synthesis of
complex polycyclic benzo[b]thiophenes in high yields.
Further studies to develop chemoselective catalysts for
removal of SMe group in these benzo[b]thiophenes are in
progress.
sodium bicarbonate solution (200 mL). The organic layer
was separated, washed with water (2£100 mL), dried over
anhydrous sodium sulfate and evaporated to give crude
benzo[b]thiophene which was puri®ed by column chroma-
tography (silica gel) using hexane±ethyl acetate (97:3) as
eluent.
5-Cyano-4-methylthio-5-(2-thienyl)pent-4-en-2-one (4a).
Colourless crystals (chloroform±ether); mp 78±798C; Yield
;
88%; IR (KBr): 2213, 1710, 1549 cm21 1H NMR
(300 MHz, CDCl3): 2.33 (s, 3H), 2.42 (s, 3H), 4.01 (s,
2H), 7.06±7.09 (m, 1H), 7.41±7.46 (m, 2H); 13C NMR
(75 MHz): 15.73, 29.46, 49.79, 105.41, 117.47, 126.79,
127.62, 129.67, 135.32, 148.81, 202.08; MS: m/z (%): 237
(M1, 16), 147 (49); Anal. Calcd for C11H11NOS2 (237.35):
C, 55.67; H, 4.67; N, 5.90%; Found: C, 55.38; H, 4.70; N,
5.98%.
Experimental
Melting points were obtained on a Thomas Hoover and Mel-
Temp capillary melting point apparatuses and are uncor-
rected. Infrared spectra were recorded on a Perkin±Elmer
983 and Perkin±Elmer-1082 spectrophotometers. NMR
spectra were recorded on Bruker ACF-300 and Jeol LA-
400 spectrometers. Chemical shifts are reported in d
(ppm) relative to tetramethyl silane and coupling constants
(J) are given in Hertz. Mass spectra were obtained on a Jeol
D-300 mass spectrometer. Elemental analyses were carried
out on a Heraeus CHN±O-Rapid analyzer.
5-Cyano-4-methylthio-5-(3-thienyl)pent-4-en-2-one (6a).
Light yellow liquid; Yield 93%; IR (KBr): 2204, 1705,
1501 cm21 1H NMR (400 MHz, CDCl3): 2.33 (s, 3H),
;
2.34 (s, 3H), 3.99 (s, 2H), 7.34±7.43 (m, 2H), 7.63±7.65
(m, 1H); 13C NMR (100 MHz): 15.34, 29.46, 49.67, 105.48,
118.22, 125.66, 126.17, 127.95, 133.01, 151.07, 202.12;
MS: m/z (%): 237 (M1, 75); Anal. Calcd for C11H11NOS2
(237.35): C, 55.67; H, 4.67; N, 5.90%; Found: C, 55.94; H,
4.74; N, 5.84%.
All reactions were monitored by TLC on glass plates coated
with silica gel (Acme's) containing 13% calcium sulfate as
binder and visualization of compounds was accomplished
by exposure to iodine vapour or by spraying potassium per-
manganate (acidic) solution. Column chromatography was
carried out using Acme's silica gel (60±120 mesh).
7-Cyano-4-methyl-6-(methylthio)benzo[b]thiophene (5a).
Colourless crystals (chloroform±ether); mp 160±1618C;
1
Yield 70%; IR (KBr): 2207, 1560, 1428 cm21; H NMR
(300 MHz, CDCl3): 2.62 (s, 3H), 2.64 (s, 3H), 7.12 (s,
1H), 7.35 (d, Jˆ5.4 Hz, 1H), 7.47 (d, Jˆ5.4 Hz, 1H); 13C
NMR (75 MHz): 17.00, 20.24, 116.03, 122.27, 124.16,
126.71, 126.77, 137.54, 138.29, 140.63, 143.72; MS: m/z
(%): 219 (M1, 100); Anal. Calcd for C11H9NS2 (219.33):
C, 60.24; H, 4.14; N, 6.39%; Found: C, 60.43; H, 4.19; N,
6.23%.
Thiophene-2-acetonitrile and thiophene-3-acetonitrile were
purchased from Aldrich. Oxoketene-S,S-acetals, ±N,S-
acetals and O,S-acetal were prepared according to the
earlier reported procedures.34
General procedure for the synthesis of substituted and
condensed benzo[b]thiophenes
4-Cyano-7-methyl-5-(methylthio)benzo[b]thiophene (7a).
Colourless crystals (chloroform±ether); mp 150±1518C;
To a stirring suspension of sodium hydride (10 mmol) in
DMF (10 mL) and benzene (10 mL) at 08C, a solution of
thiophene-2-acetonitrile or thiophene-3-acetonitrile (5 mmol)
in benzene (5 mL) was added dropwise. After 15 min, the
appropriate a-oxoketene acetal (5 mmol) in DMF (10 mL)
was slowly added and the reaction mixture was allowed to
warm to room temperature with stirring during 8±10 h. It
was poured into saturated ammonium chloride solution
(200 mL) and extracted with benzene (3£50 mL). The
combined organic extracts were washed with water
(3£100 mL), dried over anhydrous sodium sulfate and
evaporated to give the crude 1,4-adducts. The addition±
elimination products 4a and 6a were puri®ed by passing
through silica gel column using hexane±ethyl acetate
(19:1) and characterised by spectral and analytical data
and the other 1,4-adducts were used as such for further
cyclization.
1
Yield 78%; IR (KBr): 2208, 1649, 1562, 1421 cm21; H
NMR (300 MHz, CDCl3): 2.62 (s, 6H), 7.15 (s, 1H), 7.53
(d, Jˆ6.0 Hz, 1H), 7.65 (d, 1H, Jˆ6.0 Hz); MS: (m/z, %):
219 (M1, 100); Anal. Calcd for C11H9NS2 (219.33): C,
60.24; H, 4.14; N, 6.39%; Found: C, 60.49; H, 4.18; N,
6.43%.
7-Cyano-6-methylthio-4-i-propylbenzo[b]thiophene (5b).
Colourless crystals (chloroform±ether); mp 106±1078C;
1
Yield 60%; IR (KBr): 2207, 1564, 1428 cm21; H NMR
(400 MHz, CDCl3): 1.39 (d, Jˆ7.1 Hz, 6H), 2.65 (s, 3H),
3.48 (septet, Jˆ7.1 Hz, 1H), 7.26 (s, 1H), 7.46 (d, Jˆ5.6 Hz,
1H), 7.51 (d, Jˆ5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
17.35, 22.95, 31.91, 104.01, 116.05, 120.46, 121.97, 126.81,
136.66, 140.69, 144.14, 148.80; MS: m/z (%): 247 (M1,
100); Anal. Calcd for C13H13NS2 (247.38): C, 63.12; H,
5.30; N, 5.66%; Found: C, 63.39; H, 5.23; N, 5.77%.
To a solution of crude 1,4-adduct (ca. 5 mmol) in dry
benzene (40 mL), p-toluenesulfonic acid (10 mmol) was
added and the reaction mixture was re¯uxed with stirring
for 3±4 h. The solvent was evaporated, the residue was
dissolved in chloroform (100 mL), poured into saturated
4-Cyano-5-(methylthio)-7-i-propylbenzo[b]thiophene (7b).
Yellow crystals (chloroform±ether); mp 56±578C; Yield
63%; IR (KBr): 2215, 1546, 1429 cm21
;
1H NMR
(400 MHz, CDCl3): 1.42 (d, Jˆ6.6 Hz, 6H), 2.64 (s, 3H),

8158
J. R. Suresh et al. / Tetrahedron 56 (2000) 8153±8160
3.25 (brm, 1H), 7.24 (s, 1H), 7.48 (brm, 1H), 7.62 (brm,
1H); 13C NMR (100 MHz, CDCl3): 17.23, 22.29, 33.96,
104.36, 116.49, 119.78, 122.64, 130.02, 136.84, 140.93,
141.68, 148.01; MS: (m/z, %): 247 (M1, 100); Anal.
Calcd for C13H13NS2 (247.38): C, 63.12; H, 5.30; N,
5.66%; Found: C, 63.34; H, 5.34; N, 5.74%.
122±1238C; Yield 67%; IR (KBr): 2209, 1535, 1447 cm21
;
1H NMR (400 MHz, CDCl3): 2.47 (s, 3H), 2.54 (s, 3H), 7.32
(d, 1H, J ˆ 1.6 Hz), 7.47±7.52 (m, 3H), 7.54±7.55 (m, 3H);
13C NMR (100 MHz, CDCl3): 18.82, 19.71, 112.32, 117.12,
122.69, 128.42, 128.91, 130.42, 135.38, 138.21, 139.50,
140.80, 142.24; MS: (m/z, %): 295 (M1, 100); Anal.
Calcd for C17H13NS2 (295.43): C, 69.12; H, 4.44; N,
4.74%; Found: C, 69.35; H, 4.38; N, 4.70%.
7-Cyano-6-(methylthio)-4-phenylbenzo[b]thiophene (5c).
Colourless crystals (chloroform±ether); mp 141±1428C;
1
Yield 72%; IR (KBr): 2213, 1550, 1422 cm21; H NMR
4-Cyano-7,8-dihydro-5-methylthio-6H-indeno[5,4-b]thio-
phene (5f). Colourless crystals (chloroform±ether); mp
129±1308C; Yield 66%; IR (KBr): 2213, 1549,
(300 MHz, CDCl3): 2.63 (s, 3H), 7.28 (s, 1H), 7.36 (d,
Jˆ5.5 Hz, 1H), 7.42±7.52 (m, 6H); 13C NMR (75 MHz):
16.83, 104.20, 115.84, 123.54, 123.61, 127.00, 128.65,
128.81, 136.09, 138.98, 140.80, 141.90, 144.60; MS: m/z
(%): 281 (M1, 100); Anal. Calcd for C16H11NS2 (281.40):
C, 68.29; H, 3.94; N, 4.98%; Found: C, 68.60; H, 3.87; N,
5.03%.
1
1428 cm21; H NMR (300 MHz, CDCl3): 2.44 (quintet,
Jˆ7.5 Hz, 2H), 2.54 (s, 3H), 3.15 (t, Jˆ7.5 Hz, 2H), 3.24
(t, Jˆ7.6 Hz, 2H), 7.25 (d, Jˆ5.6 Hz, 1H), 7.53 (d,
Jˆ5.6 Hz, 1H); 13C NMR (75 MHz): 19.06, 24,39, 33.07,
33.20, 108.62, 116.90, 122.10, 128.57, 134.26, 136.29,
142.78, 143.67, 144.23; MS: m/z (%): 245 (M1, 100);
Anal. Calcd for C13H11NS2 (245.37): C, 63.64; H, 4.52; N,
5.71%; Found: C, 63.86; H, 4.59; N, 5.67%.
4-Cyano-5-(methylthio)-7-phenylbenzo[b]thiophene (7c).
Colourless crystals; mp 111±1128C; Yield 87%; IR (KBr):
2208, 1558, 1418 cm21; 1H NMR (300 MHz, CDCl3): 2.66
(s, 3H), 7.34 (s, 1H), 7.49±7.60 (m, 4H), 7.67±7.71 (m, 3H);
13C NMR (75 MHz, CDCl3): 17.10, 109.30, 116.40, 122.70,
123.10, 128.10, 129.10, 129.30, 131.50, 136.80, 138.80,
141.20, 142.30; MS: (m/z, %): 281 (M1, 100); Anal.
Calcd for C16H11NS2 (281.40): C, 68.29; H, 3.94; N,
4.98%; Found: C, 68.55; H, 3.98; N, 5.04%.
4-Cyano-7,8-dihydro-5-methylthio-6H-indeno[4,5-b]thio-
phene (7f). Colourless crystals (chloroform±ether); mp 8C;
1
Yield 71%; IR (KBr): 2208, 1562, 1421 cm21; H NMR
(400 MHz, CDCl3): 2.25 (pentet, Jˆ7.6 Hz, 2H), 2.52 (s,
3H), 3.10±3.18 (m, 4H), 7.45 (d, Jˆ5.6 Hz, 1H), 7.54 (d,
Jˆ5.6 Hz, 1H); 13C NMR (100 MHz): 18.81, 24.06, 33.21,
33.27, 109.12, 117.11, 122.57, 129.04, 134.04, 135.73,
141.15, 142.35, 143.63; MS: m/z (%): 245 (M1, 100);
Anal. Calcd for C13H11NS2 (245.37): C, 63.64; H, 4.52; N,
5.71%; Found: C, 63.87; H, 4.57; N, 5.78%.
7-Cyano-4,5-dimethyl-6-(methylthio)benzo[b]thiophene
(5d). Colourless crystals (chloroform±ether); mp 115±
1
1168C; Yield 64%; IR (KBr): 2209, 1547, 1416 cm21; H
NMR (300 MHz, CDCl3): 2.43 (s, 3H), 2.58 (s, 3H), 2.60 (s,
3H), 7.37 (d, Jˆ5.5 Hz, 1H), 7.51 (d, Jˆ5.5 Hz, 1H); 13C
NMR (75 MHz): 17.55, 18.11, 19.96, 110.41, 116.95,
122.77, 127.98, 136.42, 137.03, 139.97, 140.81; MS: (m/z,
%): 233 (M1, 100); Anal. Calcd for C12H11NS2 (233.36): C,
61.76; H, 4.75; N, 6.00%; Found: C, 61.48; H, 4.78; N, 6.06%.
4-Cyano-5-(methylthio)-6,7,8,9-tetrahydronaphtho[2,1-
b]thiophene (5g). Colourless crystals(chloroform±ether);
mp 136±1378C; Yield 60%; IR (KBr): 2925, 2213, 1535,
1
1428 cm21; H NMR (300 MHz, CDCl3): 1.88±1.90 (brm,
4H), 2.47 (s, 3H), 3.03±3.07 (brm, 4H), 7.34 (d, Jˆ5.5 Hz,
1H), 7.52 (d, Jˆ5.5 Hz, 1H); 13C NMR (75 MHz): 19.63,
22.06, 22.88, 28.07, 28.31, 110.12, 116.90, 121.88, 128.19,
136.83, 137.60, 137.67, 139.40, 140.39; MS: m/z (%): 259
(M1, 100); Anal. Calcd for C14H13NS2 (259.40): C, 64.83;
H, 5.05; N, 5.40%; Found: C, 65.09; H, 5.02; N, 5.35%.
4-Cyano-6,7-dimethyl-5-(methylthio)benzo[b]thiophene
(7d). Colourless crystals (chloroform±ether); mp 123±
1
1258C; Yield 64%; IR (KBr): 2205, 1470, 1440 cm21; H
NMR (400 MHz, CDCl3): 2.46 (s, 3H), 2.59 (s, 3H), 2.60 (s,
3H), 7.51 (d, 1H, Jˆ5.6 Hz), 7.55 (d, 1H, Jˆ5.5 Hz); 13C
NMR (100 MHz): 17.56, 19.78, 19.95, 111.19, 117.41,
123.35, 128.94, 135.84, 135.99, 137.63, 139.33, 141.72;
MS: (m/z, %): 233 (M1, 100); Anal. Calcd for C12H11NS2
(233.36): C, 61.76; H, 4.75; N, 6.00%; Found: C, 61.54; H,
4.78; N, 5.95%.
4-Cyano-5-(methylthio)-6,7,8,9-tetrahydronaphtho[1,2-
b]thiophene (7g). Colourless crystals (chloroform±ether);
mp 131±1328C; Yield 65%; IR (KBr): 2205, 1525,
1
1440 cm21; H NMR (300 MHz, CDCl3): 1.91±1.93 (m,
4H), 2.48 (s, 3H), 2.93±2.95 (m, 2H), 3.07±3.08 (m, 2H),
7.50 (d, 1H, Jˆ5.6 Hz), 7.53 (d, 1H, Jˆ5.5 Hz); 13C NMR
(100 MHz): 19.59, 22.04, 23.19, 28.32, 29.07, 110.87,
117.29, 123.03, 128.59, 136.43, 136.73, 137.79, 139.04,
140.77; MS: (m/z, %): 259 (M1, 82), 233 (100); Anal.
Calcd for C14H13NS2 (259.40): C, 64.83; H, 5.05; N,
5.40%; Found: C, 65.06; H, 5.11; N, 5.46%.
7-Cyano-5-methyl-6-(methylthio)-4-phenylbenzo[b]thio-
phene (5e). Colourless crystals (chloroform±ether); mp
124±1258C; Yield 64%; IR (KBr): 2921, 2214, 1485,
1440 cm21 1H NMR (400 MHz, CDCl3): 2.45 (s, 3H),
;
2.55 (s, 3H), 6.88 (d, Jˆ5.4 Hz, 1H), 7.25±7.28 (m, 2H),
7.43±7.53 (m, 4H); 13C NMR (100 MHz, CDCl3): 18.84,
19.80, 112.04, 116.75, 124.35, 127.97, 128.05, 128.60,
128.88, 136.09, 137.86, 138.88, 140.09, 141.06, 141.68;
MS: m/z (%): 295 (M1, 78), 233 (100); Anal. Calcd for
C17H13NS2 (295.43): C, 69.12; H, 4.44; N, 4.74%; Found:
C, 69.41; H, 4.36; N, 4.82%.
4-Cyano-5-(methylthio)¯uoreno[3,4-b]thiophene (5h).
Colourless crystals (chloroform±ether); mp 210±2118C;
1
Yield 56%; IR (KBr): 2212, 1531, 1479 cm21; H NMR
(300 MHz, CDCl3): 2.65 (s, 3H), 4.04 (s, 2H), 7.42±7.52
(m, 2H), 7.65 (d, Jˆ7.3 Hz, 1H), 7.73 (d, Jˆ5.5 Hz, 1H),
7.94 (d, Jˆ5.5 Hz, 1H), 8.06 (d, Jˆ7.2 Hz, 1H); 13C NMR
(75 MHz): 19.26, 37.71, 108.48, 116.92, 121.46, 122.85,
125.19, 127.37, 128.28, 129.36, 133.46, 134.16, 139.49,
4-Cyano-6-methyl-5-(methylthio)-7-phenylbenzo[b]thio-
phene (7e). Colourless crystals (chloroform±hexane); mp

J. R. Suresh et al. / Tetrahedron 56 (2000) 8153±8160
8159
140.41, 143.46, 144.38, 144.62; MS: m/z (%): 293 (M1, 79),
246 (100); Anal. Calcd for C17H11NS2 (293.41): C, 69.59; H,
3.78; N, 4.77%; Found: C, 69.34; H, 3.70; N, 4.85%.
7-Cyano-4-phenyl-6-(1-piperidino)benzo[b]thiophene
(12c). Colourless crystals (chloroform±ether); mp 151±
1
1528C; Yield 70%; IR (KBr): 2212, 1565, 1448 cm21; H
NMR (300 MHz, CDCl3): 1.61±1.67 (m, 2H), 1.76±1.81
(m, 4H), 3.28±3.32 (m, 4H), 7.00 (s, 1H), 7.30 (s, 2H),
7.43±7.54 (m, 5H); 13C NMR (75 MHz): 24.06, 26.19,
53.53, 97.03, 116.66, 117.40, 123.37, 124.68, 138.33,
128.68, 128.78, 132.30, 139.80, 142.36, 145.41, 155.34;
MS: m/z (%): 318 (M1, 100); Anal. Calcd for C20H18N2S
(318.44): C, 75.44; H, 5.70; N, 8.80%; Found: C, 75.76; H,
5.77; N, 8.73%.
4-Cyano-5-(methylthio)¯uoreno[4,3-b]thiophene (7h).
Colourless crystals (chloroform±ether); mp 214±2158C;
1
Yield 62%; IR (KBr): 2210, 1567, 1470 cm21; H NMR
(400 MHz, CDCl3): 2.59 (s, 3H), 3.92 (s, 2H), 7.38±7.46
(m, 2H), 7.54 (d, 2H, Jˆ4.5 Hz), 7.63 (d, 1H, Jˆ5.2 Hz),
7.79 (d, 1H, Jˆ6.0 Hz); 13C NMR (100 MHz, CDCl3):
19.07, 37.90, 109.01, 117.31, 122.47, 124.90, 127.28,
128.32, 131.84, 134.17, 138.99, 139.20, 142.52, 142.60,
144.06; MS: (m/z, %): 293 (M1, 88.9); Anal. Calcd for
C17H11NS2 (293.41): C, 69.59; H, 3.78; N, 4.77%; Found:
C, 69.83; H, 3.73; N, 4.71%.
4-Cyano-7-phenyl-5-(1-piperidino)benzo[b]thiophene
(13c). Colourless crystals (chloroform±ether); mp 141±
1
1428C; Yield 75%; IR (KBr): 2212, 1565 cm21; H NMR
(400 MHz, CDCl3): 1.62±1.63 (m, 2H), 1.80±1.81 (m, 4H),
3.30±3.32 (m, 4H), 7.00 (s, 1H), 7.29 (s, 2H), 7.44±7.51 (m,
5H); 13C NMR (100 MHz, CDCl3): 24.03, 26.15, 53.47,
96.99, 116.62, 117.33, 123.33, 124.63, 128.27, 128.62,
128.72, 132.27, 139.78, 142.32, 145.38, 155.27; MS: (m/z,
%): 318 (M1, 100); Anal. Calcd for C20H18N2S (318.44): C,
75.44; H, 5.70; N, 8.80%. Found: C, 75.71; H, 5.66; N,
8.72%.
4-Cyano-6,7-dihydro-5-(methylthio)phenanthro[3,4-b]thio-
phene (5i). Colourless crystals (chloroform±ether); mp
132±1338C; Yield 62%; IR (KBr): 2207, 1549,
1427 cm21 1H NMR (300 MHz, CDCl3): 2.46 (s, 3H),
;
2.77±2.82 (m, 2H), 3.17±3.22 (m, 2H), 7.34±7.37 (m,
3H), 7.60 (d, Jˆ5.6 Hz, 1H), 7.83 (d, Jˆ5.6 Hz, 1H),
7.83±7.85 (m, 1H); 13C NMR (75 MHz): 19.80, 27.15,
28.90, 111.2, 116.87, 124.14, 126.72, 127.82, 128.79,
128.92, 133.46, 135.58, 136.04, 136.44, 139.03, 139.57,
143.28; MS: m/z (%): 307 (M1, 100); Anal. Calcd for
C18H13NS2 (307.44): C, 70.32; H, 4.26; N, 4.56%; Found:
C, 70.53; H, 4.29; N, 4.49%.
7-Cyano-6-methoxy-4-phenylbenzo[b]thiophene (15c).
Colourless crystals (chloroform±ether); mp 115±1168C;
1
Yield 69%; IR (KBr): 2214, 1597, 1413 cm21; H NMR
(400 MHz, CDCl3): 4.04 (s, 3H), 7.02 (s, 1H), 7.33 (d,
1H, Jˆ5.2 Hz), 7.37 (d, 1H, Jˆ5.4 Hz) 7.49±7.54 (m,
5H); MS: (m/z, %): 265 (M1, 100), 222 (42.7); Anal.
Calcd for C16H11NOS (265.34): C, 72.43; H, 4.18; N,
5.28%; Found: C, 72.66; H, 4.25; N, 5.44%.
4-Cyano-6,7-dihydro-5-(methylthio)phenanthro[4,3-b]-
thiophene (7i). Colourless crystals (chloroform±ether); mp
122±1238C; Yield 65%; IR (KBr): 2210, 1567, 1470 cm21
;
1H NMR (400 MHz, CDCl3): 2.48 (s, 3H), 2.84 (t, 2H,
Jˆ6.8 Hz), 3.30 (t, 2H, Jˆ6.8 Hz), 7.25±7.45 (m, 3H),
7.61±7.66 (m, 3H), 8.27 (d, 1H, Jˆ7.6 Hz); 13C NMR
(100 MHz, CDCl3): 19.85, 27.15, 28.68, 112.00, 117.36,
123.03, 126.16, 126.90, 128.06, 129.77, 133.13, 134.83,
136.66, 136.95, 138.26, 139.59, 141.52; MS: (m/z, %):
307 (M1, 81), 259 (100); Anal. Calcd for C18H13NS2
(307.44): C, 70.32; H, 4.26; N, 4.56%; Found: C, 70.57;
H, 4.21; N, 4.48%.
4-Cyano-5-methoxy-7-phenylbenzo[b]thiophene (16c).
Colourless crystals (chloroform±ether); mp 119±1208C;
1
Yield 71%; IR (KBr): 2204, 1575, 1430 cm21; H NMR
(400 MHz, CDCl3): 4.05 (s, 3H), 7.04 (s, 1H), 7.48±7.56
(m, 4H), 7.69±7.72 (m, 3H); 13C NMR (100 MHz, CDCl3):
56.84, 109.78, 115.32, 123.37, 125.31, 125.34, 128.66,
128.83,132.56, 139.57, 143.35, 144.77; MS: (m/z, %): 265
(M1, 100); Anal. Calcd for C16H11NOS (265.34): C, 72.43;
H, 4.18; N, 5.28%; Found: C, 72.12; H, 4.55; N, 5.34%.
7-Cyano-4-methyl-6-(4-morpholino)benzo[b]thiophene
(10a). Colourless crystals (chloroform±ether); mp 141±
4-(Diethylamino)methyl-7-phenylbenzo[b]thiophene (17c).
To a solution of 7c (2.5 mmol) in absolute ethanol (30 mL),
Raney Ni (W2, six times by weight) was added and the
suspension was re¯uxed for 5 h (monitored by TLC). The
reaction mixture was ®ltered through sintered funnel and
the residue was washed with ethanol. The bulk of the
ethanol was distilled off and chloroform was added. The
solution was washed with water, dried over anhydrous
sodium sulphate, concentrated and the crude product
obtained was passed through silica gel column using
hexane±ethyl acetate (19:1) as eluent. Yellow crystals
(chloroform±ether); mp 71±728C; Yield 68%; IR (KBr):
1
1438C; Yield 67%; IR (KBr): 2205, 1572, 1440 cm21; H
NMR (300 MHz, CDCl3): 2.62 (s, 3H), 3.25±3.28 (m, 4H),
3.89±3.93 (m, 4H), 6.85 (s, 1H), 7.30 (d, Jˆ5.5 Hz, 1H),
7.36 (d, Jˆ5.5 Hz, 1H); 13C NMR (75 MHz): 20.42, 52.22,
66.96, 96.21, 116.40, 117.19, 122.07, 125.02, 134.47,
139.10, 144.31, 154.08; MS: m/z (%): 258 (M1, 71), 200
(100); Anal. Calcd for C14H14N2OS (258.34): C, 65.09; H,
5.46; N, 10.84%; Found: C, 65.37; H, 5.42; N, 10.77%.
4-Cyano-7-methyl-5-(4-morpholino)benzo[b]thiophene
(11a). Colourless crystals (chloroform±ether); mp 91±
1
928C; Yield 68%; IR (KBr): 2201, 1579 cm21; H NMR
2900, 1650, 1600, 1550 cm21 1H NMR (400 MHz,
;
(400 MHz, CDCl3): 2.63 (s, 3H), 3.27 (t, 4H, Jˆ4.4 Hz),
3.91 (t, 4H, Jˆ4.4 Hz), 6.84 (s, 1H), 7.30 (d, 1H,
Jˆ5.2 Hz), 7.36 (d, 1H, Jˆ5.2 Hz); 13C NMR (100 MHz):
20.39, 52.27, 66.94, 96.56, 116.36, 116.96, 121.95, 125.09,
134.51, 138.86, 144.49, 154.06; MS: (m/z, %): 258 (M1,
100); Anal. Calcd for C14H14N2OS (258.34): C, 65.09; H,
5.46; N, 10.84%; Found: C, 65.31; H, 5.52; N, 10.95%.
CDCl3): 1.07 (t, 6H), 2.61 (q, 4H), 3.92 (s, 2H), 7.31±
7.50 (m, 6H), 7.71 (m, 3H); MS: (m/z, %): 295 (M1, 52),
223 (100); Anal. Calcd for C19H21NS (295.44): C, 77.24; H,
7.16; N, 4.74%; Found: C, 77.40; H, 7.29, N, 4.56%.
4-Cyano-7,8-dihydro-6H-indeno[4,5-b]thiophene (18f).
Colourless crystals (chloroform±ether); mp 101±1028C;

8160
J. R. Suresh et al. / Tetrahedron 56 (2000) 8153±8160
Yield 55%; IR (KBr): 2200, 1579 cm21
;
1H NMR
5. Scrowston, R. M. In Advances in Heterocyclic Chemistry,
Katritzky, A. R. Ed.; Academic: New York, 1981; Vol. 29, p 171.
6. Iddon, B.; Scrowston, R. M. In Advances in Heterocyclic
Chemistry, Katritzky, A. R., Boulton, A. J. Eds.; Academic: New
York, 1970; Vol. 11, p 177.
(400 MHz, CDCl3): 2.26±2.31 (m, 2H), 3.08 (m, 4H),
7.55±7.75 (m, 3H); MS: (m/z, %): 199 (M1, 100); Anal.
Calcd for C12H9NS (199.27): C, 72.33; H, 4.55; N, 7.02%;
Found: C, 72.55; H, 4.67; N, 7.11%.
7. El-Rayyes, N. R.; Al-Salman, N. A. J. Heterocycl. Chem. 1976,
13, 285.
4,5-Dimethylbenzo[b]thiophene-7-carboxamide (19d).
Procedure is same as that of 17c except that recti®ed spirit
is used instead of absolute ethanol. Colourless solid (chloro-
form±hexane); mp 220±2218C; Yield 66%; IR (KBr): 3412,
8. Kitchen, R.; Sandin, R. B. J. Am. Chem. Soc. 1945, 67, 1645.
9. Mac Dowell, D. W. H.; Greenwood, T. D. J. Heterocycl. Chem.
1965, 2, 44.
1
3195, 2922, 1641, 1610, 1412 cm21; H NMR (400 MHz,
10. Samanta, S. S.; Ghosh, S. C.; De, A. J. Chem. Soc., Perkin
Trans. 1 1997, 2683.
CDCl3): 2.46 (s, 3H), 2.59 (s, 3H), 6.00 brs, 2H), 7.45 (d,
Jˆ5.6 Hz, 1H), 7.48 (s, 1H), 7.57 (d, Jˆ5.6 Hz, 1H); MS:
m/z (%): 205 (M1, 100); Anal Calcd for C11H11NOS
(205.28): C, 64.36; H, 5.40; N, 6.82%; Found: C, 64. 62;
H, 5.35; N, 6.90%.
11. Loozen, H. J. J.; Godefroi, E. F. J. Org. Chem. 1973, 38, 1056.
12. Jutz, C.; Wagner, R. M.; Lobering, H. G. Angew. Chem., Int.
Ed. Engl. 1974, 13, 737.
13. Oikawa, Y.; Setoyama, O.; Yonemitsu, O. Heterocycles 1974,
21.
14. (a) van Leusen, A. M.; Terpstra, J. W. Tetrahedron Lett. 1981,
22, 5097. (b) Terpstra, J. W.; van Leusen, A. M. J. Org. Chem.
1986, 51, 230.
Procedure for decyanation of 5c and 7c
To a mixture of sulfuric acid (5 mL), acetic acid (5 mL) and
water (5 mL), compound 5c or 7c (2.5 mmol) was added and
the mixture was heated at 1808C for 8 h. It was then diluted
with water, extracted with chloroform, washed with water,
dried and evaporated. The residue obtained was passed
through silica gel column using hexane as eluent.
15. Scully, J. F.; Brown, E. V. J. Am. Chem. Soc. 1953, 75, 6329.
16. Keil, J. M.; Kampchen, T.; Seitz, G. Tetrahedron Lett. 1990,
31, 4581.
17. Sasaki, T.; Ishibashi, Y.; Ohno, M. J. Chem. Res., Synopsis
1984, 218.
18. Chadwick, D. J.; Plant, A. Tetrahedron Lett. 1987, 28, 6085.
19. van Leusen, A. M.; van den Berg, K. J. Tetrahedron Lett.
1988, 9, 2689.
6-Methylthio-4-phenylbenzo[b]thiophene (20c). Colour-
less viscous liquid; IR (CH2Cl2): 1610, 1575, 1430 cm21
;
1H NMR (400 MHz, CDCl3): 2.50 (s, 3H), 7.24±7.27 (m,
2H), 7.30±7.37 (m, 2H), 7.39±7.45 (m, 2H), 7.49±7.52 (m,
2H), 7.70 (m, 1H); 13C NMR (100 MHz, CDCl3): 16.50,
119.01, 123.01, 124.39, 125.33, 127.54, 128.46, 128.90,
134.68, 135.72, 137.84, 140.34, 141.35; MS: (m/z, %):
256 (M1, 100); Anal Calcd for C15H12S2 (256.39): C,
70.27; H, 4.72%; Found: C, 70.51; H, 4.65%.
20. Crew, A. P. A.; Jenkins, G.; Storr, R. C.; Yelland, M.
Tetrahedron Lett. 1990, 31, 1491.
21. Schoning, A.; Debaerdemaeker, T.; Zander, M.; Friedrichsen,
W. Chem. Ber. 1989, 122, 1119.
22. Kuroda, T.; Takahashi, M.; Ogiku, T.; Ohmizu, H.; Kondo, K.;
Iwasaki, T. J. Chem. Soc., Chem. Commun. 1991, 1635.
23. Kappe, C. O.; Padwa, A. J. Org. Chem. 1996, 61, 6166.
24. Sha, C. K.; Tsou, C. P. J. Org. Chem. 1990, 55, 2446.
25. Jackson, P. M.; Moody, C. J.; Shah, P. J. Chem. Soc. Perkin
Trans. 1 1990, 2909.
5-Methylthio-7-phenylbenzo[b]thiophene (21c). Colour-
less viscous liquid; IR (CH2Cl2): 1585, 1443 cm21 1H
;
26. (a) Iwasaki, M.; Li, J-p.; Kobayashi, Y.; Matsuzaka, H.; Ishii,
Y.; Hidai, M. Tetrahedron Lett. 1989, 30, 95. (b) Iwasaki, M.;
Kobayashi, Y.; Li, J-p.; Matsuzaka, H.; Ishii, Y.; Hidai, M.
J. Org. Chem. 1991, 56, 1922.
NMR (400 MHz, CDCl3): 2.52 (s, 3H), 7.24±7.27 (m,
2H), 7.30±7.37 (m, 2H), 7.39±7.45 (m, 2H), 7.49±7.52
(m, 2H), 7.70 (m, 1H); 13C NMR (100 MHz, CDCl3):
16.50, 119.01, 123.01, 124.39, 125.33, 127.54, 128.46,
128.90, 134.68, 135.72, 137.84, 140.34, 141.35; MS: (m/z,
%): 256 (M1, 100); Anal Calcd for C15H12S2 (256.39): C,
70.27; H, 4.72%; Found: C, 70.01; H, 4.84%.
27. Katritzky, A. R.; Serdyuk, L.; Xie, L.; Ghiviriga, I. J. Org.
Chem. 1997, 62, 6215.
28. Liebeskind, L. S.; Wang, J. J. Org. Chem. 1993, 58, 3550.
29. Danheiser, R. L.; Brisbois, R. G.; Kowalczyk, J. J.; Miller,
R. F. J. Am. Chem. Soc. 1990, 112, 3093.
30. Dotz, K. H.; Dittz, R. Chem. Ber. 1978, 111, 2517.
31. Syam Kumar, U. K.; Patra, P. K.; Ila, H.; Junjappa, H.
Tetrahedron Lett. 1998, 39, 2029.
Acknowledgements
J. R. S., O. B. and H. J. thank CSIR for Research Fellowship
and Emeritus Scientistship, respectively. Financial
assistance under DST project is also acknowledged.
32. Patra, P. K.; Suresh, J. R.; Ila, H.; Junjappa, H. Tetrahedron
Lett. 1997, 38, 3119.
33. Suresh, J. R.; Patra, P. K.; Ila, H.; Junjappa, H. Tetrahedron
1997, 53, 14737.
References
34. Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedon 1990, 46,
5423.
1. Hartough, H. D.; Meisel, S. L. Chem. Heterocycl. Comp. 1954, 7, 1.
2. (a) Campaigne, E.; Knapp, D. R.; Neiss, E. S.; Bosin, T. R. Adv.
Drug. Res. 1970, 5, 1. (b) Bosin, T. R.; Campaigne, E. Adv. Drug.
Res. 1977, 11, 191.
35. Rao, M. V. B.; Syam Kumar, U. K.; Ila, H.; Junjappa, H.
Tetrahedron 1999, 55, 11563.
36. Patra, P. K.; Suresh, J. R.; Ila, H.; Junjappa, H. Tetrahedron
1998, 54, 10167.
3. Campaigne, E. Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W. Eds.; Pergamon: Oxford, 1984, p 911.
4. Zhang, T. Y.; O'Toole, J.; Proctor, C. S. Sulfur Rep. 1999, 22, 1.
37. (a) Pailer, M.; Gruenhaus, H. Monatsh. Chem. 1974, 105,
1362. (b) Gruenhaus, H.; Pailer, M.; Stof, S. J. Heterocycl.
Chem. 1976, 13, 1161.