Novel route to 2,3-substituted benzo[b]thiophenes via intramolecular radical cyclization

Article abstract of DOI:10.1021/jo900615p

(Chemical Equation Presented) A novel route to 2,3-substituted benzo[b]thiophenes by intramolecular radical cyclization of polarized ketene dithioacetals derived from o-bromoarylacetonitriles or the corresponding 3-(methylthio)-3-alkyl/aryl/heteroaryl ana

Full text of DOI:10.1021/jo900615p

pubs.acs.org/joc
Novel Route to 2,3-Substituted Benzo[b]thiophenes via Intramolecular
Radical Cyclizationq
Prabal P. Singh, A. K. Yadav, H. Ila,* and H. Junjappa
Department of Chemistry, Indian Institute of Technology, Kanpur-208016, India
hila@iitk.ac.in
Received March 23, 2009
A novel route to 2,3-substituted benzo[b]thiophenes by intramolecular radical cyclization
of polarized ketene dithioacetals derived from o-bromoarylacetonitriles or the corresponding
3-(methylthio)-3-alkyl/aryl/heteroaryl analogues has been reported.
Introduction
cognition enhancer,6 antifungal,7 antiviral,8 antiallergic,9 pros-
taglandin,10 dopamine receptor antagonist,11 and 5-lipoxy-
genase inhibitor.12 A number of 2-arylbenzo[b]thiophene deri-
vatives have been recognized as therapeutically useful selective
estrogen receptor modulators (SERMs) for the treatment of
postmenopausal disorders,13,14 which eventually led to the
new commercial drug Raloxifene 1 (Evista, Lilly) for pre-
vention and treatment of osteoporosis in postmenopausal
women.13a,13b Recently, Raloxifene and its derivatives (such
as Arzoxifene 2)13c are also under investigation for breast
cancer therapy,15a,15b as well as for control and treatment
of uterine cancer and Alzhiemer’s disease.16 Recently, a few
of the 2-arylbenzo[b]thiophenes such as 3a,b have been
Benzo[b]thiophene represents an important heterocyclic
core,1 as several of its derivatives are shown to display a range
of promising pharmaceutical properties such as antipsycho-
tic,2 antidepressive,3 antithrombolytic,4 anti-inflammatory,5
q Dedicated to Professor Alan R. Katritzky on his 80th birthday.
(1) For reviews on the synthesis and application of benzo[b]thiophenes,
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Meli, A. Synlett 1997, 643. (d) Russell, R. K.; Press, J. B. Comprehensive
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5496 J. Org. Chem. 2009, 74, 5496–5501
Published on Web 07/02/2009
DOI: 10.1021/jo900615p
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2009 American Chemical Society

Singh et al.
JOCArticle
recognized as tubulin polymerization inhibitors17-19 as rigid
analogues of Combretastatin A4.20
Our own interest in the synthesis of 2,3-substituted benzo[b]
thiophenes derives from our longstanding experience in the
synthesis of a widerangeof substituted and fused five- andsix-
membered heterocycles utilizing polarized ketene dithioace-
tals as synthetic precursors.29-32 During the course of these
studies, we became interested in exploring intramolecular
radical cyclizations of the appropriately substituted polarized
ketene dithioacetals33 and envisaged a general synthetic route
for 2,3-substituted benzo[b]thiophenes through a tandem
intramolecular attack of a carbon-centered aryl radical on a
suitably located sulfur atom of bis(methylthio)methylene
moiety of ketene dithioacetals and subsequent C-S bond
cleavage.34,35 Our literature survey at this stage revealed that
Harrowven and co-workers in their pioneering studies have
reported cascade radical transformations of few unpolarized
cyclic (o-bromoarylidene) ketene dithioacetals yielding 2-(3-
mercaptopropyl)/(tributylstannyl)-3-unsubstituted benzo[b]
thiophenes as the major products along with few minor
products by further cyclization of the initially formed radical
intermediates.36 However, these cyclic ketene dithioacetals
have limitations for developing this reaction as a general
concise approach for the synthesis of biologically important
2-aryl/heteroaryl-3-substituted benzo[b]thiophenes. We have
realized this objective by subjecting either polarized ketene
dithioacetals of the type 4 or the related 2-(2-bromoaryl)-3-
methylthio-3-alkyl/aryl/heteroarylacrylonitrile analogues of
the type 7 to radical cyclization affording 2-substituted-3-
cyanobenzo[b]thiophenes in good yields (Schemes 1 and 2).
We report the results of these studies in this paper.
Emergence of such promising chemotherapeutic agents
has stimulated new investigations into the concise synthesis
of 2,3-substituted benzo[b]thiophenes.1,21 The 2-arylbenzo-
[b]thiophenes are usually synthesized by multistep intramo-
lecular cyclization of thiophenol derivatives developed by
Kost and other workers.13b,22 However, these methods
usually required both acidic and/or basic conditions, proved
to be nonregioselective,13b,22f and were not compatible with
acid- and base-sensitive functional groups. Therefore, other
methods have been developed starting from thiobenzyls23 or
thioanisole24 derivatives along with useful catalytic routes
via direct Heck type arylation of 2-unsubstituted benzo[b]-
thiophenes25-27 and iodine-induced intramolecular oxida-
tive cyclization of o-acetylenic thiobenzyl derivatives.19,28
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Results and Discussion
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bromophenyl)acetonitrile with TBTH was first examined
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SCHEME 1. Synthesis of 3-Cyano-2-(methylthio)benzo[b]thio-
phenes 5
TABLE 2. Synthesis of 3-Cyano-2-aryl/alkyl/heteroarylbenzo[b]thio-
phenes 8
TABLE 1. Synthesis of 3-Cyano-2-(methylthio)benzo[b]thiophenes 5
entry
X
R1
R2
5
% yield 5
1
2
3
4
5
4a
4a
6
4b
4c
Br
Br
I
Br
Br
H
H
H
OMe
F
H
H
H
OMe
H
5a
5a
5a
5b
5c
25a
59b
61b
68b
59b
aTBTH (1.2 equiv)/AIBN (10 mol %)/toulene/Δ/12 h. bn-Bu3SnCl
(20 mol %), NaCNBH3 (2 equiv)/AIBN (10% mol), t-BuOH/Δ/12 h.
(Scheme 1). Thus, when 4a was exposed to TBTH under
standard radical-forming conditions (Table 1, entry 1),
workup of the reaction mixture gave one product (25%
yield) (along with unreacted 4a), which was characterized
as 3-cyano-2-(methylthio)benzo[b]thiophene 5a on the basis
of its spectral and analytical data (Table 1, entry 1).37 The
benzo[b]thiophene 5a was obtained in increased and repro-
ducible yield (59-60%), when 4a was subjected to Stork’s
catalytic tin hydride conditions38 using tributyltin chloride in
the presence of NaCNBH3 and AIBN in refluxing tert-
butanol (Table 1, entry 2). Under identical conditions, the
corresponding o-iodo derivative 6 furnished the 3-cyano-2-
(methylthio)benzo[b]thiophene 5a in comparable yield of
61% (Table 1, entry 3). Consequently, catalytic tributyltin
chloride/NaCNBH3 was used as the reagent of choice for all
radical cyclizations described in the paper. The substrates
bearing (o-bromoaryl) group were preferred over the co-
rresponding (o-iodoaryl) analogues, because of the ease
of preparation of the former by direct bromination of
arylacetonitrile precursors. Ketene dithioacetals 4b-c bear-
ing electron-donating (4b) and electron-withdrawing (4c)
substituents were also subjected to radical cyclization under
(37) 2-(Methylthio)-3-cyanobenzo[b]thiophene (5a) is reported to be
formed in 86% yield on treatment of 2-bromophenylacetonitrile with carbon
disulfide in the presence of NaH in DMSO and subsequent warming and
alkylation with methyl iodide: Rudorf, W.-D; Schierhorn, A.; Augustin, M.
J. Prakt. Chem. 1979, 321, 1021. However, we could isolate 5a in only 28%
yield under these conditions. Similarly, the benzothiophenes 5b and 5c were
obtained in 30% and 32% yields, respectively, when the corresponding 2-
bromo-4,5-dimethoxy- and 2-bromo-4-fluorophenylacetonitriles 20a and
20b were reacted with carbon disulfide and methyliodide under Rudorf’s
conditions. On the otherhand, treatment of 20a and 20b with either methyl 2-
thienyl- or 4-(methoxyphenyl)dithioates in the presence of NaH/DMSO
under these conditions furnished only the acyclic compounds 21a and 21b
in 34% and 36% yields, respectively, and no trace of benzothiophenes 8g or
8d could be isolated from the reaction mixture.
identical conditions affording 2-(methylthio)-3-cyano-5,6-
substituted benzo[b]thiophenes 5b-c in 68% and 59%
yields, respectively (Table 1, entries 4 and 5).
To further explore the generality and scope of this reac-
tion, especially for the synthesis of 2-aryl/heteroarylbenzo[b]-
thiophenes, we next examined analogous radical cyclization
of the corresponding 3-(methylthio)-3-(aryl/heteroaryl/
alkyl)-2-(2-bromoaryl)acrylonitriles 7 under identical condi-
tions (Scheme 2, Table 2). We have previously developed
a general synthetic protocol for these intermediates via
(38) (a) Stork, G.; Sher, P. M. J. Am. Chem. Soc. 1986, 108, 303. (b)
Curran, D. P.; Kim, D.; Liu, H. T.; Shen, W. J. Am. Chem. Soc. 1988, 110,
5900.
5498 J. Org. Chem. Vol. 74, No. 15, 2009

Singh et al.
JOCArticle
SCHEME 2. Synthesis of 3-Cyano-2-alkyl/aryl/heteroarylbenzo-
[b]thiophenes 8
SCHEME 4. Synthesis of 2-Anilino/cycloamino-3-cyanobenzo[b]-
thiophenes 11a-d
SCHEME 3. Radical Cyclization of 7l and 7m
SCHEME 5. Attempted Synthesis of 2-Methylthio-3-aroylbenzo-
[b]thiophenes 13
base-induced condensation of the substituted (o-bromo)
arylacetonitriles with the corresponding aryl/heteroaryl/
alkyl dithioesters followed by in situ S-methylation of the
resulting enethiolate salts with methyl iodide.39 With a
number of substrates in hand, we first subjected the repre-
sentative 3-methylthio-3-phenylacrylonitrile 7a to radical
cyclization under previously described conditions, and we
were pleased to observe that the anticipated 3-cyano-5-
methoxy-2-phenylbenzo[b]thiophene 8a was obtained in
81% yield (Table 2, entry 1). The other substituted 2-aryl-
3-cyanobenzo[b]thiophenes 8b-d were similarly obtained in
high yields from the respective 3-aryl-3-(methylthio)acrylo-
nitrile precursors 7b-d (Table 2, entries 2-4). The metho-
dology could also be extended successfully for the synthesis
of 2-alkyl-3-cyanobenzo[b]thiophenes 8e-f in reasonably
good yields from the appropriate 3-alkyl-3-(methylthio)acry-
lonitrile precursors 7e-f (Table 2, entries 5 and 6). Similarly,
we were further delighted to find that the corresponding
3-(heteroaryl)-3-(methylthio)acrylonitriles 7g-k also under-
went facile cyclization under identical radical-mediated condi-
tions providing the novel hitherto unreported 2-(2-thienyl)-,
2-(2-furyl), 2-(2-N-methylpyrrolyl), 2-(2-N-methylimidazolyl),
and 2-(3-pyridyl)-3-cyanobenzo[b]thiophenes 8g-k in high
yields (except 8j) (Table 2, entries 7-11).
ing 3-(methylthio)-3-(2-pyrrolyl) derivative 7l bearing elec-
tron-withdrawing fluorine on the phenyl ring also behaved in
the similar fashion (unlike its electron-rich counterpart 7i)
(Table 2, entry 9) yielding the substituted benzo[e]indole 9l
instead of the anticipated 2-(2-pyrrolyl)-3-cyano-6-fluoro-
benzo[b]thiophene 8l (Scheme 3).
After successful synthesis of various 2-aryl/heteroaryl/alkyl-
3-cyanobenzo[b]thiophenes, we next extended this radical
cyclization protocol to few N,S-acetals 10a-d derived from
(o-bromoaryl)acetonitriles and primary/secondary amines
(Scheme 4). The resulting 2-(cycloamino/arylamino)-3-cyano-
benzo[b]thiophenes 11a-d are useful substrates for further
synthetic elaboration.21a Thus, when 10a-d were exposed to
n-Bu3SnCl/NaCNBH3 under earlier reported conditions, the
reaction proceeded as expected yielding 2-N-anilino and 2-
(N-methylanilino)- and 2-(N-benzylpiperazino)-3-cyanobenzo-
[b]thiophenes 11a-d in moderate to good yields (Scheme 4).
After successfully achieving the synthesis of 2-substituted-
3-cyanobenzo[b]thiophenes via radical-mediated cyclization,
we next focused our attention toward creating functional
group diversity at the 3-position of benzo[b]thiophenes and
therefore examined the intramolecular radical cyclization of
ketene dithioacetals 12a-c derived from (o-bromoaryl)desoxy-
benzoins and the related 3-aryl analogues 14 (Schemes 5 and 6).
The resulting 3-aroylbenzo[b]thiophenes 13 and 15 are struct-
ural analogues of few therapeutically important benzo[b]thio-
phenes such as Raloxifene 1 and tubulin-binding agents
such as 3. Thus, when the ketene dithioacetal 12a was sub-
jected to radical cyclization under earlier reported conditions
(n-Bu3SnCl/NaCNBH3), the desired 3-benzoyl-2-(methylthio)
benzo[b]thiophene 13a was isolated in 62% yield (Scheme 5).
However, the reaction of the related ketene dithioacetals 12b-c
from methoxy/fluoro substituted desoxybenzoins yielded only
Interestingly, the radical cyclization of the corresponding
3-methylthio-3-(3-indolyl)acrylonitrile 7m under similar re-
action conditions did not follow the expected protocol to
afford the desired 2-(3-indolyl)-3-cyanobenzo[b]thiophene
8m, and the product isolated (65%) was found to be benzo
[1,2-a]carbazole derivative 9m (Scheme 3). The correspond-
(39) Kumar, S.; Peruncheralathan, S; Ila, H.; Junjappa, H. Org. Lett.
2008, 10, 965.
J. Org. Chem. Vol. 74, No. 15, 2009 5499

Singh et al.
JOCArticle
SCHEME 6. Attempted Synthesis of 2-Aryl-3-aroylbenzo[b]thio-
phenes 15
give the desired 3-aroylbenzo[b]thiophenes 15a-b or 13b-c
(Schemes 5 and 6) appears to be due to insolubility of starting
compounds 14a-b and 12b-c in the reaction solvents and
also due to steric crowding in these precursors (14a-b and
12b-c), thus resisting the abstraction of bromine by bulkier
tributyltin radical in the initial step (Scheme 7).
Interestingly, the X-ray diffraction data of pure stereo-
isomers 7b, 7d, 7g, 7k, and 7m showed that they exist in
Z form with o-bromoaryl and SMe groups being trans to
each other.41 Thus, the facile cyclization of Z isomers of 7 to
benzo[b]thiophenes appears to proceed via a cis-trans iso-
merization of the double bond in 7 involving either an
addition-elimination of tributytin radical42,43 or a thermal
isomerization to E isomers, under the present reaction con-
ditions, for their favorable cyclization to 8.44
SCHEME 7. Probable Mechanism for Formation of Benzo[b]thio-
phenes 5, 8, 11, and 9l-m
Conclusion
In summary, we have demonstrated that the appropriately
substituted polarized ketene dithioacetals derived from
o-bromoarylacetonitriles or the corresponding 3-(methy-
lthio)-3-aryl/heteroarylacrylonitrile analogues are useful sub-
strates for the synthesis of 2,3-substituted benzo[b]thiophenes
via an intramolecular radical cyclization protocol involving
tandem attack of a carbon-centered radical on sulfur and
subsequent C-S bond cleavage. This new methodology al-
lows direct one-step access to 2-substituted-3-cyanobenzo[b]
thiophenes with potential biological activity. Also, this versa-
tile methodology will be a good alternative for the synthesis of
Raloxifene analogues despite our initial unsuccessful at-
tempts, and further efforts in this direction and to study scope
and limitations of this methodology are in progress.
Experimental Section
General details are described in Supporting Information. The
known S,S-acetals 4a-c, 6, 7b-c, and 7g-i and the unknown
7a, 7d-f, 7j-k, and 7l-m were prepared according to the our
earlier reported procedure.39,45 Similarly, the unknown S,S-
acetals 12a-c and 14a-b were prepared from the appropriate
desoxybenzoins.29a,39,45 The unknown N,S-acetals 10a-d were
obtained either by arylisothiocyanate method29a,46 (10a-c) or
by direct displacement on the ketene dithioacetals by amine
(10d).29a,46
unreacted starting materials under these conditions due to the
insolubility of 12b-c in tert-butanol. Similarly, the attempted
radical cyclization of the newly synthesized 3-aryl-3-methyl-
thio-2-(2-bromoaryl)-1-arylpropenones 14a-b to the desired
2-aryl-3-aroylbenzo[b]thiophenes under identical conditions or
by varying the solvent or reagent (toluene or TBTH/toluene)
did not meet with any success and yielded only unreacted
14a-b without any trace of 15 (Scheme 6).
The probable mechanism for the formation of various
substituted benzo[b]thiophenes from the respective precur-
sors is shown in Scheme 7. Thus, the initially formed 2-
(o-aryl) radical species 16 attacks intramolecularly the sulfur
atom of methylthio group of either ketene dithioacetals 4 or
of 3-(methylthio) moiety of acrylonitriles 7 or N,S-acetals 10
to give the cyclized radical intermediate 17, which on homo-
lytic C-S bond cleavage affords the product benzo[b]thio-
phenes 5, 8, or 11 in good yields (Scheme 7).
In the case of 3-(2-N-methylpyrrolyl) and 3-(3-N-methy-
lindolyl)acrylonitriles 7l-m, the initially formed aryl radical
in intermediate 18 attacks intramolecularly either 3-position
of pyrrole 7l or 2-position of indole 7m rather than the
methylthio group, yielding the products benzo[e]indole 9l
or the corresponding benzo[a]carbazole 9m instead of the
expected benzo[b]thiophenes 8l-m (Scheme 4). Failure of
the corresponding 1-(methylthio)-1,2,3-triarylpropen-3-ones
14a-b or 12b-c to undergo radical-mediated cyclization to
General Procedure for Radical Cyclization of 2-(2-Bromoaryl-
3-(alkyl/aryl/heteroaryl)-3-(methylthio)-2-propenenitriles 4, 6, 7,
10, 12, and 14. To a solution of corresponding 2-(2-bromoaryl)
(40) Branum, S. T.; Colburn, R. W.; Dax, S. L.; Flores, C. M.; Jetter, M.
C.; Liu, Y.; Ludovici, D.; Macielag, M. J.; Matthews, J. M.; Mcnally, J. J.
PCT Int. Appl. 2009, WO 2009012430 A1 20090122; Chem. Abstr. 2009, 150,
168153.
(41) The stereochemical assignments for 7a, 7c, 7e, 7f, 7h, and 7j existing
as E/Z mixtures are based on the chemical shift value of the SMe signal that
appears at higher δ value (δ 2.05-2.45) in Z isomers (also in pure Z isomers
7b, 7d, 7g, 7i, 7k, 7l and 7m) in comparison to E isomers (δ 1.8-2.11)
probably due to shielding by the cis (o-bromoaryl group) in E isomers.
(42) (a) Harrowven, D. C.; Nunn, M. I. T.; Fenwick, D. R. Tetrahedron
Lett. 2002, 43, 3185. (b) Sonnet, P. E. Tetrahedron 1980, 36, 557. (c) Flanagan,
S. R.; Harrowven, D. C.; Bradley, M. Tetrahedron Lett. 2003, 44, 1795.
(43) A detailed analysis of reaction mixtures from 7a-k showed exclusive
formation of benzo[b]thiophene products 8a-k with no trace of fused
products such as 9l-m.
(44) We are thankful to one of the reviewers for this suggestion and in
fact, when 7a (E/Z 1:2.3) was refluxed in t-BuOH for 10 h in the absence of
n-Bu3SnCl/AIBN/NaCNBH3, the E/Z ratio was found to change to 18:1
(estimated by 1H NMR spectrum).
(45) Chauhan, S. M. S.; Junjappa, H. Tetrahedron Lett. 1976, 32, 1779.
(46) Kumar, A.; Aggarwal, V.; Ila, H.; Junjappa, H. Synthesis 1980, 784.
5500 J. Org. Chem. Vol. 74, No. 15, 2009

Singh et al.
JOCArticle
EtOAc/hexane); IR (KBr) 2924, 2219, 1564, 1468, 1416, 1192,
acrylonitriles 4, 6, 7, 10, 12, or 14 (0.25 mmol), AIBN (10 mol
%), and NaCNBH3 (0.50 mmol) in degassed t-BuOH (15 mL)
was added n-Bu3SnCl (20 mol %), and the reaction mixture was
refluxed for 5-8 h. It was then cooled to room temperature, and
solvent was evaporated followed by addition of water (25 mL).
It was extracted with ethylacetate (3 ꢀ 15 mL), and the com-
bined organic extracts were washed with H2O (2 ꢀ 50 mL) and
brine (50 mL), dried (Na2SO4), and evaporated under reduced
pressure to afford crude product, which was purified by column
chromatography over silica gel using EtOAc-hexane as eluent
to give pure benzo[b]thiophenes 5, 8, 11, or 13 and 9l-m.
2-Methylthiobenzo[b]thiophene-3-carbonitrile (5a)37. White
solid; yield 59% (0.31 g); mp 79-80 °C; Rf 0.63 (1:19 EtOAc/
1133, 900, 805 cm-1 1H NMR (400 MHz, CDCl3) δ 9.05
;
(brs,1H), 8.76(brs,1H), 8.25 (dd, J=7.9 Hz, 1.7 Hz, 1H), 7.96 (dd,
J=8.8 Hz, 4.8 Hz, 1H), 7.60 (dd, J=8.0 Hz, 2.2 Hz, 1H), 7.50 (dd,
J=8.1 Hz, 4.9 Hz, 1H), 7.35-7.30 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 161.6(d, J=248.0 Hz), 151.4, 150.6, 148.9, 138.73 (d, J=
10.7 Hz), 135.4, 135.2, 127.7, 124.4, 124.09, 115.84 (d, J=23.8 Hz),
114.4, 109.0 (d, J=26.2 Hz), 103.3; HRMS (ESI) m/z calcd for
C14H8FN2S (Mþ þ H) 255.0396, found 255.0391.
3-Methoxy-11-N-methyl-6-methylthiobenzo[a]carbazole-5-car-
bonitrile (9m). Light yellow solid; yield 65% (0.24 g); mp 203-
204 °C; Rf 0.56 (1:6 EtOAc/hexane); IR (KBr) 2916, 2200, 1618,
1564, 1467, 1224, 1047, 733 cm-1; 1H NMR (500 MHz, CDCl3) δ
8.95 (d, J=8.1 Hz, 1H), 8.61 (d, J=9.5 Hz, 1H), 7.71-7.70 (m,
1H), 7.57-7.55 (m, 2H), 7.42-7.38 (m, 1H), 7.32-7.29 (m, 1H),
4.35 (s, 3H), 4.01 (s, 3H), 2.65 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 158.6, 141.2, 138.5, 138.1, 134.7, 125.7, 124.4, 123.1,
122.5, 121.2, 118.8, 118.5, 118.2, 116.3, 109.1, 107.1, 105.5, 55.6,
34.4, 19.6; MS (FAB) (m/z, %) 333 (M þ 1, 88), 332 (Mþ, 100);
HRMS (ESI) m/z calcd for C20H17N2OS (Mþ þ H) 333.1062,
found 333.1068.
hexane); IR (KBr) 2923, 2207, 1456, 1419, 747, 719 cm-1; H
1
NMR (400 MHz, CDCl3) δ 7.77 (d, J=8.1 Hz, 1H), 7.72 (d,
J=8.1 Hz, 1H), 7.45 (t, J=7.6 Hz, 1H), 7.36 (t, J=7.7 Hz, 1H),
2.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 154.4, 138.3, 137.6,
126.1, 125.3, 121.9, 121.4, 113.7, 104.8, 18.9; MS (FAB) m/z (%)
206 (M þ Hþ, 90), 205 (Mþ, 100); HRMS (ESI) m/z calcd for
C10H8NS2 (Mþ þ H) 206.0098, found 206.0093.
5,6-Dimethoxy-2-phenyl-benzo[b]thiophene-3-carbonitrile (8b).
White solid; yield 74% (0.55 g); mp 179-180 °C; Rf 0.45 (1:9
EtOAc/hexane); IR (KBr) 2933, 2217, 1520, 1492, 1437, 1359,
1264, 1251, 1035, 835 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.85-
7.83 (m, 2H), 7.52-7.45 (m, 3H), 7.32 (s, 1H), 7.24 (s, 1H), 4.00
(s, 3H), 3.97 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 152.7, 149.6,
149.6, 133.1, 131.8, 130.3, 130.1, 129.4, 127.9, 115.7, 103.6, 103.5,
101.5, 56.4, 56.3; HRMS (ESI) m/z calcd for C17H14NSO2 (Mþ þ
H) 296.0745, found 296.0746.
6-Phenylamino-1,3-dioxa-5-thia-s-indacene-7-carbonitrile (11a).
White solid; yield 80% (0.58 g); mp 221-222 °C; Rf 0.70 (1:9
EtOAc/hexane); IR (KBr) 3251, 2886, 2203, 1597, 1559, 1498,
1
1472, 1446, 1294, 1217, 1050, 1038, 946 cm-1; H NMR (400
MHz, CDCl3) δ 7.39 (t, J=7.8 Hz, 2H), 7.29 (t, J=7.8 Hz, 2H),
7.17 (t, J=7.4 Hz, 1H), 7.06 (s, 1H), 7.04 (brs, 1H), 6.99 (s, 1H),
6.01 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 158.5, 147.7, 145.7,
140.1, 130.5, 129.8, 124.6, 121.5, 119.4, 115.1, 101.8, 101.5, 99.9,
85.0; MS (FAB) m/z (%) 294 (Mþ, 100); HRMS (ESI) m/z calcd
for C16H10N2O2S (Mþ) 294.0463, found 294.0482.
(2-Methylthiobenzo[b]thiophen-3-yl)-phenylmethanone (13a).
Yellow liquid; yield 62% (0.44 g); Rf 0.28 (1:9 EtOAc/hexane);
IR (KBr) 3057, 2924, 1638, 1557, 1464, 1434, 1347, 1316, 1250,
1076, 1026, 728 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=
7.1 Hz, 2H), 7.55 (d, J=7.8 Hz, 1H), 7.46-7.42 (m, 1H), 7.38-
7.28 (m, 3H), 7.19-7.14 (m, 2H), 2.29 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 191.9, 151.9, 138.5, 136.9, 132.9, 131.7, 131.5,
129.8, 129.3, 128.7, 128.1, 127.5, 123.5, 17.8; MS (FAB) m/z (%)
284 (Mþ 100); HRMS (ESI) m/z calcd for C16H12OS2 (Mþ)
284.0330, found 284.0348.
2-Isopropyl-5,6-dimethoxybenzo[b]thiophene-3-carbonitrile (8f).
Viscous liquid; yield 55% (0.36 g); Rf 0.48 (1:9 EtOAc/hexane);
IR (CH2Cl2) 2936, 2239, 1517, 1464, 1263, 1227, 1145, 1026,
809 cm-1;1H NMR (500 MHz, CDCl3)δ6.83 (s, 1H), 6.77 (s, 1H),
3.83 (s, 3H), 3.80 (s, 3H), 3.80-3.75 (m, 1H), 1.55 (d, J=9.2 Hz,
6H); 13C NMR (125 MHz, CDCl3) δ 149.4, 148.8, 129.6, 121.9,
119.0, 111.5, 109.8, 56.1, 56.1, 30.9, 21.6; MS (FAB) m/z (%) 261
(Mþ 100), 232 (75%); HRMS (ESI) m/z calcd for C14H15NSO2
(Mþ) 261.0823, found 261.0826.
5,6-Dimethoxy-2-(1-methyl-1H-pyrrol-2-yl)benzo[b]thiophene-3-
carbonitrile (8i). White solid; yield 78% (0.58 g); mp 139-140 °C;
Rf 0.42 (1:9 EtOAc/hexane); IR (KBr) 3010, 2932, 2213, 1601,
1521, 1468, 1285, 1235, 1206, 1030, 833 cm-1; 1H NMR (400 MHz,
CDCl3)δ7.24 (s, 1H), 7.16 (s, 1H), 6.78 (t, J=2.2Hz, 1H), 6.65(dd,
J=6.3 Hz, 1.7 Hz, 1H), 6.20 (t, J=3.3 Hz, 1H), 3.94 (s, 3H), 3.91 (s,
3H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 149.5, 149.2,
143.4, 132.1, 130.2, 126.8, 123.9, 115.6, 113.8, 109.0, 103.3, 103.1,
102.5, 56.3, 56.2, 35.7; MS (ESI) m/z (%) 299 (Mþ þ 1, 100);
HRMS (ESI) m/z calcd for C16H15N2O2S (Mþ þ H) 299.0854,
found 299.0858.
Acknowledgment. PPS and AKY thank DST and CSIR,
New Delhi, respectively for Senior Research Fellowships. Finan-
cial assistance under DST and CSIR projects is acknowledged.
Supporting Information Available: General experimental
procedures, characterization data and copies of 1H NMR
and 13C NMR spectra of all new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
6-Fluoro-2-(pyridin-3-yl)benzo[b]thiophene-3-carbonitrile (8k).
White solid; yield 74% (0.47 g); mp 187-188 °C; Rf 0.60 (1:4
J. Org. Chem. Vol. 74, No. 15, 2009 5501