Synthesis of arylated highly congested indans using a domino sequence

Article abstract of DOI:10.1016/j.tet.2007.07.050

A novel and efficient regioselective synthesis of various arylated highly congested 7-aryl-5-methylsulfanylindan-4-carbonitriles (3a-f), methyl 7-aryl-5-methylsulfanylindan-4-carboxylates (10a-e) and 7-aryl-5-methylsulfanylindan-4-carboxylic acids (11a-e)

Full text of DOI:10.1016/j.tet.2007.07.050

Tetrahedron 63 (2007) 10300–10308
Synthesis of arylated highly congested indans
using a domino sequence*
Ramendra Pratap,a Brijesh Kumarb and Vishnu Ji Rama,
*
aMedicinal and Process Chemistry Division, Central Drug Research Institute, Chattar Manzil, Lucknow—226 001, UP, India
bDivision of SAIF, Central Drug Research Institute, Lucknow—226 001, UP, India
Received 18 April 2007; revised 1 July 2007; accepted 19 July 2007
Available online 25 July 2007
Abstract—A novel and efficient regioselective synthesis of various arylated highly congested 7-aryl-5-methylsulfanylindan-4-carbonitriles
(3a–f), methyl 7-aryl-5-methylsulfanylindan-4-carboxylates (10a–e) and 7-aryl-5-methylsulfanylindan-4-carboxylic acids (11a–e) through
base-catalyzed reaction of 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (1a–f) and methyl 6-aryl-4-methylsulfanyl-2-oxo-2H-
pyran-3-carboxylates (9a–e) by cyclopentanone (2) has been delineated. The synthetic potential of 2-pyranone was explored further to
generate molecular diversity using 6-aryl-4-sec-amino-2-oxo-2H-pyran-3-carbonitriles (7a–h), 5,6-diaryl-4-methylsulfanyl-2-oxo-
2H-pyran-3-carbonitriles (5a,b) and methyl 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (12a,b) as precursors for the ring
transformation by cyclopentanone to assess the effects of substituents on the course of the reaction to obtain highly congested indans, 6,7-
diaryl-5-methylsulfanylindan-4-carbonitriles (6a,b), 7-aryl-5-(piperidin-1-yl)indan-4-carbonitriles (8a–h) and methyl 6,7-diaryl-5-methyl-
sulfanylindan-4-carboxylates (13a,b).
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
substituents to the aryl as well as cyclopentane rings of the
indan. Recently, 4,7-disubstituted indan-2-ols have been
prepared from the aryl titanium compounds obtained from
two acetylenes and ethynyl p-tolylsulfone.15,16 Arylboronic
acid esters bearing a pendant Michael-acceptor add to nor-
bornene and cyclize to give the indan ring system.17 An intra-
molecular addition of an organolithium to a tethered benzyne
intermediate is one of the versatile approaches for the con-
struction of arylated indans.18 A new synthesis of indan de-
rivatives has been recently reported19 by the coupling of
carbene complexes with 2-alkynylstyrenes. The difficulties
in obtaining various precursors in multiple steps and limita-
tions to introduce substituents in both the aryl and cyclopen-
tane rings prompted us to develop an easy, viable synthetic
route for the construction ofindans with multiple substituents
in the aryl ring.
The indan skeleton occurs in a variety of natural products and
is a substructure1 of therapeutic importance.2 Various indan
derivatives have been reported to display aldosterone syn-
thase3 and thrombin4 inhibitoryactivities, besides respiratory
stimulating,5 antispasmodic6 and antiHIV7 properties.
Through an extensive literature survey it was realized that
the compounds containing this ring system have been synthe-
sized generally either by anionic8,9 or radical-mediated10 cy-
clization strategies. The newer approaches provide an easy
access to the construction of chiral indan derivatives with
substitution on the cyclopentane ring. The cyclization of
the aryl radical derived from 4-(2-bromophenyl)-1-pentene
also yields11 a mixture of cis- and trans-1,3-dimethylindans.
The cycloisomerization of the organolithium derived from
4-(2-bromophenyl)-1-pentene is more selective12 compared
to radical cyclization for the synthesis of indans. An alterna-
tive route has been developed13 for the construction of 1,3-
disubstituted indans through cyclization of styrene tethered
primary radical or alkyl lithium derived from 2-(2-iodo-1-
methylethyl)styrene. Cyclotrimerization of three different
acetylenes in the presence of titanium alkoxide is an elegant
approach for the preparation of highly functionalized in-
dans.14 This methodology provides an avenue to introduce
Here, we report an elegant synthesis of indans through a carb-
anion induced ring transformation of suitably functionalized
2H-pyran-2-ones by cyclopentanone. The presence of elec-
tron-acceptor and electron-donor substituents at positions
3 and 4 of the pyran ring makes it a very valuable synthon
for the construction of various mono and polycyclic arenes
and heteroarenes depending upon the nature of the nucleo-
philes20–24 used. The synthetic potential of suitably func-
tionalized 2H-pyran-2-one is enormous and can be used
for generating molecular diversity through careful maneu-
verings of nucleophiles and reaction conditions. Bases
such as NaH and sodium methoxide also contribute to the
regioselectivity.
*
CDRI communication no. 6960.
Keywords: Indan; 2-Oxo-2H-pyrans; Regioselective.
* Corresponding author. Tel.: +91 522 2612411; fax: +91 522 2623405;
e-mail: vjiram@yahoo.com
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.050

R. Pratap et al. / Tetrahedron 63 (2007) 10300–10308
10301
2. Results and discussion
formation of product 4. The plausible mechanism of the
reaction is shown in Scheme 2.
Various 2H-pyran-2-ones used as precursors for the ring
transformation reactions are 6-aryl-4-methylsulfanyl- (1),
5,6-diaryl-4-methylsulfanyl- (5), 6-aryl-4-(piperidin-1-yl)-
2-oxo-2H-pyran-3-carbonitriles (7), methyl 6-aryl-4-meth-
ylsulfanyl- (9) and methyl 5,6-diaryl-4-methylsulfanyl-2-
oxo-2H-pyran-3-carboxylates (12). The 2H-pyran-2-ones 1
and 5 have been prepared23,25 from the reaction of an aryl
methyl ketone and 1,2-diarylethanone with methyl 2-cyano-
3,3-dimethylthioacrylate separately. The precursors 6-aryl-
4-(piperidin-1-yl)-2-oxo-2H-pyran-3-carbonitriles (7) have
been synthesized20 by refluxing a mixture of 1 and piper-
idine in ethanol for 5 h, while 9 has been obtained from
the reaction of an aryl methyl ketone and methyl 2-carbome-
thoxy-3,3-dimethylthioacrylate (Scheme 1). We had an ap-
prehension in obtaining synthon 12 from the reaction of
1,2-diarylethanone with methyl 2-carbomethoxy-3,3-dime-
thylthioacrylate because of steric crowding but the reaction
proceeded smoothly, possibly by acquiring non-planar con-
formation of both the aryl rings. Our attempts to prepare
methyl 6-aryl-4-sec-amino-2-oxo-2H-pyran-3-carboxylates
from the reaction of 9 with secondary amine in refluxing
ethanol failed. The weaker electron-withdrawing property
of –COOCH3 compared to the CN substituent made the
C-4 position of the pyran ring less electrophilic and resistant
to amination.
SCH3
O
CN
+
Ar
O
1
O
2
DMF/KOH
Path A
Path B
X
O
O
O
CN
O
CN
O
H3CS
O
H3CS
H3CS
O
Ar
Ar
N
CN
C
H3CS
O
OH
H
O
Ar
Ar
CN
OH
H3CS
N
C
H3CS
O
Ar
H
Ar
Ar
SCH3
Ar
NC
N
O
SCH3
3
H3CS
SCH3
CN
CN
O
R1
Ar
X
Ar
O
4
Yield (%)
Ar
1,3
piperidine
Ar
O
+
R1
a
b
c
d
e
f
C6H5
78
81
79
71
H3COOC
X
O
O
4-CH3C6H4
2-thienyl
3-pyridyl
7
1
5
9
R1 = H; X = CN
R1 = Ar; X = CN
R1 = H; X = COOCH3
2,4-(CH3)2C6H3 75
2-furyl
85
12 R1 = Ar; X = COOCH3
Scheme 2. The proposed mechanism for the synthesis of 7-aryl-5-methyl-
sulfanyl-indan-4-carbonitriles (3).
Scheme 1. Synthesis of various 2H-pyran-2-ones.
Cyclopentanone (2) was used as a source of carbanion for the
ring transformation reactions. The position 2 of the cyclo-
pentanone is reactive enough to form an enolate in the
presence of base like KOH/DMF and NaH/THF. The C-6
position of the 2H-pyran-2-ones (1a–f) is highly electro-
philic in nature due to extended conjugation and the pres-
ence of an electron-withdrawing substituent at C-3 of the
pyran ring and is highly susceptible to nucleophilic attack.
The first step in the formation of aryl-tethered indan 3 is
the attack of an enolate generated in situ from cyclopenta-
none (2) at C-6 of the pyran ring and thereafter it may follow
either path A or B. In the case of reaction following path A,
the first step is the ring closure followed by elimination of
carbon dioxide and water to yield indans (3a–f) in one
step. On the other hand when reaction follows path B,20a
enolization followed by ring closure involving attack of
the enolate anion at C-4 of the pyran ring with loss of methyl
mercaptan and carbon dioxide may lead to the bicyclic pyran
4. Thus, stirring an equimolar mixture of 1, cyclopentanone
(2) and powdered KOH in DMF at ambient temperature
afforded 7-aryl-5-methylsulfanylindan-4-carbonitriles (3)
in more than 71% yields. However, we did not observe the
The effect of an additional aryl substituent at C-5 of the
pyran ring on the course of the reaction was studied by
preparing 6,7-diaryl substituted indans (6a,b) through the
base-catalyzed ring transformation of 5,6-diaryl-4-methyl-
sulfanyl-2-oxo-2H-pyran-3-carbonitriles (5a,b) by 2,
Scheme 3.
CN
H3CS
R
SCH3
O
CN
DMF/KOH
+
R
O
O
R
5
2
R
6
5,6
R
Yield (%)
a
b
71
65
H
CH3O
Scheme 3. Synthesis of 6,7-diaryl-5-methylsulfanylindan-4-carbonitriles (6).

10302
R. Pratap et al. / Tetrahedron 63 (2007) 10300–10308
The presence of an aryl substituent at position 5 of the pyran
ring has no significant contribution on the course of the
reaction except a little variation in the yields.
The effect of COOCH3 as a weaker electron-withdrawing
substituent at C-3 of the pyran ring was studied to assess
its influence on the course of the reaction. Thus, a reaction
of methyl 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-
carboxylates (9a–e) and cyclopentanone (2) in the presence
of powdered KOH in dry DMF under analogous reaction con-
ditions afforded a mixture of two products in 3:2 ratio, which
were separated by column chromatography. The product
with higher Rf was identified as a methyl 7-aryl-5-methylsul-
fanylindan-4-carboxylate (10) while that with lower Rf was
7-aryl-5-methylsulfanylindan-4-carboxylic acid (11). An in-
crease in the duration of reaction from 2 to 6 h improved the
yield of acid 11 due to enhanced hydrolysis of ester 10.
The methylsulfanyl substituent at C-4 of the pyran ring,
being a good leaving group gave a substitution product on
reaction with piperidine/4-methylpiperidine in refluxing
ethanol. However, the reaction of 5a,b with piperidine failed
to provide corresponding 5,6-diaryl-4-(piperidin-1-yl)-2-
oxo-2H-pyran-3-carbonitriles, possibly due to steric hin-
drance. Amination in the absence of C-5 aryl substituent in
5 was facile to yield 6-aryl-4-sec-amino-2-oxo-2H-pyran-
3-carbonitriles (7a–h) in good yields. The ring transforma-
tion of 7 by cyclopentanone (2) under analogous reaction
conditions gave aminoindans (8a–h) in excellent yields.
This reaction is also initiated by the attack of a carbanion
generated from cyclopentanone (2) in situ at C-6 position
of the 2H-pyran-2-ones (7a–h) with ring closure followed
by concomitant loss of carbon dioxide and water as shown
in Scheme 4. The presence of the sec-amino substituent at
C-4 position of a pyran ring (7) did not influence the electro-
philic character of the C-6 position and thus the reaction
proceeded analogously to yield 7-aryl-5-sec-aminoindan-
4-carbonitriles (8a–h) in more than 86% yields. The pres-
ence of a sec-amino group decreases the electrophilicity of
C-4 position of the pyran ring and thereby reduces the pos-
sibility of side reactions by an attack of carbanion as well
as enolate anion in situ from 2 (Scheme 4).
Further, an increase in the reaction time did not result in any
significant change in the yields of 10 and 11. Different sol-
vents and bases were tried for the regioselective synthesis
of 10. Thus, a reaction of 9 with cyclopentanone (2) in the
presence of NaH in THF produced only 10, in 35–43% yields
(Scheme 5). The yield optimization data in the presence of
different bases and duration of reaction are listed in Table 1.
Ar
SCH3
COOCH3
Ar
DMF/KOH
2 h
2
+
+
SCH3
Ar
O
O
SCH3
COOH
11
COOCH3
9
10
NaH/THF
R'
36 h
R'
10
SCH3
Scheme 5. Synthesis of methyl 7-aryl-5-methylsulfanylindan-4-carboxyl-
ates (10) and 7-aryl-5-methylsulfanylindan-4-carboxylic acids (11).
N
CN
N
H
CN
O
Ar
O
1
O
EtOH/
Ar
O
7
The ring transformation of methyl 4,5,6-trisubstituted-
2-oxo-2H-pyran-3-carboxylates (12a,b) under analogous
conditions led to yield only methyl 4,5-diaryl-6-methylsulfa-
nylindan-7-carboxylates (13a,b) in good yields (Scheme 6).
DMF/KOH
2
R'
R'
O
H
+
CN
CN
O
N
N
O
O
Table 1. Yield optimization using bases and reaction times
10, 11 Ar
DMF/KOH
2 h
DMF/KOH
6 h
NaH/THF
36 h
Ar
Ar
R'
Yield (%)
Yield (%)
Yield (%)
10
R'
10
11
10
11
H
H
CN
N
+
CN
N
OH
a
b
c
d
e
C6H5
4-Cl–C6H4
32
33
57
57
53
55
57
5
8
9
7
10
71
69
74
73
67
42
43
41
35
41
O
4-Br–C6H4 35
2-Thienyl 35
2-Naphthyl 33
Ar
Ar
H
1,7,8 Ar
R' Yield (%)
R'
CN
a
C6H5
H
H
H
H
H
H
H
CH3
91
88
89
92
91
89
87
86
N
b
3. Conclusions
4-ClC6H4
4-BrC6H4
4-CH3C6H4
4-CH3OC6H4
2-Thienyl
c
d
e
f
We have developed a facile, economical and efficient route
to the regioselective synthesis of highly congested indans
that has an edge over the past literature procedures in terms
of yields and option to introduce various substituents in the
aryl ring. This methodology provides an opportunity to pre-
pare such indans in which all the positions of fused aryl ring
are occupied by different substituents.
Ar
8
C10H7
g
h
C6H5
Scheme 4. The plausible mechanism for the synthesis of 7-aryl-5-(piperi-
din-1-yl)indan-4-carbonitriles (8).

R. Pratap et al. / Tetrahedron 63 (2007) 10300–10308
COOH
10303
dH (200 MHz, CDCl3): 2.08–2.16 (m, 2H, CH2), 2.56 (s,
3H, SCH3), 2.96 (t, J 7.3 Hz, 2H, CH2), 3.15 (t, J 7.5 Hz,
2H, CH2), 7.14 (s, 1H, ArH), 7.39–7.46 (m, 5H, ArH); dC
(50 MHz, CDCl3): 17.20, 25.65, 33.17, 33.64, 108.05,
116.82, 126.22, 128.56, 128.67, 129.00, 139.95, 140.80,
140.86, 143.06, 151.31; MS m/z 266 (M++1); HRMS (EI):
M+, found 265.0925; C17H15NS requires 265.0920.
H3CS
X
R
R
SCH3
O
O
R
14
COOCH3
DMF/KOH
+
4.2.2. 7-(4-Methylphenyl)-5-methylsulfanylindan-4-car-
bonitrile (3b). It was obtained by stirring a mixture of 1b
(257 mg, 1.0 mmol), 2 (0.1 mL, 1.1 mmol) and KOH
(84 mg, 1.5 mmol) in dry DMF (10 mL) as a white solid af-
ter neutral alumina column chromatography using 60:40
chloroform/hexane as eluent; Rf (CHCl3) 0.5; yield:
226 mg (81%); mp: 112–114 ꢀC; IR (KBr): 2925, 2214,
1580, 1512, 1429, 1185, 1118, 1018, 820, 723 cmÀ1; dH
(200 MHz, CDCl3): 2.07–2.15 (m, 2H, CH2), 2.41 (s, 3H,
CH3), 2.55 (s, 3H, SCH3), 2.96 (t, J 7.3 Hz, 2H, CH2),
3.13 (t, J 7.5 Hz, 2H, CH2), 7.12 (s, 1H, ArH), 7.23–7.30
(m, 4H, ArH); MS m/z 280 (M++1); HRMS (EI): M+, found
279.1079; C18H17NS requires 279.1077.
COOCH3
O
H3CS
R
12
2
R
R
13
12,13
R
Yield (%)
a
b
75
71
H
CH3O
Scheme 6. Synthesisofmethyl6,7-diaryl-5-methylsulfanylindan-4-carboxy-
lates (13).
4.2.3. 5-Methylsulfanyl-7-(thiophen-2-yl)indan-4-car-
bonitrile (3c). It was obtained by stirring a mixture of 1c
(249 mg, 1.0 mmol), 2 (0.1 mL, 1.1 mmol) and KOH
(84 mg, 1.5 mmol) in dry DMF (10 mL). Usual work-up
gave a white solid after neutral alumina column chromato-
graphy using 40% hexane in chloroform as eluent; found:
C, 66.11; H, 4.92; N, 5.26; C15H13NS2 requires C, 66.38;
H, 4.83; N, 5.16; Rf (CHCl3) 0.55; yield: 214 mg (79%);
mp: 127–129 ꢀC; IR (KBr): 2924, 2212, 1591, 1454, 1423,
1352, 1276, 1105, 1055, 986, 701 cmÀ1; dH (200 MHz,
CDCl3): 2.15–2.26 (m, 2H, CH2), 2.58 (s, 3H, SCH3), 3.14
(t, J 7.6 Hz, 4H, CH2), 7.12–7.16 (m, 1H, ArH), 7.31–7.34
(m, 2H, ArH), 7.42–7.44 (m, 1H, ArH); dC (50 MHz,
CDCl3): 17.22, 25.22, 33.57, 34.09, 107.86, 116.09,
125.09, 127.29, 128.32, 135.58, 139.61, 140.88, 141.79,
151.85; MS m/z 272 (M++1); HRMS (EI): M+, found
271.0488; C15H13NS2 requires 271.0484.
4. Experimental
4.1. General
All reactions were conducted in flame-dried glassware. Pre-
coated Merck TLC plates were used for monitoring the reac-
tion. Column chromatographic separation was performed on
neutral alumina and silica gel (60–120 mesh). IR spectra
were recorded on a Shimadzu 8201 PC FTIR spectropho-
1
tometer. H NMR spectra were recorded on Bruker DRX
200 as well as Bruker DRX 300 spectrometers in deuterated
solvents with TMS as internal reference. Mass spectra were
recorded on JEOL SX-102 (FAB) spectrometer. HRMS were
recorded on JEOL JMS-600H (HRMS) spectrometer. Melt-
€
ing points were determined on Buchi-530 capillary melting
point apparatus and are uncorrected.
4.2.4. 5-Methylsulfanyl-7-(pyridin-3-yl)indan-4-carboni-
trile (3d). It was obtained from the reaction of 1d (244 mg,
1.0 mmol), 2 (0.1 mL, 1.1 mmol) and KOH (84 mg,
1.5 mmol) in dry DMF (10 mL) but worked up differently.
After neutralization with 10% HCl the reaction mixture
was extracted with CHCl3 (50 mLÂ3) and dried over
Na2SO4. The solvent from the extract was removed under re-
duced pressure and crude material obtained was purified by
neutral alumina column chromatography using 30% hexane
in chloroform as eluent to yield the product as a white solid;
Rf (CHCl3) 0.5; yield: 203 mg (71%); mp: 134–136 ꢀC; IR
(KBr): 2925, 2853, 2217, 1591, 1420, 1353, 1126, 1021,
806, 710 cmÀ1; dH (200 MHz, CDCl3): 2.04–2.12 (m, 2H,
CH2), 2.50 (s, 3H, SCH3), 2.89 (t, J 7.3 Hz, 2H, CH2),
3.09 (t, J 7.5 Hz, 2H, CH2), 7.04 (s, 1H, ArH), 7.30–7.36
(m, 1H, ArH), 7.65–7.69 (m, 1H, ArH), 8.57–8.61 (m, 2H,
ArH); MS m/z 267 (M++1); HRMS (EI): M+, found
266.0879; C16H14N2S requires 266.0872.
4.2. General procedure: synthesis of 7-aryl-5-methyl-
sulfanylindan-4-carbonitriles (3a–f)
A mixture of 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-
carbonitrile (1, 1.0 mmol), cyclopentanone (2, 1.1 mmol)
and KOH (1.5 mmol) in dry DMF (10 mL) was stirred for
2 h at room temperature. Thereafter, the reaction mixture
was poured onto crushed ice with vigorous stirring. Neutral-
ization with 10% HCl (10 mL) afforded a precipitate, which
was filtered, dried and purified by neutral alumina column
chromatography.
4.2.1. 5-Methylsulfanyl-7-phenylindan-4-carbonitrile
(3a). It was prepared by following the general procedure
from the reaction of 1a (243 mg, 1.0 mmol) and 2 (0.1 mL,
1.1 mmol) using KOH (84 mg, 1.5 mmol) as a base in dry
DMF (10 mL). Usual work-up and purification on neutral
alumina column using 30% hexane in chloroform as eluent
afforded a white solid; Rf (CHCl3) 0.5; yield: 207 mg
(78%); mp: 136–138 ꢀC; IR (KBr): 2923, 2217, 1585,
4.2.5. 7-(2,4-Dimethylphenyl)-5-methylsulfanylindan-4-
carbonitrile (3e). It was prepared by following the general
procedure from the reaction of 1e (271 mg, 1.0 mmol) and
2 (0.1 mL, 1.1 mmol) using KOH (84 mg, 1.5 mmol) as
1493, 1425, 1352, 1321, 1213, 1000, 861, 774, 705 cmÀ1
;

10304
R. Pratap et al. / Tetrahedron 63 (2007) 10300–10308
a base in dry DMF (10 mL). Usual work-up and purification
on neutral alumina column using 30% hexane in chloroform
as eluent afforded a white solid; Rf (CHCl3) 0.55; yield:
220 mg (75%); mp: 97–99 ꢀC; IR (KBr): 2924, 2851,
2219, 1607, 1579, 1513, 1436, 1291 cmÀ1; dH (200 MHz,
CDCl3): 1.98–2.09 (m, 5H, CH2 and CH3), 2.29 (s, 3H,
CH3), 2.43 (s, 3H, SCH3), 2.57 (t, J 7.3 Hz, 2H, CH2),
3.07 (t, J 7.5 Hz, 2H, CH2), 6.86–6.88 (m, 1H, ArH), 6.92
(s, 1H, ArH), 6.96 (s, 1H, ArH), 7.00–7.03 (m, 1H, ArH);
MS m/z 294 (M++1); HRMS (EI): M+, found 293.1237;
C19H19NS requires 293.1232.
solid after neutral alumina column chromatography using
30% hexane in chloroform as eluent; Rf (CHCl3) 0.42;
yield: 261 mg (65%); mp: 152–154 ꢀC; IR (KBr): 2960,
2218, 1607, 1514, 1460, 1388, 1290, 1247, 1176, 1110,
1029, 837, 800, 761 cmÀ1; dH (200 MHz, CDCl3): 2.07–
2.15 (m, 2H, CH2), 2.20 (s, 3H, SCH3), 2.76 (t, J
7.4 Hz, 2H, CH2), 3.21 (t, J 7.5 Hz, 2H, CH2), 3.74 (s,
3H, OCH3), 3.76 (s, 3H, OCH3), 6.67–6.74 (m, 4H,
ArH), 6.81–6.92 (m, 4H, ArH); dC (50 MHz, CDCl3):
20.25, 25.07, 33.95, 34.02, 55.46, 55.50, 113.28, 113.26,
114.09, 117.70, 130.69, 131.58, 132.09, 137.77, 143.36,
144.71, 145.26, 149.48, 158.67; MS m/z 402 (M++1);
HRMS (EI): M+, found 401.1451; C25H23NO2S requires
401.1444.
4.2.6. 7-(Furan-2-yl)-5-methylsulfanylindan-4-carboni-
trile (3f). It was obtained from the reaction of 1f (233 mg,
1.0 mmol), 2 (0.1 mL, 1.1 mmol) and KOH (84 mg,
1.5 mmol) in dry DMF (10 mL) under analogous reaction
conditions. Usual work-up and purification on neutral alu-
mina column using 40% hexane in chloroform as eluent af-
forded a light yellow solid; Rf (10% hexane in CHCl3) 0.5;
yield: 218 mg (85%); mp: 131–133 ꢀC; IR (KBr): 2959,
2877, 2219, 1637, 1586, 1493, 1425, 1364, 1312, 1254,
1221, 1172, 1025, 932, 859, 807, 752 cmÀ1; dH (200 MHz,
CDCl3): 2.17–2.30 (m, 2H, CH2), 2.60 (s, 3H, SCH3),
3.06–3.15 (m, 4H, CH2), 6.53–6.56 (m, 1H, ArH), 6.71–
6.73 (m, 1H, ArH), 7.55–7.56 (m, 2H, ArH); MS m/z 256
(M++1); HRMS (EI): M+, found 255.0716; C15H13NOS re-
quires 255.0712.
4.4. General procedure for the synthesis of
7-aryl-5-(piperidin-1-yl)indan-4-carbonitriles (8a–h)
A mixture of 6-aryl-4-(piperidin-1-yl)-2-oxo-2H-pyran-3-
carbonitriles (7, 1.0 mmol), cyclopentanone (2, 0.1 mL,
1.1 mmol) and KOH (84 mg, 1.5 mmol) in dry DMF
(10 mL) was stirred for 2 h under dry condition at 30 ꢀC. Af-
ter completion of the reaction, DMF was removed under re-
duced pressure and the mixture was poured onto crushed ice
with vigorous stirring and thereafter neutralized with 10%
HCl. The resulting precipitate was filtered, dried and purified
by neutral alumina column chromatography.
4.3. General procedure: synthesis of 6,7-diaryl-5-meth-
ylsulfanylindan-4-carbonitriles (6a,b)
4.4.1. 7-Phenyl-5-(piperidin-1-yl)indan-4-carbonitrile
(8a). It was prepared by following the general procedure
from the reaction of 7a (280 mg, 1 mmol) and 2 (0.1 mL,
1.1 mmol) using KOH (84 mg, 1.5 mmol) as a base in dry
DMF. Usual work-up and purification on neutral alumina
column using 30% hexane in chloroform as eluent provided
a white solid; Rf (10% hexane in CHCl3) 0.45; yield: 275 mg
(91%); mp: 124–126 ꢀC; IR (KBr): 2935, 2801, 2215, 1588,
1452, 1358, 1220, 1110, 1068, 996, 867, 771, 703,
666 cmÀ1; dH (200 MHz, CDCl3): 1.60–1.63 (m, 2H,
CH2), 1.73–1.84 (m, 4H, CH2), 2.02–2.16 (m, 2H, CH2),
2.92 (t, J 7.3 Hz, 2H, CH2), 3.08–3.17 (m, 6H, CH2), 6.80
(s, 1H, ArH), 7.34–7.48 (m, 5H, ArH); MS m/z 303
(M++1); HRMS (EI): M+, found 302.1783; C21H22N2 re-
quires 302.1778.
A solution of 5,6-disubstituted-4-methylsulfanyl-2-oxo-2H-
pyran-3-carbonitrile (5, 1.0 mmol) and cyclopentanone (2,
0.1 mL, 1.1 mmol) in dry DMF (10 mL) was stirred for 2 h
under dry condition at room temperature in the presence of
KOH (84 mg, 1.5 mmol). Thereafter, the solution was
poured onto crushed ice with vigorous stirring and neutral-
ized with 10% HCl (10 mL). The resulting precipitate
was filtered, dried and purified by neutral alumina column
chromatography.
4.3.1. 6,7-Diphenyl-5-methylsulfanylindan-4-carboni-
trile (6a). It was prepared by following the general proce-
dure from the reaction of 5a (319 mg, 1.0 mmol) and 2
(0.1 mL, 1.1 mmol) using KOH (84 mg, 1.5 mmol) as
a base in dry DMF. Usual work-up and purification on
neutral alumina column chromatography using 40% hex-
ane in chloroform as eluent produced a white solid; Rf
(CHCl3) 0.44; yield: 243 mg (71%); mp: 145–147 ꢀC;
IR (KBr): 2939, 2853, 2363, 2186, 1585, 1444, 1383,
1351, 1257, 1212, 1125, 1076, 1019, 996, 925, 905,
851, 750, 687 cmÀ1; dH (200 MHz, CDCl3): 2.08–2.16
(m, 2H, CH2), 2.21 (s, 3H, SCH3), 2.75 (t, J 7.4 Hz,
2H, CH2), 3.23 (t, J 7.5 Hz, 2H, CH2), 6.89–7.03 (m,
4H, ArH), 7.12–7.25 (m, 6H, ArH); MS m/z 342
(M++1); HRMS (EI): M+, found 341.1239; C23H19NS re-
quires 341.1233.
4.4.2. 7-(4-Chlorophenyl)-5-(piperidin-1-yl)indan-4-car-
bonitrile (8b). It was synthesized from the reaction of 7b
(314 mg, 1.0 mmol), 2 (0.1 mL, 1.1 mmol) and KOH
(84 mg, 1.5 mmol) in dry DMF (10 mL) as a white solid af-
ter neutral alumina column chromatography using 30% hex-
ane in chloroform as eluent; Rf (CHCl3) 0.5; yield: 297 mg
(88%); mp: 176–178 ꢀC; IR (KBr): 2938, 2806, 2365,
2214, 1594, 1454, 1381, 1354, 1224, 1109, 1067, 1003,
825, 767 cmÀ1; dH (200 MHz, CDCl3): 1.55–1.58 (m, 2H,
CH2), 1.76–1.80 (m, 4H, CH2), 2.02–2.17 (m, 2H, CH2),
2.88 (t, J 7.0 Hz, 2H, CH2), 3.07–3.13 (m, 6H, CH2),
6.74–6.77 (m, 1H, ArH), 7.29–7.32 (m, 2H, ArH), 7.56 (d,
J 8.3 Hz, 2H, ArH); MS m/z 337 (M++1); HRMS (EI): M+,
found 336.1392; C21H21ClN2 requires 336.1388.
4.3.2. 6,7-Bis(4-methoxyphenyl)-5-methylsulfanyl-in-
dan-4-carbonitrile (6b). It was obtained by following
the general procedure from the reaction of 5b (379 mg,
1.0 mmol), 2 (0.1 mL, 1.1 mmol) and KOH (84 mg,
1.5 mmol) in dry DMF (10 mL) and isolated as a white
4.4.3. 7-(4-Bromophenyl)-5-(piperidin-1-yl)indan-4-car-
bonitrile (8c). It was obtained from the reaction of 7c
(358 mg, 1.0 mmol), 2 (0.1 mL, 1.1 mmol) and KOH
(84 mg, 1.5 mmol) in dry DMF (10 mL) as a white solid

R. Pratap et al. / Tetrahedron 63 (2007) 10300–10308
10305
after neutral alumina column chromatography using 30%
hexane in chloroform as eluent; Rf (CHCl3) 0.5; yield:
339 mg (89%); mp: 166–168 ꢀC; IR (KBr): 2943, 2808,
2363, 2216, 1594, 1491, 1455, 1383, 1225, 1085, 878,
830, 762, 665 cmÀ1; dH (200 MHz, CDCl3): 1.57–1.63 (m,
2H, CH2), 1.73–1.84 (m, 4H, CH2), 2.02–2.17 (m, 2H,
CH2), 2.89 (t, J 7.3 Hz, 2H, CH2), 3.07–3.16 (m, 6H,
CH2), 6.74 (s, 1H, ArH), 7.33 (d, J 8.7 Hz, 2H, ArH), 7.41
(d, J 8.7 Hz, 2H, ArH); MS m/z 380 (M+), 382 (M++2);
HRMS (EI): M+, found 380.0885; C21H2179BrN2 requires
380.0883.
(84 mg, 1.5 mmol) in dry DMF (10 mL) as a white solid af-
ter neutral alumina column chromatography using 30% hex-
ane in chloroform as eluent; Rf (CHCl3) 0.45; yield: 306 mg
(87%); mp: 120–122 ꢀC; IR (KBr): 3054, 2937, 2212, 1587,
1453, 1375, 1241, 1116, 821, 749 cmÀ1; dH (200 MHz,
CDCl3): 1.55–1.58 (m, 2H, CH2), 1.70–1.80 (m, 4H, CH2),
2.03–2.18 (m, 2H, CH2), 2.97 (t, J 7.3 Hz, 2H, CH2),
3.06–3.20 (m, 6H, CH2), 6.90 (s, 1H, ArH), 7.49–7.56 (m,
3H, ArH), 7.78–7.92 (m, 4H, ArH); MS m/z 353 (M++1);
HRMS (EI): M+, found 352.1934; C25H24N2 requires
352.1934.
4.4.4. 7-(4-Methylphenyl)-5-(piperidin-1-yl)indan-4-car-
bonitrile (8d). It was prepared from the reaction of 7d
(294 mg, 1.0 mmol), 2 (0.1 mL, 1.1 mmol) and KOH
(84 mg, 1.5 mmol) in dry DMF (10 mL) as a white solid af-
ter neutral alumina column chromatography using 30% hex-
ane in chloroform as eluent; Rf (CHCl3) 0.54; yield: 291 mg
(92%); mp: 135–137 ꢀC; IR (KBr): 2933, 2215, 1593, 1516,
1454, 1355, 1271, 1219, 1113, 822, 764 cmÀ1; dH
(200 MHz, CDCl3): 1.57–1.63 (m, 2H, CH2), 1.73–1.84
(m, 4H, CH2), 2.01–2.16 (m, 2H, CH2), 2.40 (s, 3H, CH3),
2.92 (t, J 7.3 Hz, 2H, CH2), 3.07–3.16 (m, 6H, CH2), 6.78
(s, 1H, ArH), 7.23 (d, J 7.5 Hz, 2H, ArH), 7.31 (d, J
8.5 Hz, 2H, ArH); MS m/z 317 (M++1); HRMS (EI): M+,
found 316.1937; C22H24N2 requires 316.1934.
4.4.8. 5-(4-Methylpiperidin-1-yl)-7-phenylindan-4-car-
bonitrile (8h). It was obtained from the reaction of 7h
(294 mg, 1.0 mmol), 2 (0.1 mL, 1.1 mmol) and KOH
(84 mg, 1.5 mmol) in dry DMF (10 mL) as a white solid af-
ter neutral alumina column chromatography using 30% hex-
ane in chloroform as eluent; Rf (CHCl3) 0.47; yield: 272 mg
(86%); mp: 114–116 ꢀC; IR (KBr): 2941, 2807, 2215, 1590,
1456, 1384, 1251, 1217, 1149, 1118, 1066, 975, 869, 776,
705, 669 cmÀ1; dH (200 MHz, CDCl3): 0.99 (d, J 5.0 Hz,
3H, CH3), 1.48–1.52 (m, 3H, CH and CH2), 1.73–1.78 (m,
2H, CH2), 2.02–2.16 (m, 2H, CH2), 2.70–2.81 (m, 2H,
CH2), 2.92 (t, J 7.4 Hz, 2H, CH2), 3.11 (t, J 7.4 Hz, 2H,
CH2), 3.52–3.58 (m, 2H, CH2), 6.80 (s, 1H, ArH), 7.33–
7.48 (m, 5H, ArH); dC (50 MHz, CDCl3): 22.24, 25.69,
31.06, 32.92, 33.81, 34.94, 53.38, 102.29, 117.50, 118.16,
128.21, 128.67, 128.86, 135.71, 140.80, 143.21, 151.39,
156.14; MS m/z 317 (M++1); HRMS (EI): M+, found
316.1938; C22H24N2 requires 316.1934.
4.4.5. 7-(4-Methoxyphenyl)-5-(piperidin-1-yl)indan-
4-carbonitrile (8e). It was prepared from the reaction of
7e (310 mg, 1.0 mmol), 2 (0.1 mL, 1.1 mmol) and KOH
(84 mg, 1.5 mmol) in dry DMF (10 mL) as a white solid af-
ter neutral alumina column chromatography using 30% hex-
ane in chloroform; Rf (CHCl3) 0.54; yield: 302 mg (91%);
mp: 144–146 ꢀC; IR (KBr): 2934, 2802, 2211, 1592, 1512,
4.5. General procedure for the synthesis of 7-aryl-5-
methylsulfanylindan-4-carboxylic acid methyl esters
(10a–e) and 7-aryl-5-methylsulfanylindan-4-carboxylic
acids (11a–e)
1455, 1356, 1292, 1250, 1174, 1111, 1030, 835, 761 cmÀ1
;
dH (200 MHz, CDCl3): 1.57–1.62 (m, 2H, CH2), 1.75–1.78
(m, 4H, CH2), 2.05–2.16 (m, 2H, CH2), 2.92 (t, J 7.2 Hz,
2H, CH2), 3.06–3.16 (m, 6H, CH2), 3.85 (s, 3H, OCH3),
6.77 (s, 1H, ArH), 6.96 (d, J 8.6 Hz, 2H, ArH), 7.36 (d, J
8.6 Hz, 2H, ArH); dC (50 MHz, CDCl3): 24.58, 25.74,
26.68, 33.08, 33.81, 54.06, 55.76, 101.87, 114.31, 117.21,
118.23, 129.89, 133.14, 135.57, 142.88, 151.33, 156.38,
159.79; MS m/z 333 (M++1); HRMS (EI): M+, found
332.1890; C22H24N2O requires 332.1883.
Procedure A. These were obtained by stirring a mixture
of methyl 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carb-
oxylates (9, 1.0 mmol), cyclopentanone (2, 0.1 mL,
1.1 mmol) and KOH (84 mg, 1.5 mmol) in dry DMF
(10 mL) for 2 h under dry condition at room temperature.
After completion, the reaction mixture was poured onto
crushed ice and neutralized with 10% HCl (15 mL), which
gave a mixture of an ester and the corresponding acid. The
crude product was purified by silica gel column chromato-
graphy using 30% hexane in chloroform for ester 10 and
1% methanol in chloroform for acid 11 as eluents. Yields
for 10 were in the range of 32–35% and those for 11 were
in the range of 53–57%.
4.4.6. 5-(Piperidin-1-yl)-7-(thiophen-2-yl)indan-4-car-
bonitrile (8f). It was obtained from the reaction of 7f
(286 mg, 1.0 mmol), 2 (0.1 mL, 1.1 mmol) and KOH
(84 mg, 1.5 mmol) in dry DMF (10 mL). Usual work-up
and purification on neutral alumina column using 30% hex-
ane in chloroform as eluent provided a cream coloured solid;
Rf (CHCl3) 0.5; yield: 274 mg (89%); mp: 106–108 ꢀC; IR
(KBr): 2933, 2814, 2213, 1590, 1436, 1353, 1224, 1117,
1059, 994, 725 cmÀ1; dH (200 MHz, CDCl3): 1.57–1.64
(m, 2H, CH2), 1.73–1.89 (m, 4H, CH2), 2.08–2.23 (m, 2H,
CH2), 3.05–3.17 (m, 8H, CH2), 6.98 (s, 1H, ArH), 7.10–
7.14 (m, 1H, ArH), 7.28–7.29 (m, 1H, ArH), 7.38–7.41
(m, 1H, ArH); MS m/z 309 (M++1); HRMS (EI): M+, found
308.1347; C19H20N2S requires 308.1342.
Procedure B. Under analogous conditions, except a change
in duration of reaction from 2 to 6 h and usual work-up,
the yield of 11 increased (67–74%) in the mixture possibly
due to further hydrolysis of ester 10.
Procedure C. A mixture of pyran-2-one (9, 1.0 mmol), cy-
clopentanone (2, 0.1 mL, 1.1 mmol) and NaH (36 mg,
1.5 mmol) in dry THF was stirred for 36 h under dry condi-
tion at room temperature. After completion of the reaction,
excess THF was removed under reduced pressure and excess
NaH quenched by the addition of methanol. The resulting
mixture was poured onto crushed ice with vigorous stirring
and neutralized with 10% HCl (15 mL). The resulting
4.4.7. 7-(Naphthalen-2-yl)-5-(piperidin-1-yl)indan-4-car-
bonitrile (8g). It was prepared from the reaction of 7g
(330 mg, 1.0 mmol), 2 (0.1 mL, 1.1 mmol) and KOH

10306
R. Pratap et al. / Tetrahedron 63 (2007) 10300–10308
precipitate was filtered off, dried and purified on silica gel
column as 5-methylsulfanyl-7-arylindan-4-carboxylic acid
methyl esters (10a–e).
4.5.5. 7-(4-Bromophenyl)-5-methylsulfanylindan-4-carb-
oxylic acid methyl ester (10c). It was obtained by stirring
a mixture of 9c (354 mg, 1.0 mmol), 2 (0.1 mL, 1.1 mmol)
and KOH (84 mg, 1.5 mmol) in dry DMF (10 mL), and the
desired compound was isolated as a white solid after silica
gel column chromatography using 20% hexane in chloro-
form as eluent; Rf (CHCl3) 0.45; yield: 132 mg (35%); mp:
82–84 ꢀC; IR (KBr): 2822, 2366, 2341, 1719, 1598, 1519,
1490, 1437, 1353, 1272, 1187, 1138, 1073, 1005, 950,
814, 773, 700 cmÀ1; dH (300 MHz, CDCl3): 2.02–2.11 (m,
2H, CH2), 2.48 (s, 3H, SCH3), 2.89 (t, J 7.5 Hz, 2H, CH2),
3.11 (t, J 7.5 Hz, 2H, CH2), 3.96 (s, 3H, OCH3), 7.11 (s,
1H, ArH), 7.34–7.38 (m, 4H, ArH); MS m/z 378 (M+), 380
(M++2); HRMS (EI): M+, found 376.0130; C18H1779BrO2S
requires 376.0127.
4.5.1. 5-Methylsulfanyl-7-phenylindan-4-carboxylic acid
methyl ester (10a). It was prepared by following the general
procedure A from the reaction of 9a (276 mg, 1.0 mmol) and
2 (0.1 mL, 1.1 mmol) using KOH (84 mg, 1.5 mmol) as
a base in dry DMF (10 mL). Usual work-up and purification
on silica column using 30% hexane in chloroform as eluent
produced a white solid; Rf (CHCl3) 0.54; yield: 95 mg
(32%); mp: 84–86 ꢀC; IR (KBr): 2949, 2376, 1709, 1590,
1494, 1428, 1381, 1352, 1272, 1134, 1105, 990, 770,
703 cmÀ1; dH (200 MHz, CDCl3): 1.99–2.07 (m, 2H,
CH2), 2.47 (s, 3H, SCH3), 2.90 (t, J 7.3 Hz, 2H, CH2),
3.09 (t, J 7.4 Hz, 2H, CH2), 3.94 (s, 3H, OCH3), 7.13 (s,
1H, ArH), 7.36–7.44 (m, 5H, ArH); MS m/z 299 (M++1);
HRMS (EI): M+, found 298.1027; C18H18O2S requires
298.1022.
4.5.6. 7-(4-Bromophenyl)-5-methylsulfanylindan-4-carb-
oxylic acid (11c). From the above reaction mixture it
was obtained as a white solid by eluting the column using
1% methanol in chloroform as eluent; Rf (2% methanol in
CHCl3) 0.5; yield: 191 mg (53%); mp: 228–230 ꢀC; IR
(KBr): 3421, 2957, 2362, 1682, 1590, 1493, 1432, 1389,
4.5.2. 5-Methylsulfanyl-7-phenylindan-4-carboxylic acid
(11a). It was isolated from the above reaction mixture after
eluting the silica gel column by 1% methanol in chloroform
as eluent, as a white crystalline solid; Rf (2% methanol in
CHCl3) 0.4; yield: 162 mg (57%); mp: 225–227 ꢀC; IR
(KBr): 3426, 2945, 2363, 1674, 1573, 1498, 1429, 1293,
1353, 1286, 1246, 1142, 1103, 1012, 914, 825, 755 cmÀ1
;
dH (200 MHz, DMSO-d6): 1.94–2.01 (m, 2H, CH2), 2.44
(s, 3H, SCH3), 2.87 (t, J 7.2 Hz, 2H, CH2), 2.99 (t, J
7.2 Hz, 2H, CH2), 7.10 (s, 1H, ArH), 7.48 (d, J 8.5 Hz,
2H, ArH), 7.66 (d, J 8.5 Hz, 2H, ArH); MS m/z 362 (M+),
364 (M++2); HRMS (EI): M+, found 361.9977;
C17H1579BrO2S requires 361.9971.
1248, 1146, 1110, 1078, 1028, 934, 861, 762, 698 cmÀ1
;
dH (200 MHz, DMSO-d6): 1.90–2.04 (m, 2H, CH2), 2.44
(s, 3H, SCH3), 2.87 (t, J 7.3 Hz, 2H, CH2), 3.01 (t, J
7.3 Hz, 2H, CH2), 7.11 (s, 1H, ArH), 7.36–7.53 (m, 5H,
ArH); MS m/z 285 (M++1); HRMS (EI): M+, found
284.0871; C17H16O2S requires 284.0866.
4.5.7. 5-Methylsulfanyl-7-(thiophen-2-yl)indan-4-carb-
oxylic acid methyl ester (10d). It was prepared from the re-
action of 9d (282 mg, 1.0 mmol), 2 (0.1 mL, 1.1 mmol) and
KOH (84 mg, 1.5 mmol) in dry DMF (10 mL) as awhite solid
after silica gel column chromatography using 20% hexane in
chloroform as eluent; Rf (CHCl3) 0.45; yield: 106 mg (35%);
mp: 108–110 ꢀC; IR (KBr): 3106, 2946, 2364, 1705, 1578,
1428, 1350, 1267, 1130, 1092, 985, 919, 839, 796,
711 cmÀ1; dH (200 MHz, CDCl3): 2.05–2.17 (m, 2H, CH2),
2.48 (s, 3H, SCH3), 3.04–3.14 (m, 4H, CH2), 3.93 (s, 3H,
OCH3), 7.09–7.14 (m, 1H, ArH), 7.25–7.28 (m, 1H, ArH),
7.31 (s, 1H, ArH), 7.36–7.39 (m, 1H, ArH); dC (50 MHz,
CDCl3): 17.76, 25.62, 33.58, 34.03, 52.27, 125.13, 126.32,
126.62, 127.20, 128.05, 133.82, 137.64, 139.61, 142.71,
146.89, 168.47; MS m/z 305 (M++1); HRMS (EI): M+, found
304.0589; C16H16O2S2 requires 304.0586.
4.5.3. 7-(4-Chlorophenyl)-5-methylsulfanylindan-4-car-
boxylic acid methyl ester (10b). It was prepared from
the reaction of 9b (310 mg, 1.0 mmol), 2 (0.1 mL,
1.1 mmol) and KOH (84 mg, 1.5 mmol) in dry DMF
(10 mL) as a white solid after silica gel column chromato-
graphy using 20% hexane in chloroform as eluent; Rf
(CHCl3) 0.4; yield: 110 mg (33%); mp: 91–93 ꢀC; IR
(KBr): 2948, 2640, 2359, 1720, 1588, 1490, 1434, 1364,
1252, 1137, 1105, 1013, 832, 767 cmÀ1; dH (200 MHz,
CDCl3): 2.0–2.07 (m, 2H, CH2), 2.46 (s, 3H, SCH3),
2.87 (t, J 7.3 Hz, 2H, CH2), 3.09 (t, J 7.4 Hz, 2H, CH2),
3.94 (s, 3H, OCH3), 7.08 (s, 1H, ArH), 7.31–7.43 (m,
4H, ArH); dC (50 MHz, CDCl3): 24.52, 25.66, 26.62,
32.85, 33.79, 54.00, 117.15, 122.47, 126.69, 129.08,
130.30, 132.02, 135.50, 139.66, 141.92, 151.60, 156.42;
MS m/z 333 (M++1); HRMS (EI): M+, found 332.0633;
C18H17ClO2S requires 332.0632.
4.5.8. 5-Methylsulfanyl-7-(thiophen-2-yl)indan-4-carb-
oxylic acid (11d). It was obtained by eluting the above silica
gel column using 1% methanol in chloroform as a white
crystalline solid; Rf (2% methanol in CHCl3) 0.44; yield:
160 mg (55%); mp: 228–230 ꢀC; IR (KBr): 3420, 2951,
2369, 1670, 1594, 1504, 1432, 1389, 1335, 1290, 1245,
1135, 1098, 1017, 944, 823 cmÀ1; dH (200 MHz, DMSO-
d6): 1.97–2.12 (m, 2H, CH2), 2.51 (s, 3H, SCH3), 2.98–
3.18 (m, 4H, CH2), 7.17–7.22 (m, 1H, ArH), 7.30 (s, 1H,
ArH), 7.47–7.49 (m, 1H, ArH), 7.66–7.69 (m, 1H, ArH);
MS m/z 291 (M++1); HRMS (EI): M+, found 290.0434;
C15H14O2S2 requires 290.0430.
4.5.4. 7-(4-Chlorophenyl)-5-methylsulfanylindan-4-carb-
oxylic acid (11b). Eluting the above silica gel column by
1% methanol in chloroform afforded a white crystalline
solid; Rf (25% methanol in CHCl3) 0.45; yield: 181 mg
(57%); mp: 224–226 ꢀC; IR (KBr): 3432, 2958, 2363,
1670, 1594, 1492, 1433, 1392, 1353, 1287, 1245, 1142,
1108, 1089, 1012, 975, 913, 871, 826, 780, 750,
717 cmÀ1; dH (200 MHz, DMSO-d6): 1.93–2.01 (m, 2H,
CH2), 2.45 (s, 3H, SCH3), 2.86 (t, J 7.2 Hz, 2H, CH2), 3.0
(t, J 7.3 Hz, 2H, CH2), 7.11 (s, 1H, ArH), 7.51–7.55 (m,
4H, ArH); MS m/z 319 (M++1); HRMS (EI): M+, found
318.0475; C17H15ClO2S requires 318.0476.
4.5.9. 5-Methylsulfanyl-7-(naphthalen-2-yl)indan-4-carb-
oxylic acid methyl ester (10e). It was obtained from the re-
action of 9e (326 mg, 1.0 mmol), 2 (0.1 mL, 1.1 mmol) and

R. Pratap et al. / Tetrahedron 63 (2007) 10300–10308
10307
KOH (84 mg, 1.5 mmol) in dry DMF (10 mL). It was iso-
lated as a white solid by eluting the silica gel column with
20% hexane in chloroform; found C, 76.20; H, 6.02;
C22H20O2S requires C, 75.83; H, 5.79; Rf (CHCl3) 0.5; yield:
114 mg (33%); mp: 84–86 ꢀC; IR (KBr): 2948, 2363, 1717,
1594, 1502, 1429, 1502, 1429, 1383, 1353, 1270, 1128,
1096, 989, 912, 859, 825, 796, 759 cmÀ1; dH (200 MHz,
CDCl3): 2.0–2.08 (m, 2H, CH2), 2.48 (s, 3H, SCH3), 2.50
(t, J 7.3 Hz, 2H, CH2), 3.12 (t, J 7.4 Hz, 2H, CH2), 3.96 (s,
3H, OCH3), 7.23 (s, 1H, ArH), 7.50–7.57 (m, 3H, ArH),
7.85–7.92 (m, 4H, ArH); dC (50 MHz, CDCl3): 17.84,
26.04, 32.86, 34.13, 52.33, 126.18, 126.71, 126.86,
126.94, 127.76, 128.14, 128.45, 128.57, 134.31, 135.01,
138.08, 139.31, 142.21, 143.33, 146.07, 168.01; MS m/z
349 (M++1); HRMS (EI): M+, found 348.1183; C22H20O2S
requires 348.1179.
30.43, 32.34, 33.68, 52.64, 55.40, 113.02, 113.45, 130.46,
130.93, 132.30, 132.54, 135.82, 140.58, 141.22, 144.64,
145.42, 158.29, 158.37, 169.78; MS m/z 435 (M++1);
HRMS (EI): M+, found 434.1553; C26H26O4S requires
434.1546.
Acknowledgements
Authors are thankful to CSIR, New Delhi for their financial
supports.
References and notes
1. (a) Capon, R. J.; MacLeod, J. K.; Scammells, P. J. Tetrahedron
1986, 42, 6545; (b) MacLeod, J. K.; Monahan, L. C. Aust. J.
Chem. 1990, 43, 329; (c) Lee, M.; Ikeda, I.; Kawabe, T.;
Mori, S.; Kanematsu, K. J. Org. Chem. 1996, 61, 3406; (d)
Ho, T.-L.; Lee, K.-Y.; Chen, C.-K. J. Org. Chem. 1997, 62,
3365.
2. (a) Ly, T.-M.; Quiclet-Sire, B.; Sortais, B.; Zard, S. Z.
Tetrahedron Lett. 1999, 40, 2533; (b) Hisaindee, S.; Clive,
D. L. J. Tetrahedron Lett. 2001, 42, 2253; (c) Degos, L. Leuk.
Res. 1990, 14, 717.
4.5.10. 5-Methylsulfanyl-7-(naphthalen-2-yl)indan-4-
carboxylic acid (11e). From the above reaction mixture
the product was isolated as a white crystalline solid after
eluting the silica gel column by 1% methanol in chloroform;
Rf (2% methanol in CHCl3) 0.44; yield: 190 mg (57%); mp:
200–202 ꢀC; IR (KBr): 3432, 3052, 2951, 2369, 1670, 1594,
1504, 1389, 1353, 1290, 1245, 1135, 1098, 1017, 944, 855,
823, 750 cmÀ1; dH (200 MHz, DMSO-d6): 1.96–2.06 (m,
2H, CH2), 2.49 (s, 3H, SCH3), 2.96 (t, J 7.2 Hz, 2H, CH2),
3.06 (t, J 7.3 Hz, 2H, CH2), 7.26 (s, 1H, ArH), 7.54–7.63
(m, 2H, ArH), 7.66–7.73 (m, 1H, ArH), 7.93–8.12 (m, 4H,
ArH); MS m/z 335 (M++1); HRMS (EI): M+, found
334.1024; C21H18O2S requires 334.1022.
€
3. Ulmschneider, S.; Muller-Vieira, U.; Klein, C. D.; Antes, L.;
Lengauer, T.; Hertmann, R. W. J. Med. Chem. 2005, 48, 1563.
4. Pass, M.; Abu-Rabie, S.; Baxter, A.; Conroy, R.; Coote, S. J.;
Craven, A. P.; Finch, H.; Hindley, S.; Kelly, H. A.; Lowdon,
A. W.; McDonald, E.; Mitchell, W. L.; Pegg, N. A.;
Procopiou, P. A.; Ramsden, N. G.; Thomas, R.; Walker,
D. A.; Watson, N. S.; Jhoti, H.; Mooney, C. J.; Tang, C.-M.;
Thomas, P. J.; Parry, S.; Patel, C. Bioorg. Med. Chem. Lett.
1999, 9, 1657.
5. Nash, H. W.; Boatman, D. L.; Long, J. P. Toxicol. Appl.
Pharmacol. 1965, 7, 25.
6. Sheridan, H.; Lemon, S.; Frankish, N.; McArdle, P.; Higgins,
T.; Jamse, J. P.; Bhandari, P. Eur. J. Med. Chem. 1990, 25, 603.
7. Demir, A. S.; Aksoy-cam, H.; Camkertan, N.; Hamamct, H.;
4.5.11. 6,7-Diphenyl-5-methylsulfanylindan-4-carboxylic
acid methyl ester (13a). It was obtained by following the
general procedure A from the reaction of 12a (352 mg,
1.0 mmol), 2 (0.1 mL, 1.1 mmol) and KOH (84 mg,
1.5 mmol) in dry DMF (8 mL), as a white solid after silica
gel column chromatography using 30% hexane in chloro-
form as eluent; Rf (CHCl3) 0.42; yield: 281 mg (75%); mp:
128–130 ꢀC; IR (KBr): 2971, 2931, 2833, 2716, 2364,
1704, 1629, 1591, 1495, 1425, 1363, 1244, 1177, 1070,
1028, 971, 914, 844, 780, 747, 706 cmÀ1; dH (300 MHz,
CDCl3): 2.02 (s, 3H, SCH3), 2.05–2.14 (m, 2H, CH2), 2.75
(t, J 7.3 Hz, 2H, CH2), 3.5 (t, J 7.4 Hz, 2H, CH2), 3.99 (s,
3H, OCH3), 6.90–7.16 (m, 10H, ArH); MS m/z 375
(M++1); HRMS (EI): M+, found 374.1338; C24H22O2S re-
quires 374.1335.
˘
Doganel, F. Turk. J. Chem. 2004, 24, 141.
8. Bailey, W. F.; Ovaska, T. V. Advances in Detailed Reaction
Mechanisms; Coxon, J. M., Ed.; JAI: Greenwich, CT, 1994;
Vol. 3, pp 251–273.
9. Bailey, W. F.; Punzalan, E. R. J. Am. Chem. Soc. 1994, 116,
6577.
10. (a) Giese, B. Radical in Organic Synthesis; Pergamon: New
York, NY, 1986; (b) Curran, D. P. Synthesis 1988, 417
and 489; (c) Giese, B. Angew. Chem., Int. Ed. Engl. 1989,
28, 969; (d) Curran, D. P.; Porter, N. A.; Giese, B.
Stereochemistry of Radical Reactions; VCH: New York, NY,
1995.
11. Beckwith, A. L. J.; Gerba, S. Aust. J. Chem. 1992, 45, 289.
12. Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K.; Ovaska, T. V.;
Rossi, K.; Thiel, Y.; Wiberg, K. B. J. Am. Chem. Soc. 1991,
113, 5720.
13. Bailey, W. F.; Mealy, M. J.; Wiberg, K. B. Org. Lett. 2002, 4,
791.
14. (a) Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2001, 123,
7925; (b) Hanazawa, T.; Sasaki, K.; Takayama, Y.; Sato, F.
J. Org. Chem. 2003, 68, 4980.
15. (a) Suzuki, D.; Tanaka, R.; Urabe, H.; Sato, F. J. Am. Chem.
Soc. 2002, 124, 3518; (b) Tanaka, R.; Nakano, Y.; Suzuki,
D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2002, 124, 9682.
4.5.12. 6,7-Bis(4-methoxyphenyl)-5-methylsulfanyl-in-
dan-4-carboxylic acid methyl ester (13b). It was obtained
from the reaction of 12b (294 mg, 1.0 mmol), 2 (0.1 mL,
1.1 mmol) and KOH (84 mg, 1.5 mmol) in dry DMF
(8 mL) by following the general procedure A as a white solid
by silica gel column chromatography using 20% hexane in
chloroform as eluent; found: C, 71.52; H, 6.26; C26H26O4S
requires C, 71.86; H, 6.03; Rf (CHCl3) 0.44; yield: 308 mg
(71%); mp: 152–154 ꢀC; IR (KBr): 2956, 2838, 2363,
2054, 1725, 1601, 1512, 1456, 1386, 1345, 1288, 1248,
1172, 1114, 1031, 835, 776 cmÀ1; dH (200 MHz, CDCl3):
2.0 (s, 3H, SCH3), 1.97–2.07 (m, 2H, CH2), 2.70 (t, J
7.3 Hz, 2H, CH2), 2.98 (t, J 7.4 Hz, 2H, CH2), 3.72 (s, 3H,
OCH3), 3.74 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 6.65–
6.72 (m, 4H, ArH), 6.84 (d, J 8.5 Hz, 2H, ArH), 6.96 (d, J
8.5 Hz, 2H, ArH); dC (50 MHz, CDCl3): 20.58, 25.37,

10308
R. Pratap et al. / Tetrahedron 63 (2007) 10300–10308
16. (a) Sato, F.; Urabe, H.; Okamoto, S. Chem. Rev. 2000, 100,
2835; (b) Sato, F.; Okamoto, S. Adv. Synth. Catal. 2001, 343,
759; (c) Sato, F.; Urabe, H. Titanium and Zirconium in
Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim,
Germany, 2002; pp 319–354.
17. Lautens, M.; Mancuso, J. Org. Lett. 2002, 4, 2105.
18. (a) Hoffmann, R. W. Dehydrobenzene and Cycloalkynes;
Academic: New York, NY, 1967; (b) Wakefield, B. J. The
Chemistry of Organolithium Compounds; Pergamon: New
York, NY, 1974; (c) Bailey, W. F.; Longstaff, S. C. J. Org.
Chem. 1998, 63, 432.
19. Zhang, L.; Herndon, J. W. Organometallics 2004, 23, 1231.
20. (a) Ram, V. J.; Goel, A. Tetrahedron Lett. 1996, 37, 93; (b)
Ram, V. J.; Nath, M.; Srivastava, P.; Sarkhel, S.; Maulik,
P. R. J. Chem. Soc., Perkin Trans. 1 2000, 3719; (c) Ram,
V. J.; Agarwal, N. Tetrahedron Lett. 2001, 42, 7127.
Maulik, P. R. Tetrahedron Lett. 2002, 43, 307; (d)
Farhanullah; Agarwal, N.; Goel, A.; Ram, V. J. J. Org. Chem.
2003, 68, 2983.
22. (a) Sharon, A.; Pratap, R.; Maulik, P. R.; Ram, V. J. Tetrahedron
2005, 61, 3781; (b) Ram, V. J.; Srivastava, P.; Goel, A.
Tetrahedron 2003, 59, 7141; (c) Srivastava, P.; Saxena, A. S.;
Ram, V. J. Synthesis 2000, 541.
23. (a) Ram, V. J.; Verma, M. Indian J. Chem. 1990, 29B, 624; (b)
Ram, V. J.; Verma, M.; Hussaini, F. A.; Shoeb, A. Liebigs Ann.
Chem. 1991, 1229; (c) Ram, V. J.; Singh, S. K.; Hussaini, F. A.;
Shoeb, A. J. Chem. Res., Synop. 1993, 110; (d) Ram, V. J.;
Haque, N.; Shoeb, A. Sulfur Lett. 1993, 16, 165; (e) Ram,
V. J.; Mumtazuddin, S.; Pragya; Haque, N.; Hussaini, F. A.;
Shoeb, A.; Bhaduri, A. P. J. Chem. Res., Synop. 1994, 354;
(f) Tominaga, Y.; Ushirogochi, A.; Matsuda, Y. J. Heterocycl.
Chem. 1987, 24, 1557.
21. (a) Ram, V. J.; Srivastava, P. J. Chem. Res., Synop. 2001, 421;
(b) Nath, M.; Srivastava, P.; Goel, A.; Ram, V. J. Eur. J. Org.
Chem. 1998, 2083; (c) Ram, V. J.; Agarwal, N.; Sharon, A.;
24. Pratap, R.; Sil, D.; Ram, V. J. Tetrahedron Lett. 2005, 46, 5025.
25. Goel, A.; Singh, F. V.; Dixit, M.; Verma, D.; Raghunandan, R.;
Maulik, P. R. Chem. Asian J. 2006, 2, 239.