Heteroaromatic annulation studies on 2-[bis(methylthio)methylene]-1,3- indanedione: Efficient routes to indenofused heterocycles

Article abstract of DOI:10.1016/j.tet.2010.07.031

2-[Bis(methylthio)methylene]-1,3-indanedione has been shown to be a useful three carbon 1,3-dielectrophilic synthon for the highly efficient regiospecific synthesis of a variety of indenofused five- and six-membered heterocycles via heteroaromatic annulation. The methodology has been further elaborated to the corresponding N,S-acetals leading to amino substituted heterocycles, thus providing further point of diversity in the newly synthesized heterocyclic frameworks. Further, the facile access to cytotoxic indeno[2,1-c]quinolin-7-ones and the novel polycyclic heteroaromatics demonstrates the versatility of heteroaromatic annulation protocol via α-oxoketene-S,S-acetal in generating novel biologically important polycyclic heteroaromatics.

Full text of DOI:10.1016/j.tet.2010.07.031

Tetrahedron 66 (2010) 7389e7398
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Heteroaromatic annulation studies on 2-[bis(methylthio)methylene]-
1,3-indanedione: efficient routes to indenofused heterocycles
,
Rajiv K. Verma a, Hiriyakkanavar Ila b, Maya Shankar Singh a
*
a Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
b New Chemistry Unit, Jawahar Lal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 64, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 June 2010
Received in revised form 9 July 2010
Accepted 12 July 2010
Available online 21 July 2010
2-[Bis(methylthio)methylene]-1,3-indanedione has been shown to be a useful three carbon 1,3-dielec-
trophilic synthon for the highly efficient regiospecific synthesis of a variety of indenofused five- and six-
membered heterocycles via heteroaromatic annulation. The methodology has been further elaborated to
the corresponding N,S-acetals leading to amino substituted heterocycles, thus providing further point of
diversity in the newly synthesized heterocyclic frameworks. Further, the facile access to cytotoxic indeno
[2,1-c]quinolin-7-ones and the novel polycyclic heteroaromatics demonstrates the versatility of heter-
Keywords:
2-[Bis(methylthio)methylene]-1,3-
indanedione
oaromatic annulation protocol via
polycyclic heteroaromatics.
a
-oxoketene-S,S-acetal in generating novel biologically important
Ó 2010 Elsevier Ltd. All rights reserved.
a
-Oxoketene-S,S and N,S-acetals
Indenofused heterocycles
Polycyclic heteroaromatics
Heteroaromatic annulation
1. Introduction
Similarly, indenofused thiophene derivatives have been exten-
sively explored in the field of organometallic chemistry because their
transition metal complexes have been found to be promising catalysts
for olefin polymerization.8 However, despite their biological activities
and other applications, synthesis of these indenofused heterocycles
has not received much attention, ranging over diverse methods with
many limitations and lacking generality. Therefore more general and
Indenofused heterocycles have attracted considerable atten-
tion from both medicinal and synthetic chemists in recent years,
because of the broad range of biological activity displayed by this
class of compounds. Thus, indeno[1,2-c]pyrazol-4-ones 1 have
recently been identified as potent and selective cyclin dependent
kinase (CDK)1 and check point kinase (CHK 1) inhibitors2,3
showing excellent activity against various tumor cell linings
and in vivo activity in human xenograph models. A few of these
compounds exhibit antidepressive activity also.4 Similarly,
a number of indeno[2,1-c]quinolin-7-ones, such as 2 (TAS-103)
N
O
HN
O
R1
N
and indeno[1,2-c]isoquinolin-5,11-dione
3 (NSC 314622) are
N
reported to display marked cytotoxic activity and have been
identified5a,b as potent DNA topoisomerase I and II inhibitors and
in fact, indenoquinoline 2 has been advanced to phase I and II
clinical trials (Chart 1).5a A number of indenofused pyrimidines,
pyridazines, and 1,2,4-triazines are reported to show inhibitory
potency toward monoamine oxidase (MAO) A and B,6 whereas,
an indenofused pyridone has been found to exhibit cardiotonic
activity (PDE 3 inhibitor).7a Some indenofused pyrimidines are
identified as a novel class of potent A2A receptor antagonists7b
(Chart 1, 4).
N
H
R
R
OH
2
(TAS -103)
1
O
O
O
O
MeO
N
N
MeO
Me
N
NH2
O
4
3 (NSC 314622)
* Corresponding author. Fax: þ91 542 2368127; e-mail address: mssinghbhu@
Yahoo.co.in (M.S. Singh).
Chart 1.
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.031

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R.K. Verma et al. / Tetrahedron 66 (2010) 7389e7398
efficient methods for these compounds are very much desirable in
view of their broad range of biological activity.
synthesis of indenofused five-membered heterocycles was first
undertaken. Thus, when 5 was reacted with hydrazine hydrate
in refluxing ethanol, the corresponding 3-(methylthio)indeno
[1,2-c]pyrazol-4-one 6 was obtained in 65% yield (Scheme 1).
Similarly, treatment of 5 with phenyl hydrazine in refluxing
EtOH/AcOH (1:1) furnished 3-(methylthio)-1-N-phenyl-indeno
[1,2-c]pyrazol-4-one 7 in 55% yield (Scheme 1). The structure
and regiochemistry of 7 was established with the help of
spectral, analytical data and also by X-ray crystallographic
data13 (Fig. 1). On the other hand, our attempts to obtain
regioisomeric 2-N-phenyl-3-(methylthio)indeno[1,2-c]pyrazol-
4-one 8 by reacting 5 with phenyl hydrazine in the presence of
either NaH/DMF or in the presence of potassium tert-butoxide
in refluxing tert-butanol under earlier described conditions14a
gave only mixture of several products. Similarly, attempted
cycloannulation of 5 with hydroxylamine under varying con-
ditions (Ba(OH)2/MeOH, MeONa/MeOH, Et3N/MeOH, NaOAc/
AcOH) led only to intractable product mixture from which no
trace of the desired indenoisooxazoles 9a or 9b could be
isolated.14b
We therefore became interested in devising more general
synthetic methods for indenofused five- and six-membered
heterocycles via heteroaromatic annulation of 2-[bis(methylthio)
methylene]-1,3-indanedione 5 (as 1,3-bielectrophile) with various
1,2- and 1,3-heterobinucleophiles in line with the extensive studies
reported earlier by Junjappa-Ila (J-I) and co-workers.9
Our literature survey at this stage revealed that ketene
dithioacetal 5 has been reported in the literature10,11 and there are
scattered reports of its reactions with anilines,10a,11 active methy-
lene compounds,12a ylides,12b S,S-dialkylsulfur diimides,12d and
conversion to indenofused pyrimidines.10a,12 Also, there is no report
of synthesis of indenofused five-membered heterocycles from 5
thus, warranting a more elaborate investigation. We therefore un-
dertook a systematic study toward utilizing ketene dithioacetal 5
and the derived N,S-acetals 20, 21 as the versatile templates for the
construction of indenofused five-, six-membered and condensed
heterocycles. We herein, report the results of these studies in the
present paper.
The ketene dithioacetal 5 was next subjected to treatment with
methylene iodide and Zn/Cu couple yielding the corresponding
7-(methylthio)-8H-indeno[1,2-c]thiophene-8-one 10 in 55% yield
in line with the earlier observations on SimmoneSmith reaction on
2. Results and discussion
The desired 2-[bis(methylthio)methylene]-1,3-indanedione
5 was prepared in 60% yield by modified procedure10a from 1,3-
indanedione by treatment with carbon disulfide in the pres-
ence of KOH followed by alkylation with dimethylsulfate. The
a
-oxoketene dithioacetals (Scheme 1).15 To further add diversity to
indeno[1,2-b]thiophene framework, the ketene dithioacetal 5 was
also subjected to cyclocondensation with ethyl thioglycolate in
O
SMe
N2H4.H2O
N
N
EtOH / Δ / 5 h
H
O
6, 65%
O
O
O
SMe
SMe
SMe
Ph
PhNHNH2
1. KOH/THF/ 0oC
N
O
N
2. CS2/THF/ 0oC
3. Me2SO4/EtOH
EtOH-AcOH /
N
Ph
N
Δ / 6 h
8
7, 55%
O
SMe
SMe
O
O
SMe
H2NOH
O
5
N
X
O
N
9a
9b
O
SMe
S
CH2I2
Zn-Cu / Et2O /
THF / Δ / 10 h
H
10, 55%
O
O
SMe
S
HS
OEt
K2CO3 / EtOH /
Δ / 8 h
COOEt
11, 42%
Scheme 1.

R.K. Verma et al. / Tetrahedron 66 (2010) 7389e7398
7391
O
O
SMe
NC
CN
O
NH2
t
t
Bu OK / Bu OH /
Δ / 8 h
N
H
O
SMe
SMe
15, 45%
O
O
SMe
O
R
CH3
5
16a, R = C6H5, 75%
16b, R = 4-MeOC6H4, 72%
16c, R = 2-Pyridyl, 74%
NaH / DMF /
0
R
O
O
oC / 8-10 h
16a-c
NH4OAc
AcOH / Δ / 5-7 h
O
SMe
N
R
17a-c
17a, R = C6H5, 70%
17b, R = 4-MeOC6H4, 66%
17c, R = 2-Pyridyl, 62%
Scheme 3.
Figure 1. Ortep diagram of 7.
(75%), which on cyclization with ammonium acetate in refluxing
acetic acid provided the corresponding 2-phenyl-5-oxo-4-(meth-
ylthio)-5H-indeno[1,2-b]pyridine 17a in 70% yield (Scheme 3).18
The corresponding 2-(4-methoxyphenyl) and 2-(2-pyridyl)-
indenofused pyridines 17b,c were similarly obtained in good yields
following the same procedure (Scheme 3).
In one of the reactions, the ketene dithioacetal 5 was subjected
to cyclocondensation with 5-aminotetrazole 19 in the presence of
K2CO3 in DMSO at 120 ꢀC, yielding a novel tetracyclic condensed
polyaza heteroaromatic framework 18 in 65% yield (Scheme 4).
presence of potassium carbonate in ethanol to afford 7-(methyl-
thio)-5-carboethoxy-8H-indeno[1,2-c] thiophene 11 in moderate
yield (Scheme 1).
Cyclocondensation of 5 with 1,3-heterobinucleophiles was next
examined with a view to synthesize indenofused six-membered
heterocycles (Schemes 2 and 3). Thus, heterocyclization of 5 with
guanidine nitrate in the presence of K2CO3 in refluxing acetonitrile
furnished the 2-amino-4-(methylthio)-5H-indeno[1,2-d]pyrimidin-
5-one 12 in 65% yield (Scheme 2). On the other hand, a similar re-
action when conducted in the presence of sodium ethoxide in
refluxing ethanol, afforded the corresponding 2-amino-4-ethoxy-
5H-indeno[1,2-d]pyrimidine-5-one 13 in 60% yield in accordance
with earlier reported alkoxypyrimidine synthesis from oxoketene
dithioacetal by Junjappa and co-workers.16 Similarly, the 2-(phe-
nyl)-4-(methylthio)-5H-indeno[1,2-d]pyrimidin-5-one 14 could be
obtained in 65% yield by treatment of 5 with 2-phenylamidine hy-
drochloride under identical conditions (K2CO3/MeCN) (Scheme 2).
N
N
N
O
SMe
N
O
SMe
SMe
N
H
H2N
19
K2CO3 / DMSO /
N
N
N
N
O
Δ / 120 oC / 5 h
5
NH.HX
(R=NH , Ph)
O
Y
18, 65%
O
SMe
SMe
H2N
R
2
N
Scheme 4.
Reaction conditions
a or b
N
R
O
We further extended heteroaromatic annulation studies to the
corresponding N,S-acetals 20 and 21 for the synthesis of amino
substituted indenofused heterocycles with a view to add further
point of diversity in these compounds (Scheme 5). Thus, the N,S-
acetals 20 from primary amines and 21 from secondary cyclic
amines could be smoothly obtained in high yields by direct
12, R = NH2; Y = SMe; 65% (a)
13, R = NH2; Y = OEt; 60% (b)
14, R = Ph; Y = SMe; 65% (a)
5
NH.HX
a.
, K2CO3, CH3CN, Δ / 8-10 h
H2N
H2N
R
NH.HNO3
NH2
b.
R1
R2
R1
, NaOEt/ EtOH/ Δ / 7 h
Scheme 2.
H
O
N
O
N
O
SMe
SMe
R1NH2
SMe
SMe
or
or
HN
R1
R2
O
O
O
20
21
5
The versatility of heteroaromatic annulation was further dem-
onstrated by synthesis of pyrido-fused indenones 15, 17 as shown
in the Scheme 3. Thus heteroannulation of 5 with cyanoacetamide
in the presence of potassium tert-butoxide in tert-butanol yielded
highly functionalized 4-(methylthio)-2,5-dioxo-2,5-dihydro-1H-
indeno[1,2-b]pyridine-3-carbonitrile 15 in moderate yield (45%)
(Scheme 3).17 In an another strategy for pyridine annulation, the
ketene dithioacetal 5 was subjected to conjugate additioneelimi-
nation with acetophenone enolate to give conjugate adduct 16a
EtOH / Δ / 2-3 h
1,2- or 1,3-
binucleophiles
R2
R1
O
N
Y
5 / 6
X
Amino heterocycles (Table 1)
Scheme 5.

7392
R.K. Verma et al. / Tetrahedron 66 (2010) 7389e7398
replacement of methylthio group in 5 by various amines (Scheme 5,
Table 1). It should be noted that although synthesis of N,S-anili-
noacetals have been reported in the literature,19 no attempts were
made to utilize them for further synthetic applications. Thus, the
cycloannulation of N,S-acetals 20a,b and 21a,b with hydrazine hy-
drate under earlier described conditions afforded the corresponding
3-anilino/cycloamino indeno[1,2-c]pyrazol-4-ones 22a,b (Table 1,
entries 1 and 2) and 23a,b (Table 1, entries 3 and 4) in 55e70%
overall yields.19 Similarly, treatment of N,S-acetals 20aed and 21b
with either guanidine nitrate or 2-phenylamidine hydrochloride in
the presence of K2CO3 in refluxing acetonitrile afforded the
respective 4-(anilino/benzylamino/N-phenylpiperazino)-2-amino
(or 2-phenyl)indenopyrimidin-5-ones 24aee and 25 (Table 1, en-
tries 5e9 and 10) in overall good yields.20 Similarly, cyclization of
21b with cyanoacetamide in the presence of potassium tert-but-
oxide in tert-butanol gave 2,5-dioxo-4-(4-phenyl-piperazin-1-yl)-
2,5-dihydro-1H-indeno[1,2-b]pyridine- 3-carbonitrile 26 in 50%
yield (Table 1, entry 11).21 The structures of all the newly syn-
thesized compounds were established with the help of spectral
and analytical data.
In view of the potent DNA topoisomerase inhibitory activity
reported for indenoquinolines,4a,b such as 2 (Chart 1), we planned
to synthesize this tetracyclic planar heterocyclic scaffold as shown
in the Scheme 6. Thus, the N,S-aminoacetals 20e and 20b from 3-
methoxy and 3,4-dimethoxyanilines, respectively, were subjected
to cyclization in the presence of polyphosphoric acid at 90 ꢀC
affording the desired 2-methoxy (or 2,3-dimethoxy)-6-(methyl-
thio)indeno[2,1-c]quinolin-7-ones 27a,b in excellent yields
(Scheme 6).22 The quinolines 27a,b on oxidation with m-chlor-
operbenzoic acid yielded the corresponding 6-(methylsulfonyl)
derivatives 28a,b in high yields (Scheme 6). Subsequent re-
placement of methylsulfonyl group in 28b by aliphatic amines gave
the amino substituted indenofused quinolines 29a,b in high yields
(Scheme 6).
Table 1
Synthesis of amino substituted indenofused heterocycles
Entry
N,S-acetals 20, 21
Yield (%)
Reaction condition
Product (22e26)
Yield (%)
H
Ar
H
Ar
O
O
N
N
SMe
N
N
H
O
a
a
1
2
20a, Ar¼4-MeOC6H4
90
95
22a, Ar¼4-MeOC6H4
68
70
20b, Ar¼3,4-(MeO)2C6H3
22b, Ar¼3,4-(MeO)2C6H3
X
X
O
O
N
N
SCH3
N
N
H
O
a
a
3
4
21a, X¼CH2,
80
75
23a, X¼CH2
23b, X¼NePh
60
55
21b, X¼NePh,
Ar / R1
H
H
O
Ar / R1
O
N
N
N
N
SMe
O
R2
b
b
b
c
5
6
7
8
9
20a, Ar¼4-MeOC6H4
20b, Ar¼3,4-(MeO)2C6H3
20c, Ar¼C6H5
90
95
90
95
85
24a, Ar¼4-MeOC6H4, R2¼NH2
24b, Ar¼3,4-(MeO)2C6H3, R2¼NH2
24c, Ar¼C6H5, R2¼NH2
75
75
78
50
60
20b, Ar¼3,4-(MeO)2C6H3
24d, Ar¼3,4-(MeO)2C6H3, R2¼Ph
24e, R1¼4-MeC6H4CH2, R2¼NH2
20d, R1¼4-MeC6H4CH2
b
Ph
N
Ph
N
O
N
O
N
SMe
N
O
NH2
N
b
10
21b
75
25
75
Ph
N
O
N
CN
O
N
H
d
11
21b
75
26
50
a
Reaction Conditions: N2H4/EtOH/reflux/6e10 h.
Guanidine nitrate/K2CO3/CH3CN/reflux/8e10 h.
Benzamidine hydrochloride/K2CO3/CH3CN/reflux/8 h.
Cyanoacetamide/KButO/ButOH/reflux/12 h.
b
c
d

R.K. Verma et al. / Tetrahedron 66 (2010) 7389e7398
7393
O
SMe / Y
4. Experimental
4.1. General
O
SMe
NH
PPA / Δ
N
X
90 oC / 6-8 h
O
All reagents were commercial and purchased from Merck,
Aldrich and Fluka and were used as received. All 1H and 13C NMR
spectra were recorded on JEOL AL 300 FT-NMR spectrometer.
OMe
OMe
X
20e, X = H, 85%
20b, X = OMe, 95%
27a, X = H, 85%
a
28a, X = H, Y = SO2Me, 90%
27b, X = OMe, 80%
Chemical shifts are given as
d value with reference to tetrame-
thylsilane (TMS) as the internal standard. The IR spectra were
recorded on Varian 3100 FT-IR spectrophotometer. Mass spectra
were recorded at 70 eV ionizing voltage on a JEOL-D300 MS in-
strument. The C, H, and N analyses were performed from micro-
analytical laboratory, Department of Chemistry, Banaras Hindu
University, Varanasi with an Exeter Analytical Inc. ‘Model CE-400
CHN Analyzer’. X-ray diffraction was measured on Xcalibur Oxford
CCD Diffractometer. All the reactions were monitored by TLC using
precoated sheets of silica gel G/UV-254 of 0.25 mm thickness
(Merck 60F254) using UV light (254 nm/365 nm) for visualization.
Melting points were determined with Büchi B-540 melting point
apparatus and are uncorrected.
a
28b, X = OMe, Y = SO2Me, 89%
a, mCPBA / DCM / 0 oC-RT / 3-5 h
H2NR / Δ
H
R
N
O
N
OMe
OMe
29a, R = n-phenylpiperazinyl, 63 %
29b, R = n-Bu, 67 %
4.2. Synthesis of 2-[bis(methylthio)methylene]-1,3-
indanedione (5)
Scheme 6.
KOH (4 g, 68 mmol) in THF (20 mL) was suspended in round
bottom flask fitted with a dropping funnel and CaCl2 guard tube.
CS2 (3 mL, 41 mmol) was added to the reaction mixture at 0 ꢀC
with continuous stirring. After 45 min a solution of indane-1,3-
dione (5 g, 34 mmol) in dry THF (20 mL) was added drop-wise at
0 ꢀC and the reaction mixture was stirred overnight (8e10 h). The
precipitated yellow colored dipotassium salt was filtered, washed
with dry ether, and dried. The suspension of dipotassium salt in
dry ethanol (100 mL) was methylated at 0 ꢀC using neutral
Me2SO4 (10 mL, 103 mmol) followed by stirring for further 5 h.
Ethanol was distilled off and resulting slurry was poured over ice
cold water and extracted with CHCl3 (4ꢁ30 mL). The combined
organic extract was washed with water (1ꢁ40 mL), brine
(1ꢁ30 mL), and dried over anhydrous Na2SO4. The solvent was
evaporated under reduced pressure to give crude product, which
was purified by column chromatography over silica gel using
hexane/ethyl acetate (9:1) as eluent to give pure 2-[bis(methyl-
thio)-methylene]-1,3-indanedione 5 as a yellow solid (5.1 g, 60%);
mp 124e125 ꢀC (reported mp 124e125 ꢀC).10a Rf¼0.57 (hexane/
In a further elaboration to construct novel indenofused poly-
cyclic heteroaromatics, the 4-(3,4-dimethoxyanilino) indenopyr-
imidine 24b was exposed to polyphosphoric acid at 90 ꢀC for 5 h to
afford an insoluble product, which was characterized as the novel
pentacyclic planer heterocycle 30 on the basis of its spectral and
analytical data (Scheme 7).
OMe
OMe
MeO
MeO
NH
N
N
O
PPA / Δ / 90 oC/ 5 h
N
N
NH2
N
NH2
24b
30, 70 %
Scheme 7.
EtOAc, 80:20); IR (KBr): 3191, 2928, 1672, 1562 cmꢂ1 1H NMR
;
(300 MHz, CDCl3):
d 7.85e7.82 (m, 2H, ArH), 7.68e7.65 (m, 2H,
3. Conclusion
ArH), 2.64 (s, 6H, 2ꢁSCH3). 13C NMR (75 MHz, CDCl3):
d 186.8,
181.3, 140.3, 133.9, 122.5, 121.6, 21.6. ESIMS (m/z, %): 251 (Mþþ1,
100). Anal. Calcd for C12H10O2S2: C, 57.57%; H, 4.03%. Found: C,
57.69; H, 4.15%.
In summary, we have developed an efficient general pro-
tocol for indenofused five- and six-membered heterocycles via
heteroaromatic annulation of 2-[bis(methylthio)methylene]-
1,3-indanedione. The methodology has been further elaborated
to the corresponding N,S-acetals leading to amino substituted
heterocycles thus providing further point of diversity in the
newly synthesized heterocyclic frameworks. Facile access to
cytotoxic indeno[2,1-c]quinolin-7-ones 27 (Scheme 6) and the
novel polycyclic heteroaromatics, such as 18 and 30 (Schemes
4.2.1. Synthesis of 3-methylthio-1H-indeno[1,2-c] pyrazol-4-one
(6). To a stirred solution of ketene dithioacetals 5 (0.5 mmol) in
absolute ethanol (6 mL) was added a solution of hydrazine hy-
drate (0.073 mL, 0.5 mmol) in absolute ethanol (2 mL) drop-wise.
The reaction mixture was stirred and refluxed for 5 h (monitored
by TLC). Solvent was evaporated under vacuum and residue
obtained was dissolved in dichloromethane (20 mL). Organic layer
was washed with water (2ꢁ20 mL) followed by brine (1ꢁ20 mL),
and dried over anhydrous Na2SO4. The solvent was evaporated to
give the crude product, which was purified by column chroma-
tography over silica gel to give white fibrous solid, mp 248 ꢀC.
Yield 0.070 g, 65%; Rf¼0.35 (hexane/EtOAc, 80:20); IR (KBr): 3448,
4
and 7) further demonstrates the versatility of hetero-
aromatic annulation protocol via -oxoketene-S,S-acetal in
a
generating novel biologically important polycyclic hetero-
aromatics, some of them cannot be synthesized easily by tra-
ditional classical methods. In view of the broad range of
biological activities displayed by indenofused heterocycles,
these newly synthesized compounds will prove useful for
preliminary pharmacological screening. Our further efforts to
improve the yields of indenofused five-membered heterocycles
are in progress.
2934, 1699, 1562, 1452, 1262 cmꢂ1 1H NMR (300 MHz, CDCl3):
;
d
9.75 (s, 1H, NH), 7.63 (d, J¼7.2 Hz, 1H, ArH), 7.53e7.44 (m, 2H,
ArH), 7.32 (d, J¼7.5 Hz, 1H, ArH), 2.88 (s, 3H, SCH3). 13C NMR
(75 MHz, CDCl3):
d 182.6, 163.9, 140.7, 140.6, 135.6, 133.9, 129.3,

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R.K. Verma et al. / Tetrahedron 66 (2010) 7389e7398
123.7, 119.8, 15.5. ESIMS (m/z, %): 217 (Mþþ1, 100). Anal. Calcd for
C11H8N2OS: C, 61.09%; H, 3.73%; N, 12.95%. Found: C, 61.31%; H,
3.59%; N, 12.76%.
(Mþþ1, 100). Anal. Calcd for C15H12O3S2: C, 59.19%; H, 3.97%. Found:
C, 58.94%; H, 4.18%.
4.2.5. Synthesis of aminopyrimidines 12 and 14. Guanidine nitrate
or benzamidine hydrochloride (0.52 mmol) was added to a stirred
suspension of K2CO3 (0.138 g, 1 mmol) in acetonitrile (10 mL). After
30 min, ketene dithioacetal 5 (0.125 g, 0.5 mmol) was added and
the reaction mixture was refluxed for 8e10 h (monitored by TLC).
Solvent was evaporated under vacuum. The residue obtained was
treated with cold water and extracted with ethyl acetate
(3ꢁ20 mL). The combined organic extract was washed with water
(2ꢁ20 mL) followed by brine (1ꢁ20 mL) and dried over anhydrous
Na2SO4. The solvent was evaporated under vacuum and the residue
obtained was purified by column chromatography over silica gel
using hexane/ethyl acetate (6:1) as eluent to give 12 and 14.
4.2.2. Synthesis of 3-methylthio-1-phenyl-1H-indeno[1,2-c]pyrazol-
4-one (7). To a stirred solution of 5 (0.125 g, 0.5 mmol) in ethanol
and glacial acetic acid (1:1, 6 mL), a solution of phenyl hydrazine
(0.073 mL, 0.75 mmol) in glacial acetic acid (2 mL) was added drop-
wise. Reaction mixture was stirred and refluxed for 6 h (monitored
by TLC). Solvent was evaporated under vacuum and residue was
dissolved in dichloromethane (20 mL). Organic layer was washed
with water (4ꢁ20 mL) followed by brine (1ꢁ20 mL), and dried over
anhydrous Na2SO4. The solvent was evaporated under vacuum to
give the product, which was purified by column chromatography
over silica gel using hexane/ethyl acetate (19:1) to yield the desired
compound 7 as yellow crystals. Yield 0.080 g, 55%; mp 159 ꢀC;
Rf¼0.57 (hexane/EtOAc, 85:15); IR (KBr): 2932, 2845, 1689, 1592,
4.2.6. 2-Amino-4-methylthio-indeno[1,2-d] pyrimidin-5-one (12). Yel-
low solid, mp 261e263 ꢀC; yield 0.085 g, 65%; Rf¼0.18 (hexane/EtOAc,
1507, 1443 cmꢂ1
ArH), 7.31e7.28 (m, 2H, ArH), 7.17e7.14 (m, 1H, ArH), 2.73 (s, 3H,
SCH3). 13C NMR (75 MHz, CDCl3):
180.0, 157.8, 148.5, 140.7, 138.5,
; d 7.68e7.48 (m, 6H,
1H NMR (300 MHz, CDCl3):
80:20); IR (KBr): 3311, 3199, 2915, 2826, 1689, 1617, 1524, 1077 cmꢂ1
;
d
1H NMR (300 MHz, CDCl3):
ArH), 5.58 (s, 2H, NH2), 2.56 (s, 3H, SCH3). 13C NMR (75 MHz,
d 7.75e7.69 (m, 2H, ArH), 7.55e7.53 (m, 2H,
132.7, 132.2, 130.2, 129.5, 128.9, 124.6, 123.4, 119.6, 14.5. ESIMS (m/z,
%): 293 (Mþþ1, 100). Anal. Calcd for C17H12N2OS: C, 69.84%; H,
4.14%; N, 9.58%. Found: C, 69.80%; H, 4.31%; N, 9.39%.
CDCl3þDMSO-d6):
d 187.2, 173.0, 167.5, 163.3, 138.6, 135.5, 132.4, 131.3,
121.7, 120.2, 10.0. ESIMS (m/z, %): 244 (Mþþ1, 100). Anal. Calcd for
C12H9N3OS: C, 59.24%; H, 3.73%; N, 17.27%. Found: C, 59.39%; H, 3.59%;
N, 17.15%.
4.2.3. Synthesis of 1-methylthio-2-thia-cyclopenta-[a]inden-8-one
(10). A solution of CH2I2 (0.2 mL, 2.5 mmol) in dry ether (5 mL)
was added drop-wise to a stirred suspension of Zn/Cu couple
(activated by heating in oven at 100 ꢀC for 10 h) (0.4 g, 3.0 mmol)
in dry ether (20 mL) at reflux temperature under nitrogen atmo-
sphere. After 1 h, a solution of 5 (0.187 g, 0.75 mmol) in dry THF
(10 mL) was added drop-wise and refluxing was continued for
10 h (monitored by TLC). The reaction mixture was cooled to room
temperature and the organic layer was decanted. The residue was
extracted with chloroform (3ꢁ20 mL) and the combined extract
was washed with water (1ꢁ20 mL), brine (1ꢁ20 mL), and dried
over anhydrous Na2SO4. Solvent was evaporated under reduced
pressure and the crude product obtained was purified by column
chromatography over silica gel using hexane/ethyl acetate (20:1)
as eluent to give 10 as creamish fibers, mp 187 ꢀC. Yield 0.095 g,
55%; Rf¼0.45 (hexane/EtOAc, 80:20); IR (KBr): 2925, 2855, 1683,
4.2.7. 4-Methylthio-2-phenyl-indeno[1,2-d] pyrimidin-5-one (14). Yel-
low solid, mp 210e211 ꢀC; yield 0.083 g, 55%; Rf¼0.66 (hexane/EtOAc,
80:20); IR (KBr): 3161, 1585, 1487, 1394, 1265, 1194, 1157, 881 cmꢂ1; 1H
NMR (300 MHz, CDCl3):
J¼7.2 Hz, 1H, ArH), 7.76 (d, J¼6.9 Hz, 1H, ArH), 7.64e7.53 (m, 5H, ArH),
2.79 (s, 3H, SCH3). 13C NMR (75 MHz, CDCl3):
190.2, 172.2, 167.1, 166.5,
d
8.63 (dd, J¼7.8, 1.5 Hz, 2H, ArH), 7.99 (d,
d
140.7, 139.2, 136.9, 135.2, 134.4, 132.6, 131.9, 129.3, 128.5, 123.7, 122.0,
118.9, 114.0, 11.5. ESIMS (m/z, %): 304 (Mþþ1, 20). Anal. Calcd for
C18H12N2OS: C, 71.03%; H, 3.97%; N, 9.20%. Found: C, 70.95%; H, 4.05%;
N, 9.39%.
4.2.8. Synthesis of 2-amino-4-ethoxy-indeno[1,2-d] pyrimidin-5-one
(13). Guanidine nitrate (0.064 g, 0.52 mmol) was added to a stir-
red solution of sodium ethoxide (1.1 mmol, prepared in situ form
0.028 g Na and 1 mL dry ethanol) in ethanol (8 mL). After 15 min,
ketene dithioacetal 5 (0.125 g, 0.5 mmol) was added and reaction
mixture was refluxed for 7 h. After the completion of the reaction
(monitored by TLC), solvent was evaporated under reduced pres-
sure. The residue obtained was triturated with water (5 mL). The
solid obtained was filtered and recrystallized from ethanol to give
13 as yellow solid, mp 210e211 ꢀC. Yield 0.072 g, 60%; IR (KBr):
1561, 1096 cmꢂ1
; d 8.27 (s, 1H, ArH),
1H NMR (300 MHz, CDCl3):
7.91e7.88 (m, 2H, ArH), 7.75e7.72 (m, 2H, ArH), 2.66 (s, 3H, SCH3).
13C NMR (75 MHz, CDCl3):
d 190.0, 186.8, 156.0, 141.5, 140.3, 134.7,
134.6, 126.4, 123.3, 122.7, 20.1. ESIMS (m/z, %): 233 (Mþþ1, 100).
Anal. Calcd for C12H8OS2: C, 62.04%; H, 3.47%. Found: C, 62.16%; H,
3.32%.
4.2.4. Synthesis of 1-methylthio-8-oxo-8H-2-thia-cyclopenta[a]in-
dene-3-carboxylic acid ethyl ester (11). Ethyl thioglycolate
(0.045 mL, 0.5 mmol) dissolved in EtOH (2 mL) was added drop-
wise to the stirred suspension of K2CO3 (0.069 g, 0.5 mmol) and 5
(0.125 g, 0.5 mmol) in EtOH (5 mL). The solution was refluxed for
8 h (monitored by TLC). Solvent was evaporated under vacuum and
the residue obtained was dissolved in dichloromethane (20 mL).
Organic layer was washed with water (1ꢁ20 mL) followed by brine
(1ꢁ20 mL) and dried over anhydrous Na2SO4. Solvent was evapo-
rated under vacuum and the residue obtained was purified by
column chromatography over silica gel using hexane/ethyl acetate
(15:1) as eluent to afford 11 as yellow solid, mp 151 ꢀC. Yield
0.064 g, 42%; Rf¼0.61 (hexane/EtOAc, 80:20); IR (KBr): 2991, 2851,
3454, 3305, 3124, 1707, 1641, 1572, 1491, 1082 cmꢂ1
(300 MHz, DMSO-d6): 8.34e8.24 (m, 2H, ArH), 8.17e8.07 (m, 2H,
ArH), 6.78 (s, 2H, NH2), 4.46 (q, J¼7.2 Hz, 2H, CH2), 1.47 (t, J¼7.2 Hz,
3H, CH3). 13C NMR (75 MHz, DMSO-d6):
: 186.4, 169.4, 166.8,
;
1H NMR
d
d
165.9, 165.5, 139.5, 136.7, 133.7, 132.6, 122.9, 122.7, 61.2, 14.3. ESIMS
(m/z, %): 242 (Mþþ1, 20). Anal. Calcd for C13H11N3O2: C, 64.72%; H,
4.60%; N, 17.42%. Found: C, 64.60%; H, 4.75%; N, 17.39%.
4.2.9. Syntheis of 4-methylthio-2,5-dioxo-2,5-dihydro-1H-indeno
[1,2-b]pyridine-3-carbonitrile (15). To a stirred suspension of ButOK
(0.168 g, 1.5 mmol) in ButOH (10 mL) at room temperature, cya-
noacetamide (0.067 g, 0.5 mmol) was added. After 10 min, ketene
dithioacetal 5 (0.125 g, 0.5 mmol) was added and the reaction
mixture was refluxed for 8 h. After the completion of the reaction
(monitored by TLC), the solvent was evaporated under reduced
pressure to give the salt of pyridine 15, which was dissolved in
water (10 mL) followed by acidification with dilute HCl (5 mL, 5%).
The solid obtained was filtered, washed with water, and recrys-
tallized from ethanol to give the desired compound 15 as yellow
1698, 1597, 1572 cmꢂ1 1H NMR (300 MHz, CDCl3):
; d 8.38 (d,
J¼7.5 Hz,1H, ArH), 7.68 (d, J¼7.5 Hz,1H, ArH), 7.53 (dd, J¼7.5, 7.2 Hz,
1H, ArH), 7.36 (dd, J¼7.5, 7.2 Hz, 1H, ArH), 4.40 (q, J¼7.2 Hz, 2H,
CH2), 2.70 (s, 3H, SCH3), 1.43 (t, J¼7.2 Hz, 3H, CH3). 13C NMR
(75 MHz, CDCl3): d 184.8, 160.9, 151.1, 151.0, 141.5, 139.0, 136.1, 134.3,
129.9, 125.9, 124.2, 121.3, 94.5, 61.6, 17.8, 14.3. ESIMS (m/z, %): 305

R.K. Verma et al. / Tetrahedron 66 (2010) 7389e7398
7395
solid, mp 320 ꢀC (decompose). Yield 0.060 g, 45%; IR (KBr): 3449,
2921, 2859, 2357, 1635, 1556, 1459 cmꢂ1 1H NMR (300 MHz,
DMSO-d6): 14.0 (s, 1H, OH), 8.00e7.63 (m, 4H, ArH), 2.82 (s, 3H,
SCH3). 13C NMR (75 MHz, DMSO-d6):
186.2, 161.2, 160.6, 159.2,
134.6, 134.2, 134.1, 133.7, 123.1, 122.9, 116.1, 17.0. ESIMS (m/z, %): 269
(Mþþ1, 100). Anal. Calcd for C14H8N2O2S: C, 62.67%; H, 3.01%; N,
10.44%. Found: C, 62.55%; H, 2.87%; N, 10.67%.
8.63 (d, J¼7.8 Hz, 1H, ArH), 8.25 (s, 1H, ArH), 7.94e7.86 (m, 2H, ArH),
7.72 (d, J¼7.2 Hz, 1H, ArH), 7.59 (t, J¼7.2 Hz, 1H, ArH), 7.47e7.36 (m,
;
d
2H, ArH), 2.69 (s, 3H, SCH3). 13C NMR (75 MHz, CDCl3):
d 191.5,
d
165.0, 158.6, 155.0, 151.8, 149.2, 142.5, 137.0, 135.3, 134.5, 130.9,
124.5, 123.5, 123.4, 122.3, 121.0, 114.7, 13.3. ESIMS (m/z, %): 305
(Mþþ1, 100). Anal. Calcd for C18H12N2OS: C, 71.03%; H, 3.97%; N,
9.20%. Found: C, 71.10%; H, 3.85%; N, 9.02%.
4.2.10. General procedure for synthesis of 17aec. A solution of ace-
tophenone/4-methoxyacetophenone or 2-acetyl pyridine (0.52 mmol)
in dry DMF (2 mL) was added drop-wise to a stirred suspension of
NaH (60%, 0.032 g, 0.8 mmol) in dry DMF (3 mL) at 0 ꢀC under ni-
trogen atmosphere. The reaction mixture was further stirred for 1 h.
A solution of 5 (0.125 g, 0.5 mmol) in dry DMF (5 mL) was added
drop-wise at 0 ꢀC and the content was stirred at room temperature
for 10 h (monitored by TLC). The reaction mixture was poured into
saturated aqueous ammonium chloride solution (20 mL) and
extracted with ethyl acetate (3ꢁ30 mL). The combined organic extract
was washed with water (4ꢁ25 mL) followed by brine (1ꢁ25 mL) and
dried over anhydrous Na2SO4. Solvent was evaporated under reduced
pressure to yield adduct 16a (75%), 16b (72%) or 16c (74%).
4.2.15. Synthesis of 5-methylthio-1,2,3,4,10c-pentaazacyclopenta[c]
fluoren-6-one (18). To a stirred solution of ketene dithioacetal 5
(0.125 g, 0.5 mmol) in DMSO (4 mL), a solution of 5-aminotetrazole
19 (0.043 g, 0.5 mmol) in DMSO (4 mL) was added. Reaction mix-
ture was heated at 120 ꢀC with stirring for 5 h (monitored by TLC).
The reaction mixture was cooled to room temperature and poured
over crushed ice followed by acidification with 10% HCl solution.
Resulting yellow colored solid was recrystallized in ethanol to yield
18 as yellow solid, mp 198 ꢀC. Yield 0.087 g, 65%; IR (KBr): 2911,
1709, 1572, 1463, 1288 cmꢂ1 1H NMR (300 MHz, CDCl3):
; d 7.86 (d,
J¼6.6 Hz, 1H, ArH), 7.73 (d, J¼6.9 Hz, 1H, ArH), 7.59 (dd, J¼8.1 Hz,
2H, ArH), 2.64 (s, 3H, SCH3). 13C NMR (75 MHz, CDCl3þDMSO-d6):
d
188.6, 174.2, 169.1, 164.3, 139.2, 135.2, 134.4, 133.0, 123.5, 122.2,
117.0, 11.4. ESIMS (m/z, %): 270 (Mþþ1, 100). Anal. Calcd for
C12H7N5OS: C, 53.52%; H, 2.62%; N, 26.01 Found: C, 53.39%; H,
2.70%; N, 25.85.
4.2.11. 2-(1-Methylthio-3-oxo-3-phenyl-propylidene)-1,3-in-
danedione (16a). Yellow solid, yield 0.120 g, 75%; Rf¼0.31 (hexane/
EtOAc, 50:50); IR (KBr): 3062, 2919,1702,1687, 1606, 1561 cmꢂ1; 1H
NMR (300 MHz, CDCl3):
d
8.10e8.04 (m, 1H, ArH), 7.87 (d, J¼6.3 Hz,
1H, ArH), 7.78 (d, J¼5.7 Hz, 2H, ArH), 7.68e7.66 (m, 3H, ArH), 7.55
4.3. Synthesis of arylamino or cycloamino N,S-acetals (20, 21)
(d, J¼7.5 Hz, 2H, ArH), 5.27 (s, 2H, CH2), 2.42 (s, 3H, SCH3). 13C NMR
(75 MHz, CDCl3):
d
193.4, 190.2, 188.6, 170.5, 140.7, 140.2, 136.0,
A solution of respective amines (1 mmol) in dry ethanol (4 mL)
was added to a stirred solution of 5 (0.250 g, 1 mmol) in dry ethanol
(5 mL) at room temperature. Reaction mixture was refluxed for 2 h
(monitored by TLC). The resulting arylamino-/cycloamino N,S-ace-
tals were purified by crystallization in ethanol or by column chro-
matography over silica gel using hexane/ethyl acetate as eluent to
give pure 20 and 21.
134.6, 134.3, 133.8, 128.9, 128.2, 124.9, 122.9, 122.5, 40.6, 14.3.
Anhydrous ammonium acetate (0.115 g, 1.5 mmol) was added to
a solution of adduct 16aec in glacial acetic acid (10 mL) and the
reaction mixture was refluxed for 6 h (monitored by TLC). It was
then cooled, poured into ice cold water and extracted with ethyl
acetate (3ꢁ30 mL). The combined organic extract was washed with
water (3ꢁ30 mL) and dried over anhydrous Na2SO4. Solvent was
removed under reduced pressure to give the crude product, which
was purified by column chromatography over silica gel using hex-
ane/ethyl acetate (10:1) as eluent to afford the yellow solid 17.
4.3.1. 2-[(4-Methoxyphenylamino)methylthio-methylene]-1,3-in-
danedione (20a). Yellow crystals, mp 137e138 ꢀC (reported mp
138e140 ꢀC);10a yield 0.292 g, 90%; Rf¼0.49 (hexane/EtOAc, 80:20);
IR (KBr): 3448, 3043, 1634, 1547, 1398, 1334 cmꢂ1
;
1H NMR
4.2.12. 4-Methylthio-2-phenyl-indeno[1,2-b] pyridine-5-one (17a). Yel-
low solid, mp 174e176 ꢀC; yield 0.106 g, 70%; Rf¼0.65 (hexane/EtOAc,
(300 MHz, CDCl3):
(d, J¼8.7 Hz, 2H, ArH), 6.94 (d, J¼8.7 Hz, 2H, ArH), 3.84 (s, 3H,
OCH3), 2.32 (s, 3H, SCH3). 13C NMR (75 MHz, CDCl3):
169.4, 158.7,
d 12.23 (s, 1H, NH), 7.72e7.57 (m, 4H, ArH), 7.24
80:20); IR (KBr): 3062, 2919, 1699, 1606, 1561 cmꢂ1
;
1H NMR
d
(300 MHz, CDCl3):
7.71 (d, J¼7.2 Hz, 1H, ArH), 7.61e7.41 (m, 5H, ArH), 7.37 (s, 1H, ArH),
2.62 (s, 3H, SCH3). 13C NMR (75 MHz, CDCl3):
191.5, 165.4, 160.8, 151.1,
d
8.11e8.09 (m, 2H, ArH), 7.93 (d, J¼7.5 Hz, 1H, ArH),
148.3, 133.1, 130.3, 128.0, 126.4, 121.4, 117.4, 114.5, 105.5, 55.5, 18.0.
ESIMS (m/z, %): 326 (Mþþ1, 100). Anal. Calcd for C18H15NO3S: C,
66.44%; H, 4.65%; N, 4.30%. Found: C, 66.59%; H, 4.39%; N, 4.52%.
d
142.6, 138.5, 134.5, 130.9, 130.0, 128.8, 127.4, 123.4, 122.1, 121.1, 113.9,
13.1. ESIMS (m/z, %): 304 (Mþþ1, 100). Anal. Calcd for C19H13NOS: C,
75.22%; H, 4.32%; N, 4.62%. Found: C, 75.10%; H, 4.15%; N, 4.79%.
4.3.2. 2-[(3,4-Dimethoxyphenylamino)methylthio-methylene]-1,3-
indanedione (20b). Yellow crystals, mp 137 ꢀC; yield 0.337 g, 95%;
Rf¼0.32 (hexane/EtOAc, 80:20); IR (KBr): 3448, 3029, 2923, 1637,
4.2.13. 2-(4-Methoxyphenyl)-4-methylthio-indeno [1,2-b]pyridine-5-
1592, 1498, 1341 cmꢂ1 1H NMR (300 MHz, CDCl3):
; d 12.26 (s, 1H,
one (17b). Yellow solid, mp 193e196 ꢀC; yield 0.108 g, 65%; Rf¼0.63
NH), 7.74e7.73 (m, 2H, ArH), 7.78e7.76 (m, 2H, ArH), 6.90e6.85 (m,
(hexane/EtOAc, 80:20); IR (KBr): 2921, 1697, 1547, 1459 cmꢂ1
;
1H
3H, ArH), 3.92 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 2.35 (s, 3H, SCH3).
NMR (300 MHz, CDCl3):
d
8.09 (d, J¼8.7 Hz, 2H, ArH), 7.91 (d,
13C NMR (75 MHz, CDCl3):
d 169.4, 149.3, 148.3, 133.1, 130.4, 128.0,
J¼7.5 Hz,1H, ArH), 7.69 (d, J¼7.5 Hz,1H, ArH), 7.55 (dd, J¼8.1, 7.8 Hz,
1H, ArH), 7.42 (dd, J¼8.1, 7.8 Hz, 1H, ArH), 7.30 (s, 1H, ArH), 7.03 (d,
J¼8.7 Hz, 2H, ArH), 3.90 (s, 3H, OCH3), 2.61 (s, 3H, SCH3). 13C NMR
127.7, 127.4, 121.4, 117.4, 111.0, 108.5, 105.6, 56.1, 56.0, 18.0. ESIMS
(m/z, %): 356 (Mþþ1, 100). Anal. Calcd for C19H17NO4S: C, 64.21%; H,
4.82%; N, 3.94%. Found: C, 64.43%; H, 3.59%; N, 3.76%.
(75 MHz, CD3COCD3þDMSO-d6):
d 191.8, 164.9, 161.6, 159.8, 151.5,
142.3, 138.3, 135.1, 131.18, 130.4, 129.2, 122.9, 120.8, 114.1, 113.1, 55.0,
12.2. ESIMS (m/z, %): 334 (Mþþ1, 100). Anal. Calcd for C20H15NO2S:
C, 72.05%; H, 4.53%; N, 4.20%. Found: C, 72.10%; H, 4.35%; N, 4.09%.
4.3.3. 2-(Methylthio-phenylamino-methylene)-1,3-indanedione
(20c). Yellow
149e152 ꢀC);10a Yield 0.265 g, 90%; IR (KBr): 3459, 3038, 2945,
1619, 1587, 1479, 1332 cmꢂ1; 1H NMR (300 MHz, CDCl3):
12.31 (s,
1H, NH), 7.73e7.72 (m, 2H, ArH), 7.61e7.58 (m, 2H, ArH), 7.44e7.33
(m, 5H, ArH), 2.29 (s, 3H, SCH3). 13C NMR (75 MHz, CDCl3):
172.5,
crystals,
mp
147e149 ꢀC
(reported
mp
d
4.2.14. 4-Methylthio-2-pyridin-2-yl-indeno[1,2-b]
pyridine-5-one
(17c). Yellow solid, mp 219e221 ꢀC; yield 0.094 g, 62%; Rf¼0.55
d
(hexane/EtOAc, 80:20); IR (KBr): 2927, 2850, 1694, 1668, 1531,
169.0, 162.9, 161.6, 137.7, 137.1, 133.4, 133.2, 129.4, 127.2, 124.8, 121.5,
1421 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
8.70 (d, J¼4.2 Hz,1H, ArH),
106.1, 105.7, 101.1, 18.0. ESIMS (m/z, %): 296 (Mþþ1, 100). Anal. Calcd

7396
R.K. Verma et al. / Tetrahedron 66 (2010) 7389e7398
for C17H13NO2S: C, 69.13%; H, 4.44%; N, 4.74%. Found: C, 69.36%; H,
4.58%; N, 4.53%.
132.3, 130.9, 126.0, 120.6, 114.4, 92.6, 55.4. ESIMS (m/z, %): 292
(Mþþ1, 100). Anal. Calcd for C17H13N3O2: C, 70.09%; H, 4.50%; N,
14.42%. Found: C, 70.24%; H, 4.69%; N, 14.64%.
4.3.4. 2-[(4-Methylbenzylamino)methylthio-methylene]-1,3-in-
danedione (20d). Yellow crystals, mp 148e149 ꢀC; yield 0.292 g,
4.3.10. 3-(3,4-Dimethoxyphenylamino)-1H-indeno [1,2-c]pyrazol-4-
one (22b). Yellow solid, mp 167e169 ꢀC; yield 0.112 g, 70%; Rf¼0.53
(DCM); IR (KBr): 3448, 2933, 1627, 1585, 1511, 1233 cmꢂ1; 1H NMR
85%; IR (KBr): 3435, 2925, 2857, 1686, 1631, 1547, 1415 cmꢂ1 1H
;
NMR (300 MHz, CDCl3): d 10.93 (s, 1H, NH), 7.68e7.65 (m, 2H, ArH),
7.56e7.53 (m, 2H, ArH), 7.25e7.19 (m, 4H, ArH), 4.81 (d, J¼5.7 Hz,
(300 MHz, CDCl3):
d 11.83 (s, 1H, NH), 10.48 (s, 1H, NH), 7.62e7.51
2H, NCH2), 2.73 (s, 3H, SCH3), 2.34 (s, 3H, CH3). 13C NMR (75 MHz,
(m, 4H, ArH), 6.77e6.75 (m, 3H, ArH), 3.89 (s, 3H, OCH3), 3.84 (s, 3H,
CDCl3):
d
171.4, 139.0, 137.9, 132.8, 132.9, 129.7, 127.3, 121.2, 103.8,
OCH3). 13C NMR (75 MHz, CDCl3):
d 190.1, 148.44, 138.3, 132.2, 119.9,
48.8, 21.1, 18.8. ESIMS (m/z, %): 324 (Mþþ1, 100). Anal. Calcd for
C19H17NO2S: C, 70.56%; H, 5.30%; N, 4.33%. Found: C, 70.79%; H,
5.49%; N, 4.59%.
116.1, 111.2, 108.1, 55.6, 55.4. ESIMS (m/z, %): 322 (Mþþ1, 100). Anal.
Calcd for C18H15N3O3: C, 67.28%; H, 4.71%; N, 13.08%. Found: C,
67.12%; H, 4.99%; N, 12.94%.
4.3.5. 2-[(3-Methoxyphenylamino)methylthio-methylene]-1,3-in-
danedione (20e). Yellow crystals, mp 134e136 ꢀC; yield 0.276 g,
85%; Rf¼0.33 (hexane/EtOAc, 80:20); IR (KBr): 3449, 2925, 1639,
4.3.11. 3-Piperidin-1-yl-1H-indeno[1,2-c]pyrazol-4-one (23a). Yel-
low solid, mp 246 ꢀC; yield 0.076 g, 60%; Rf¼0.21 (hexane/EtOAc,
80:20); IR (KBr): 3457, 2927, 1688, 1583, 1477, 1243 cmꢂ1; 1H NMR
1536, 1397, 1326 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
12.27 (s, 1H,
(300 MHz, CDCl3):
1H, ArH), 7.41e7.36 (m, 2H, ArH), 3.58e3.56 (m, 4H, NCH2),
1.66e1.65 (m, 6H, CH2). 13C NMR (75 MHz, CDCl3):
181.1, 163.9,
d
7.60 (d, J¼6.9 Hz, 1H, ArH), 7.45 (d, J¼6.9 Hz,
NH), 7.73 (d, J¼3.0 Hz, 2H, ArH), 7.61e7.58 (m, 2H, ArH), 7.33 (dd,
J¼8.5, 7.8 Hz, 1H, ArH), 6.94 (d, J¼8.1 Hz, 2H, ArH), 6.86 (d, J¼8.4 Hz,
1H, ArH), 3.83 (s, 3H, OCH3), 2.32 (s, 3H, SCH3). 13C NMR (75 MHz,
d
148.7, 142.9, 135.2, 132.0, 129.1, 123.4, 119.5, 102.2, 49.3, 25.0, 23.6.
ESIMS (m/z, %): 354 (Mþþ1, 100). Anal. Calcd for C15H15N3O: C,
71.13%; H, 5.97%; N, 16.59%. Found: C, 71.35%; H, 5.17%; N, 13.13%.
CDCl3):
d 169.0, 160.3, 138.8, 133.2, 130.1, 121.5, 117.0, 113.0, 110.3,
106.2, 55.4, 18.0. ESIMS (m/z, %): 326 (Mþþ1, 100). Anal. Calcd for
C18H15NO3S: C, 66.44%; H, 4.65%; N, 4.30%. Found: C, 66.57%; H,
4.42%; N, 4.49%.
4.3.12. 3-(4-Phenylpiperazin-1-yl)-1H-indeno[1,2-c]pyrazol-4-one
(23b). Yellow solid, mp 257e258 ꢀC; yield 0.090 g; 55%; Rf¼0.20
(DCM/MeOH, 99:1); IR (KBr): 3421, 2934, 1699, 1562, 1452,
4.3.6. 2-(Methylthio-piperidin-1-yl-methylene)-1,3-indanedione
(21a). Yellow thick viscous oil; yield 0.229 g, 80%; Rf¼0.10 (hexane/
EtOAc, 80:20); IR (KBr): 3439, 3023, 2945, 1644, 1583, 1477,
1262 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
7.62 (d, J¼7.2 Hz, 1H, ArH),
7.50 (d, J¼7.2 Hz,1H, ArH), 7.41 (dd, J¼7.5, 7.2 Hz,1H, ArH), 7.32e7.29
1359 cmꢂ1 1H NMR (300 MHz, CDCl3):
; d 7.69e7.65 (m, 2H, ArH),
(m, 3H, ArH), 6.97 (m, 3H, ArH), 3.81 (t, J¼4.5 Hz, 4H, 2ꢁCH2), 3.34 (t,
7.51e7.46 (m, 2H, ArH), 3.86 (br s, 4H, 2ꢁNCH2), 2.50 (s, 3H, SCH3),
J¼4.8 Hz, 4H, 2ꢁCH2).13C NMR (75 MHz, CDCl3):
d 180.2,162.1,150.7,
1.76e1.64 (m, 6H, 3ꢁCH2). 13C NMR (75 MHz, CDCl3):
d
189.4, 174.1,
148.6, 142.2, 135.2, 132.5, 128.9, 122.9, 119.5, 119.4, 116.0, 102.3, 47.7,
48.4. ESIMS (m/z, %): 331 (Mþþ1, 100). Anal. Calcd for C20H18N4O: C,
72.71%; H, 5.49%; N, 16.96%. Found: C, 72.61%; H, 5.52%; N, 16.80%.
150.9, 140.6, 131.2, 129.1, 121.2, 120.9, 102.5, 18.7, 21.4, 14.5. ESIMS
(m/z, %): 288 (Mþþ1, 100). Anal. Calcd for C16H17NO2S: C, 66.87%; H,
5.96%; N, 4.87%. Found: C, 66.63%; H, 5.69%; N, 4.63%.
4.3.13. Synthesis of aminopyrimidines (24, 25). Guanidine nitrate or
benzamidine hydrochloride (0.52 mmol) was added to a stirred
suspension of K2CO3 (0.138 g, 1 mmol) in acetonitrile (10 mL). After
30 min, arylamino or cycloamino N,S-acetals 20 or 21 (0.5 mmol)
was added and reaction mixturewas refluxed for 8e10 h (monitored
by TLC). Solvent was evaporated under vacuum; residue was treated
with cold water and extracted with ethyl acetate (3ꢁ20 mL). Com-
bined organic extract was washed with water (2ꢁ20 mL), brine
(1ꢁ20 mL), and dried over anhydrous Na2SO4. The crude product
was purified by column chromatography over silica gel using
dichloromethane: methanol (99:1) as eluent to yield 24, 25.
4.3.7. 2-[Methylthio-(4-phenyl-piperazin-1-yl)-methylene]-1,3-in-
danedione (21b). Yellow crystals, mp 120e121 ꢀC; yield 0.273 g,
75%; Rf¼0.09 (hexane/EtOAc, 70:30); IR (KBr): 3448, 3029, 2923,
2853, 1637, 1592, 1498, 1408 cmꢂ1 1H NMR (300 MHz, CDCl3):
;
d
7.69e7.68 (m, 2H, ArH), 7.56e7.55 (m, 2H, ArH), 7.31e7.29 (m, 2H,
ArH), 6.92e6.89 (m, 3H, ArH), 4.08 (t, J¼4.2 Hz, 4H, 2ꢁNCH2), 3.41 (t,
J¼4.5 Hz, 4H, 2ꢁCH2), 2.54 (s, 3H, SCH3). 13C NMR (75 MHz, CDCl3):
d
188.1,177.2,149.9,139.5,132.4,129.3,120.9,120.7,116.3,103.5, 49.2,
18.7. ESIMS (m/z, %): 365 (Mþþ1, 100). Anal. Calcd for C21H20N2O2S:
C, 69.20%; H, 5.53%; N, 7.69%. Found: C, 69.42%; H, 5.63%; N, 7.36%.
4.3.8. Synthesis of aminopyrazoles (22, 23). To a stirred solution of
N,S-acetals 20 or 21 (0.5 mmol) in absolute ethanol (6 mL), a solu-
tion of hydrazine hydrate (0.073 mL, 0.5 mmol) in absolute ethanol
(2 mL) was added drop-wise. Resulting solution was refluxed for
6e10 h with continuous stirring. After the completion of the re-
action (monitored by TLC), solvent was evaporated under vacuum
and the residue obtained was dissolved in DCM (20 mL). Organic
layer was washed with water (4ꢁ30 mL) and brine (1ꢁ30 mL) fol-
lowed by drying over anhydrous Na2SO4. The solvent was evapo-
rated under vacuum to give the crude product, which was purified
by column chromatography over silica gel.
4.3.14. Synthesis of 2-amino-4-(4-methoxyphenyl-amino)-indeno
[1,2-d]pyrimidin-5-one (24a). Yellow solid, mp 221e222 ꢀC; yield
0.119 g, 75%; Rf¼0.45 (DCM/MeOH, 99:2); IR (KBr): 3478, 3351,
3199, 2929, 2927, 1673, 1629, 1561 cmꢂ1 1H NMR (300 MHz,
;
CDCl3):
2H, ArH), 5.51 (s, 2H, NH2), 3.82 (s, 3H, OCH3). 13C NMR (75 MHz,
CDCl3): 188.3, 174.1, 165.5, 156.6, 155.6, 136.3, 132.2, 131.2, 130.4,
d
8.48 (s, 1H, NH), 7.70e7.48 (m, 6H, ArH), 6.90 (d, J¼9.0 Hz,
d
122.4, 121.8, 121.7, 120.2, 113.4, 98.3, 54.8. ESIMS (m/z, %): 319
(Mþþ1, 100). Anal. Calcd for C18H14N4O2: C, 67.91%; H, 4.43%; N,
17.60%. Found: C, 67.71%; H, 4.28%; N, 17.81%.
4.3.15. 2-Amino-4-(3,4-dimethoxyphenylamino)-indeno[1,2-d]pyr-
imidin-5-one (24b). Dark red solid, mp 248e250 ꢀC; yield 0.130 g,
75%; Rf¼0.24 (DCM/MeOH, 99:2); IR (KBr): 3475, 3356, 3201, 2931,
4.3.9. 3-(4-Methoxyphenylamino)-1H-indeno[1,2-c] pyrazol-4-one
(22a). Yellow solid, mp 173e175 ꢀC; yield 0.099 g, 68%; Rf¼0.61
(DCM); IR (KBr): 3327, 3219, 3061, 2959, 1624, 1589, 1510, 1435,
2931, 1678, 1634, 1569, 1069 cmꢂ1 1H NMR (300 MHz, DMSO-d6):
;
1296, 1236, 1033 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
10.49 (s, 1H,
d 8.54 (s, 1H, ArH), 7.79 (s, 2H, NH2), 7.67e7.60 (m, 4H, ArH), 7.49 (s,
NH), 9.85 (s, 1H, NH), 7.61e7.58 (m, 2H, ArH), 7.51e7.48 (m, 2H,
ArH), 7.18 (d, J¼8.7 Hz, 2H, ArH), 6.91 (d, J¼8.7 Hz, 2H, ArH), 3.82 (s,
1H, NH), 7.24 (d, J¼8.1 Hz, 1H, ArH), 6.89 (d, J¼8.4 Hz, 1H, ArH), 3.80
(s, 3H, OCH3), 3.74 (s, 3H, OCH3). 13C NMR (75 MHz, DMSO-d6):
3H, OCH3). 13C NMR (75 MHz, CDCl3):
d
192.1, 159.9, 158.1, 138.8,
d 188.1, 174.5, 165.8, 156.7, 148.6, 139.6, 136.6, 133.2, 132.2, 131.6,

R.K. Verma et al. / Tetrahedron 66 (2010) 7389e7398
7397
122.1, 120.7, 113.2, 111.9, 106.6, 55.7, 55.6. ESIMS (m/z, %): 349
(Mþþ1, 100). Anal. Calcd for C19H16N4O3: C, 65.51%; H, 4.63%; N,
16.08%. Found: C, 65.63%; H, 4.79%; N, 15.91%.
(m, 3H, ArH), 7.18 (dd, J¼7.5, 7.2 Hz, 2H, ArH), 6.95 (d, J¼7.8 Hz, 2H,
ArH), 6.78e6.73 (m, 1H, ArH), 3.71 (t, J¼4.2 Hz, 4H, 2ꢁCH2), 3.30 (t,
J¼4.2 Hz, 4H, 2ꢁCH2). 13C NMR (75 MHz, DMSO-d6):
d 185.4, 163.7,
162.5, 158.6, 150.6, 134.4, 134.1, 133.6, 133.3, 129.0, 122.7, 122.1,
119.3, 118.1, 115.7, 103.8, 51.4, 49.0. ESIMS (m/z, %): 383(Mþþ1, 100).
Anal. Calcd for C23H18N4O2: C, 72.24%; H, 4.74%; N,14.65%. Found: C,
72.01%; H, 4.52%; N, 14.80%.
4.3.16. 2-Amino-4-phenylamino-indeno[1,2-d] pyrimidin-5-one
(24c). Yellow crystal, mp 214e215 ꢀC; yield 0.112 g, 78%;
Rf¼0.49 (DCM/MeOH, 99:1); IR (KBr): 3473, 3297, 3135, 2925,
1690, 1623, 1572, 1436, 1024 cmꢂ1 1H NMR (300 MHz, CDCl3):
;
d
8.62 (s, 1H, NH), 7.71e7.66 (m, 4H, ArH), 7.55e7.47 (m, 2H,
ArH), 7.39e7.36 (m, 2H, ArH), 7.15e7.10 (m, 1H, ArH), 5.59 (s,
2H, NH2). 13C NMR (75 MHz, CDCl3):
188.3, 174.8, 165.9, 156.8,
4.3.21. Synthesis of indenoquinolines (27a,b). A mixture of aryl-
amino N,S-acetal 20e or 20b (0.5 mmol) and PPA (5 g) was heated at
90 ꢀC for 5-6 h (monitored by TLC). The reaction mixture was cooled,
neutralized with saturated NaHCO3 solution and extracted with DCM
(3ꢁ20 mL). The organic layer was washed with water (2ꢁ20 mL),
brine (1ꢁ20 mL), and dried over anhydrous Na2SO4. The crude prod-
uct was purified by crystallization from ethanol to give 27a and 27b.
d
148.6, 139.6, 138.4, 136.6, 133.2, 132.2, 128.7, 123.3, 122.2, 120.9,
120.7, 98.2. ESIMS (m/z, %): 389 (Mþþ1, 100). Anal. Calcd for
C17H12N4O: C, 70.82%; H, 4.20%; N, 19.43%. Found: C, 70.65%; H,
4.01%; N, 19.29%.
4.3.17. 4-(3,4-Dimethoxyphenylamino)-2-phenyl-indeno[1,2-d]pyr-
imidin-5-one (24d). Violet solid, mp 186e187 ꢀC; yield 0.103 g;
50%; Rf¼0.32 (hexane/EtOAc, 80:20); IR (KBr): 2911, 2863, 1699,
4.3.22. 3-Methoxy-6-methylthio-indeno[2,1-c] quinolin-7-one (27a). Or-
ange solid, mp 210e211 ꢀC; yield 0.130 g, 85%; Rf¼0.36 (hexane/
EtOAc, 80:20); IR (KBr): 2915, 2865, 1687, 1625, 1557, 1084 cmꢂ1; 1H
1621, 1549 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
8.59e8.57 (m, 3H,
NMR (300 MHz, CDCl3):
d
8.31 (d, J¼9.3 Hz, 1H, ArH), 8.05 (d,
ArH), 7.94 (d, J¼6.9 Hz, 1H, ArH), 7.73e7.50 (m, 7H, ArH), 6.92 (d,
J¼8.1 Hz, 1H, ArH), 7.74 (d, J¼6.9 Hz, 1H, ArH), 7.69 (d, J¼8.4 Hz, 1H,
ArH), 7.48e7.46 (m, 1H, ArH), 7.34e7.26 (m, 2H, ArH), 7.22e7.18 (m,
1H, ArH), 4.01 (s, 3H, OCH3), 2.73 (s, 3H, SCH3). 13C NMR (75 MHz,
J¼8.7 Hz, 1H, ArH), 3.98 (s, 3H, OCH3), 3.93 (s, 3H, OCH3). 13C NMR
(75 MHz, CDCl3):
d 192.5, 173.7, 169.0, 155.4, 148.9, 145.8, 141.3,
137.5,135.3,134.0,132.0,131.7,131.4,130.8,129.2,128.8,128.3,123.1,
121.7, 112.8, 111.3, 105.8, 104.4, 55.1, 55.9. ESIMS (m/z, %): 410
(Mþþ1, 100). Anal. Calcd for C25H19N3O3: C, 73.34%; H, 4.68%; N,
10.26%. Found: C, 73.47%; H, 4.51%; N, 9.97%.
CDCl3): d 192.0, 163.2, 154.4, 151.3, 149.8, 141.4, 134.3, 133.8, 130.8,
124.4, 123.9, 119.7, 116.2, 107.6, 56.6, 11.8. ESIMS (m/z, %): 308
(Mþþ1, 100). Anal. Calcd for C18H13NO2S: C, 70.34%; H, 4.26%; N,
4.56%. Found: C, 70.19%; H, 4.41%; N, 4.39%.
4.3.18. 2-Amino-4-(4-methylbenzylamino)indeno [1,2-d]pyrimidin-
5-one (24e). Yellow solid, mp 238e239 ꢀC; yield 0.094 g, 60%;
Rf¼0.64 (DCM/MeOH, 99:2); IR (KBr): 3467, 3347, 3303, 3185, 2915,
2925, 2856, 1674, 1635, 1451, 1069 cmꢂ1; 1H NMR (300 MHz, DMSO-
4.3.23. 2,3-Dimethoxy-6-methylthio-indeno[2,1-c]
quinolin-7-one
(27b). Orange solid, mp 239e240 ꢀC; yield 0.135 g, 80%; Rf¼0.23
(hexane/EtOAc, 80:20); IR (KBr): 2921, 2851, 1697, 1619, 1561,
1080 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
7.94 (dd, J¼7.5 Hz, 1H,
d6):
d
7.60e7.54 (m, 7H, ArH, NH2, NH), 7.24 (d, J¼7.8 Hz, 2H, ArH), 7.12
ArH), 7.74 (d, J¼7.2 Hz, 1H, ArH), 7.59 (d, J¼7.2 Hz, 1H, ArH), 7.54 (s,
1H, ArH), 7.45 (dd, J¼7.2 Hz, 1H, ArH), 7.34 (s, 1H, ArH), 4.11 (s, 3H,
OCH3), 4.09 (s, 3H, OCH3), 2.72 (s, 3H, SCH3). 13C NMR (75 MHz,
(d, J¼7.8 Hz, 2H, ArH), 4.62 (d, J¼6.0 Hz, 2H, CH2), 2.26 (s, 3H, CH3).13
C
NMR (75 MHz, DMSO-d6):
d 188.2, 174.7, 165.9, 158.36, 139.6, 136.7,
136.4, 135.8, 132.8, 131.9, 128.8, 127.4, 121.9, 120.5, 97.7, 42.2, 20.69.
ESIMS (m/z, %): 317 (Mþþ1,100). Anal. Calcd for C19H16N4O: C, 72.13%;
H, 5.10%; N, 17.71%. Found: C, 72.27%; H, 5.01%; N, 17.97%.
CDCl3): d 192.2, 163.2, 154.91, 150.4, 149.8, 141.6, 134.5, 133.7, 130.5,
123.9, 123.8, 116.2, 108.1, 102.1, 56.2, 56.0, 11.8. ESIMS (m/z, %): 338
(Mþþ1, 100). Anal. Calcd for C19H15NO3S: C, 67.64%; H, 4.48%; N,
4.15%. Found: C, 67.77%; H, 4.55%; N, 4.02%.
4.3.19. 2-Amino-4-(4-phenylpiperazin-1-yl)-indeno[1,2-d]pyrimidin-
5-one (25). Yellow solid, mp 180e182 ꢀC; yield 0.133 g, 75%;
Rf¼0.56 (DCM/MeOH, 99:5); IR (KBr): 3291, 3178, 2921, 2850, 1680,
4.3.24. Synthesis of 6-methanesulfonyl derivative of indenoquinolines
(28). To a stirred solution of indenoquinoline 27 (0.5 mmol) in dry
DCM (10 mL) was added a solution of m-CPBA (0.258 g, 1.5 mmol)
in dry DCM (5 mL) at 0 ꢀC. The reaction mixture was stirred at room
temperature for 4 h (monitored by TLC). The reaction was hydro-
lyzed by adding 5% sodium thiosulfate solution (15 mL). The or-
ganic layer was washed with NaHCO3 solution (2ꢁ20 mL), brine
(1ꢁ20 mL), and dried over anhydrous Na2SO4. The solvent was
evaporated under vacuum to give crude product, which was puri-
fied by recrystallization from ethanol.
1628, 1524, 1081 cmꢂ1 1H NMR (300 MHz, CDCl3):
; d 7.70 (d,
J¼6.3 Hz, 1H, ArH), 7.63 (d, J¼6.0 Hz, 1H, ArH), 7.49 (dd, J¼5.7,
5.4 Hz, 2H, ArH), 7.31e7.28 (m, 1H, ArH), 6.96 (d, J¼8.1 Hz, 2H, ArH),
6.91e6.89 (m, 2H, ArH), 5.33 (s, 2H, NH2), 4.20 (t, J¼4.8 Hz, 4H,
2ꢁCH2), 3.31 (t, J¼4.8 Hz, 4H, 2ꢁCH2). 13C NMR (75 MHz, CDCl3):
d
188.2, 178.1, 164.1, 159.3, 151.0, 139.6, 136.2, 132.9, 132.0, 129.2,
122.5, 120.5, 120.1, 116.3, 100.8, 49.6, 48.1. ESIMS (m/z, %): 358
(Mþþ1, 100). Anal. Calcd for C21H19N5O: C, 70.57%; H, 5.36%; N,
19.59%. Found: C, 70.69%; H, 5.11%; N, 19.41%.
4.3.25. 6-Methanesulfonyl-3-methoxy-indeno[2,1-c] quinolin-7-one
(28a). Yellow solid, mp 223e225 ꢀC (decompose); yield 0.159 g, 94%;
IR (KBr): 2910, 2869,1687,1598,1557,1313 cmꢂ1; 1H NMR (300 MHz,
4.3.20. Synthesis of 2,5-dioxo-4-(4-phenyl-piperazin-1-yl)-2,5-dihy-
dro-1H-indeno[1,2-b] pyridine-3-carbonitrile (26). To a stirred sus-
pension of ButOK (0.168 g, 1.5 mmol) in ButOH (10 mL) at room
temperature, cyanoacetamide (0.067 g, 0.5 mmol) was added. After
10 min, N,S-acetal 21b (0.182 g, 0.5 mmol) was added and the re-
action mixture was refluxed for 12 h. After the completion of the
reaction (monitored by TLC), the solvent was evaporated under
reduced pressure to give the salt of pyridine 26, which was dis-
solved in water (10 mL) followed by acidification with dilute HCl
(5 mL, 5%). The solid obtained was filtered, washed with water, and
recrystallized from ethanol to give the desired compound 26 as
yellow solid, mp >300 ꢀC (decompose). Yield 0.095 g, 50%; IR (KBr):
3451, 2923, 2849, 2343, 1629, 1542, 1431 cmꢂ1; 1H NMR (300 MHz,
CDCl3):
J¼7.2 Hz,1H, ArH), 7.68e7.45 (m, 4H, ArH), 4.03 (s, 3H, OCH3), 3.54 (s,
3H, SO2CH3). 13C NMR (75 MHz, CDCl3):
188.6, 163.9, 152.2, 151.4,
d
8.49(d, J¼9.3 Hz,1H, ArH), 8.13(d, J¼7.5 Hz,1H, ArH), 7.82 (d,
d
140.9, 134.7, 132.0, 125.9, 125.0, 124.7, 124.1, 119.7, 113.9, 109.5, 56.0,
40.5. ESIMS (m/z, %): 340 (Mþþ1, 100). Anal. Calcd for C18H13NO4S: C,
63.71%; H, 3.86%; N, 4.13%. Found: C, 63.59%; H, 3.61%; N, 4.29%.
4.3.26. 6-Methanesulfonyl-2,3-dimethoxy-indeno [2,1-c]quinolin-7-
one (28b). Yellow solid, mp 320 ꢀC (decompose); yield 0.173 g, 94%;
IR (KBr): 2910, 2845, 1692, 1601, 1542, 1325 cmꢂ1
;
1H NMR
(300 MHz, CDCl3):
1H, ArH), 7.66 (s, 1H, ArH), 7.58 (s, 1H, ArH), 7.54e7.50 (m, 2H, ArH),
d
8.00 (d, J¼7.5 Hz, 1H, ArH), 7.79 (d, J¼7.2 Hz,
DMSO-d6):
d
13.31 (s, 1H, OH), 7.91 (d, J¼6.6 Hz, 1H, ArH), 7.54e7.44

7398
R.K. Verma et al. / Tetrahedron 66 (2010) 7389e7398
4.18 (s, 3H, OCH3), 4.10 (s, 3H, OCH3), 3.53 (s, 3H, SO2CH3). 13C NMR
(75 MHz, CDCl3): 188.7, 164.0, 152.1, 150.7, 140.8, 134.5, 132.1,
Supplementary data
d
125.9, 125.1, 124.7, 124.2, 119.9, 113.4, 109.7, 56.1, 56.0, 40.4. ESIMS
(m/z, %): 370 (Mþþ1, 100). Anal. Calcd for C19H15NO5S: C, 61.78%; H,
4.09%; N, 3.79%. Found: C, 61.56%; H, 4.21%; N, 3.91%.
Supplementary data associated with this article can be found
online version at doi:10.1016/j.tet.2010.07.031.
References and notes
4.3.27. Synthesis of amino substituted indenoquinolines (29). A
mixture of 6-(methylsulfonyl)quinolines 28 (0.5 mmol) and the
corresponding aliphatic/sec amine (2.0 mmol) was heated at
140e150 ꢀC in a sealed tube for 3e4 h with constant stirring. After
the completion of the reaction (monitored by TLC), reaction mixture
was then cooled, diluted with DCM (20 mL), and washed with water
(2ꢁ25 mL) followed bybrine (2ꢁ25 mL). Theorganic layer was dried
over anhydrous Na2SO4 and the solvent was evaporated under re-
duced pressure to afford the crude products 29, which were purified
by column chromatography over silica gel using DCM as eluent.
1. (a) Nugiel, D. A.; Vidwans, A.; Etzkorn, A. M.; Rossi, K. A.; Benfield, P. A.; Burton, C.
R.; Cox, S.; Doleniak, D.; Seitz, S. P. J. Med. Chem. 2002, 45, 5224e5232; (b) Yue, E.
W.; Higley, C. A.; DiMeo, S. V.; Carini, D. J.; Nugiel, D. A.; Benware, C.; Benfield, P. A.;
Burton, C. R.; Cox, S.; Grafstrom, R. H.; Sharp, D. M.; Sisk, L. M.; Boylan, J. F.;
Muckelbauer, J. K.; Smallwood, A. M.; Chen, H.; Chang, C.-H.; Seitz, S. P.; Trainor, G.
L. J. Med. Chem. 2002, 45, 5233e5248; (c) Nugiel, D. A.; Etzkorn, A.-M.; Vidwans,
A.; Benfield, P. A.; Boisclair, M.; Burton, C. R.; Cox, S.; Czerniak, P. M.; Doleniak, D.;
Seitz, S. P. J. Med. Chem. 2001, 44, 1334e1336; (d) Usui, T.; Ban, H. S.; Kawada, J.;
Hirokawa, T.; Nakamura, H. Bioorg. Med. Chem. Lett. 2008,18, 285e288; (e) Yue, E.
W.; DiMeo, S. V.; Higley, C. A.; Markwalder, J. A.; Burton, C. R.; Benfield, P. A.; Graf-
strom, R. H.; Cox, S.; Muckelbauer, J. K.; Smallwood, A. M.; Chen, H.; Cheng, C.-H.;
Trainor, G. L.; Seitz, S. P. Biorg. Med. Chem. Lett. 2004, 14, 343e346.
2. Tao, Z.-F.; Li, G.; Tong, Y.; Stewart, K. D.; Chen, Z.; Bui, M.-H.; Merta, P.; Park, C.;
Kover, P.; Zhang, H.; Sham, H. L.; Rosenberg, S. H.; Sowin, T. J.; Lin, N.-H. Bioorg.
Med. Chem. Lett. 2007, 17, 5944e5951.
3. Tao, Z.-F.; Sowin, T. J.; Lin, N.-H. Tetrahedron Lett. 2005, 46, 7615e7618 and
references there.
4.3.28. 2,3-Dimethoxy-6-(4-phenyl-piperidin-1-yl)-benzo[c]fluoren-
7-one (29a). Deep red solid; yield 0.142 g, 63%; Rf¼0.51 (DCM); IR
(KBr): 3010, 2945, 1699, 1623, 1541, 1342 cmꢂ1; 1H NMR (300 MHz,
CDCl3):
d
7.95 (d, J¼7.2 Hz, 1H, ArH), 7.71e6.94 (m, 2H, ArH), 7.54 (s,
4. (a) Flores, M.C.; Loev, B. U.S. Patent 2,989,538, 1961; (b) Loev, B.; Mosher, Wm.
A. U.S. Patent 2,969,374, 1961.
5. (a) Ryckebusch, A.; Garcin, D.; Lansiaux, A.; Goossens, J.-F.; Baldeyrou, B.;
Houssin, R.; Bailly, C.; Henichart, J.-P. J. Med. Chem. 2008, 51, 3617e3629 and
references there; (b) Tseng, C.-H.; Chen, Y.-L.; Lu, P.-J.; Yang, C.-N.; Tzeng, C.-C.
Bioorg. Med. Chem. 2008, 16, 3153e3162 and references there.
6. Carotti, A.; Catto, M.; Leonetti, F.; Campagna, F.; Soto-Otero, R.; Mendez-Al-
varez, E.; Thull, U.; Tesla, B.; Altomare, C. J. Med. Chem. 2007, 50, 5364e5371.
7. (a) Fossa, P.; Menozzi, G.; Dorigo, P.; Floreani, M.; Mosti, L. Bioorg. Med. Chem.
2003, 11, 4749e4759; (b) Matasi, J. J.; Caldwell, J. P.; Hao, J.; Neustadt, B.; Arik, L.;
Foster, C. J.; Lachowicz, J.; Tuishian, D. B. Bioorg. Med. Chem. Lett. 2005, 15,
1333e1336.
1H, ArH), 7.46e7.41 (m, 1H, ArH), 7.17 (s, 1H, ArH), 7.03 (d, J¼8.4 Hz,
2H, ArH), 6.90e6.87 (m, 2H, ArH), 4.08 (s, 3H, OCH3), 4.06 (s, 3H,
OCH3), 3.81 (t, J¼4.8 Hz, 4H, 2ꢁNCH2), 3.46 (t, J¼4.6 Hz, 4H,
2ꢁNCH2). 13C NMR (75 MHz, CDCl3):
d 187.5, 170.2, 155.7, 149.5,
147.3, 143.6, 139.7, 133.2, 131.9, 129.6, 128.2, 126.7, 119.1, 117.3, 113.5,
109.3, 57.3, 56.4, 56.3, 53.2. ESIMS (m/z, %): 452 (Mþþ1, 100). Anal.
Calcd for C28H25N3O3: C, 74.48%; H, 5.58%; N, 9.31%. Found: C,
74.51%; H, 5.39%; N, 9.09%.
8. (a) Kawano, T.; Inai, H.; Miyawaki, K.; Ueda, I. Tetrahedron Lett. 2005, 46,
1233e1236; (b) Ewen, J. A. J. Am. Chem. Soc. 2001, 123, 4763e4773.
9. (a) Review: Ila, H.; Jujappa, H.; Mohanta, P. K. In Progress in Heterocyclic
Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.; Pergamon: Oxford, 2001; Chapter
1, pp 1e24 (b) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron 1990, 46,
5423e5506; Recent Papers; (c) Kumar, S.; Ila, H.; Junjappa, H. Tetrahedron 2007,
63, 10067e10076 and references there; (d) Mishra, N. C.; Panda, K.; Ila, H.;
Junjappa, H. J. Org. Chem. 2007, 72, 1246e1251 and references there; (e) Yadav,
A. K.; Yadav, S. K. S.; Siddiqui, I.; Peruncheralathan, S.; Ila, H.; Junjappa, H.
Synlett 2008, 2674e2680; (f) Singh, P. P.; Yadav, A. K.; Ila, H.; Junjappa, H. J. Org.
Chem. 2009, 74, 5496e5501.
10. (a) Augustin, M.; Grath, C.; Kristen, H.; Peseke, K.; Wiechmann, C. J. Prakt. Chem.
1979, 321, 205e214; (b) Mashraqui, S. H.; Hariharasubramaniam, H. J. Chem. Res.
Synop. 1999, 492e493.
11. Tominaga, Y.; Fujito, H.; Norisue, H.; Ushirogochi, A.; Matsuda, Y.; Kobayashi, G.
Yakugaku Zasshi 1980, 100, 699e705.
4.3.29. 6-Butylamino-2,3-dimethoxy benzo[c]fluoren-7-one (29b).
Deep red solid; yield 0.121 g, 67%; Rf¼0.54 (DCM); IR (KBr): 2930,
2865,1687,1612,1555,1345 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d 8.56
(s,1H, NH), 7.97 (d, J¼7.5 Hz,1H, ArH), 7.75 (d, J¼7.2 Hz,1H, ArH), 7.56
(s, 1H, ArH), 7.44e7.40 (m, 2H, ArH), 7.14 (s, 1H, ArH), 4.09 (s, 3H,
OCH3), 4.07 (s, 3H, OCH3), 3.42 (q, J¼7.08 Hz, 2H, CH2),1.52e1.59 (m,
2H, CH2), 1.29e1.38 (m, 2H, CH2), 0.86 (t, J¼7.32 Hz, 3H, CH3). 13
C
NMR (75 MHz, CDCl3): d 187.4,164.1,155.3, 148.3,146.8,143.7,139.0,
132.2,131.0,129.1,116.3,106.3, 56.4, 56.5, 49.5, 34.5, 20.0,13.6. ESIMS
(m/z, %): 363 (Mþþ1, 100). Anal. Calcd for C22H22N2O3: C, 72.91%; H,
6.12%; N, 7.73%. Found: C, 72.81%; H, 6.31%; N, 7.58%.
12. (a) Tominaga, Y.; Norisue, H.; Matsuda, Y.; Kobayashi, G. Yakugaku Zasshi 1984,
104, 127e133; (b) Tominaga, Y.; Norisue, H.; Matsuda, Y.; Kobayashi, G. Chem.
Pharm. Bull. 1984, 32, 2910e2914; (c) Tominaga, Y.; Sakai, S.; Kohra, S.; Tsuka, J.;
Matsuda, Y.; Kobayashi, G. Chem. Pharm. Bull. 1985, 33, 962e970; (d) Ried, W.;
Jacobi, M. A. Chem. Ber. 1988, 121, 805e808.
4.3.30. Synthesis of 10,11-dimethoxy-5,7,8-triaza-benzo[a]acean-
thrylen-6-ylamine (30). A mixture of 4-arylaminopyrimidine 24b
(0.174 g, 0.5 mmol) and PPA (5 g) was heated at 90 ꢀC for 5 h
(monitored by TLC). The reaction mixture was cooled, neutralized
with saturated NaHCO3 solution, and extracted using DCM
(3ꢁ20 mL). The organic layer was washed with water (2ꢁ20 mL),
brine (1ꢁ20 mL), and dried over anhydrous Na2SO4. The crude
product was purified by recrystallization from ethanol to give 30 as
dark red solid. Yield 0.115 g, 70%; IR (KBr): 3341, 3244, 2980, 2945,
13. Crystal data for 7: C17H12N2OS, yellow, M¼292.36, monoclinic, space group P
3
ꢀ
ꢀ
21/n, a¼7.2869(2), b¼19.8570(5), c¼19.5674(5) A, V¼2828.89(13) A ,
m¼0.
228 mmꢂ1, Z¼8, T¼293 K, F000¼1216.0, R¼0.0471, wR2¼0.1127. The CCDC de-
position number: CCDC 777778.
14. (a) Peruncheralathan, S.; Khan, T. A.; Ila, H.; Junjappa, H. J. Org. Chem. 2005, 70,
10030e10035; (b) Purkayastha, M. L.; Ila, H.; Junjappa, H. Synthesis 1989,
20e24.
15. (a) Bhat, L. N.; Thomas, A.; Ila, H.; Junjappa, H. Tetrahedron 1992, 48,
10377e10388; (b) Thomas, A.; Singh, G.; Ila, H.; Junjappa, H. Tetrahedron Lett.
1989, 30, 3093e3096.
16. (a) Chauhan, S. M. S.; Junjappa, H. Synthesis 1974, 880e882; (b) Chauhan, S. M.
S.; Junjappa, H. Tetrahedron 1976, 32, 1779e1787.
17. (a) Rastogi, R. R.; Kumar, A.; Ila, H.; Junjappa, H. J. Chem. Soc., Perkin Trans. 1
1978, 549e553; (b) Potts, K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G. J. Am.
Chem. Soc. 1981, 103, 3585e3586.
18. Barun, O.; Patra, P. K.; Ila, H.; Junjappa, H. Tetrahedron Lett. 1999, 40, 3797e3800.
19. (a) Chauhan, S. M. S.; Junjappa, H. Synthesis 1975, 798e801; (b) Vishwakarma,
J. N.; Chowdhury, B. K. R.; Ila, H.; Junjappa, H. Ind. J. Chem. 1985, 24B, 472e476;
(c) Peruncheralathan, S.; Yadav, A. K.; Ila, H.; Junjappa, H. J. Org. Chem. 2005, 70,
9644e9647.
1542, 1433, 1078 cmꢂ1 1H NMR (300 MHz, DMSO-d6):
; d 8.39 (d,
J¼7.5 Hz, 1H, ArH), 7.95 (d, J¼7.2 Hz, 1H, ArH), 7.67e7.54 (m, 5H,
ArHþNH2), 7.34 (s, 1H, ArH), 4.07 (s, 3H, OCH3), 4.00 (s, 3H, OCH3).
13C NMR (75 MHz, DMSO-d6):
d 169.5, 155.7, 153.9, 151.2, 148.3,
145.9, 135.3, 133.2, 129.7, 128.3, 127.8, 127.3, 125.6, 110.4, 108.4, 58.5,
58.3. ESIMS (m/z, %): 331 (Mþþ1, 100). Anal. Calcd for C19H14N4O2:
C, 69.08%; H, 4.27%; N,16.96%. Found: C, 69.23%; H, 4.42%; N,16.79%.
Acknowledgements
20. (a) Kumar, A.; Aggarawal, V.; Ila, H.; Junjappa, H. Synthesis 1980, 748e751; (b)
Vishwakarma, J.N.;Apparao, S.;Ila,H.;Junjappa, H.Ind.J. Chem.1985, 24B, 466e471.
21. Aggarwal, V.; Singh, G.; Ila, H.; Junjappa, H. Synthesis 1982, 214e216.
22. For quinoline synthesis from ketene dithioacetal and N,S-acetal, see: (a) Panda,
K.; Siddiqui, I.; Mahata, P. K.; Ila, H.; Junjappa, H. Synlett 2004, 449e452; (b)
Mahata, P. K.; Venkatesh, C.; Syam Kumar, U. K.; Ila, H.; Junjappa, H. J. Org.
Chem. 2003, 68, 3966e3975.
This work was carried out under financial support from Council
of Scientific and Industrial Research (Grant 01(2260)/08/EMR-II)
and Department of Science and Technology (Grant SR/S1/OC-66/
2009), New Delhi. R.K.V. is grateful to Council of Scientific and In-
dustrial Research (CSIR), New Delhi for senior research fellowship.