Expedient approach for the synthesis of novel indenothiophene derivatives

Article abstract of DOI:10.1007/s00706-011-0657-5

Gewald reaction of 2-(2,3-dihydro-5,6-dime-thoxy- 1H-inden-1-ylidene) malononitrile, elemental sulfur, and a catalytic amount of triethylamine furnished the new synthon 2-aminoindenothiophene-3-carbonitrile. Its reaction with conc. H₂SO₄ furnished the expected 2-amino-3-carbox-amide derivative instead of the corresponding carboxylic acid. The key intermediates 2-aminoindenothiophene-3-carboni-trile and -3-carboxamide were used for the synthesis of tetracyclic indenothienopyrimidine derivatives by cyclocondensation reaction with acid chlorides, amides, formic acid, or hydrazine hydrate. Neat reactions of the carbonitrile with cyclic and aliphatic ketones in the presence of anhydrous ZnCl₂ furnished pentacyclic and tetracyclic indenothieno-pyridine derivatives, respectively, in good yields. All new compounds were characterized by spectroscopic and analytical data.

Full text of DOI:10.1007/s00706-011-0657-5

Monatsh Chem (2012) 143:317–323
DOI 10.1007/s00706-011-0657-5
ORIGINAL PAPER
Expedient approach for the synthesis of novel indenothiophene
derivatives
•
Shivaraj P. Patil Muddassar A. Kazi
•
•
Shrikant B. Kanawade Prashant S. Nikam
•
•
Madhukar N. Jachak Raghunath B. Toche
Received: 6 May 2010 / Accepted: 7 September 2011 / Published online: 15 November 2011
Ó Springer-Verlag 2011
Abstract Gewald reaction of 2-(2,3-dihydro-5,6-dime-
thoxy-1H-inden-1-ylidene)malononitrile, elemental sulfur,
and a catalytic amount of triethylamine furnished the new
synthon 2-aminoindenothiophene-3-carbonitrile. Its reaction
with conc. H2SO4 furnished the expected 2-amino-3-carbox-
amidederivativeinsteadofthe correspondingcarboxylicacid.
The key intermediates 2-aminoindenothiophene-3-carboni-
trile and -3-carboxamide were used for the synthesis of
tetracyclic indenothienopyrimidine derivatives by cyclocon-
densation reaction with acid chlorides, amides, formic acid, or
hydrazine hydrate. Neat reactions of the carbonitrile with
cyclic and aliphatic ketones in the presence of anhydrous
ZnCl2 furnished pentacyclic and tetracyclic indenothieno-
pyridine derivatives, respectively, in good yields. All new
compounds were characterized by spectroscopic and analyt-
ical data.
biological activities. Thieno[2,3-b]pyridine and thieno[2,3-
b]pyrimidine derivatives are lead molecules in drug design
owing to their interesting biological activities displayed
over a broad range of therapeutic classes. For example
thieno[2,3-b]pyrimidines are inhibitors of cancer cell pro-
liferation [1–3], antimicrobial agents [4–6], and anti-
inflammatory agents particularly for treatment of arthritis
and as bone resorption inhibiting agents [7–9]. They are
also used as antihypertensive, vasodilator agents [10],
anxiolytics [11], and selective cytotoxic agents for p21-
deficient cells [12]. Thieno[2,3-b]pyridines are useful
antagonists [13–23]. On the other hand, indenone deriva-
tives are pharmaceutically useful compounds having a
broad range of activities [24–27]. These properties of thi-
enopyrimidines, thienopyridines, and indenones inspired us
to develop the synthesis of new fused polycyclic hetero-
cyclic molecules like indeno[2,1-b]thienopyridine and
indeno[2,1-b]thienopyrimidine derivatives by cyclocon-
denstaion of 2-aminoindenothiophene-3-carbonitrile 3 and
-3-carboxamide 4.
Keywords Indenothiophenes ꢀ Indenothienopyrimidines ꢀ
Indenothienopyridines ꢀ 2-Aminoindenothiophene-3-
carbonitrile ꢀ 2-Aminoindenothiophene-3-carboxamide ꢀ
Gewald reaction
Results and discussion
Introduction
Indenomalononitrile 2 was obtained in excellent yield by
reaction of indanone 1 and malononitrile in basic medium.
Gewald reaction [28] of compound 2 with elemental sulfur
and a catalytic amount of triethylamine gave 2-aminoinde-
nothiophene-3-carbonitrile 3 in 75% yield (Scheme 1). The
carbonitrile 3 on reaction with conc. H2SO4 [29, 30] fur-
nished the expected 3-carboxamide 4 in excellent yield
(Scheme 2). The reactive o-aminocarbonitrile group of
compound 3 can react with an electrophilic-nucleophilic
reagent to furnish new polycyclic pyridine derivatives.
Compound 4, having an o-aminocarboxamide functional
Significant attention has been given to the synthesis of
thieno[2,3-b]pyridines owing to their broad range of
S. P. Patil ꢀ M. A. Kazi ꢀ S. B. Kanawade ꢀ
P. S. Nikam ꢀ M. N. Jachak ꢀ R. B. Toche (&)
Department of Chemistry, Organic Chemistry Research Center,
K.T.H.M. College, University of Pune, Gangapur Road, Nashik,
Maharashtra 422002, India
e-mail: raghunath_toche@rediffmail.com
123

318
S. P. Patil et al.
Scheme 1
NC
MeO
MeO
CN
O
CN
MeO
MeO
S8,
MeO
MeO
CH2(CN)2
piperidine
NH2
S
DMF
3 h, rt
EtOH
2 h, rt
2
3
1
Scheme 2
RCOCl
5a-5d
AcOH
reflux
2-3 h
MeO
H
MeO
MeO
O
H2SO4
O
NH2
NH2
N
MeO
R
3
8 h
rt
N
S
S
6a-6d
4
Entry Acid chloride
5a-5d
CH3COCl
Ph COCl
ClCOCH2Cl
ClCO(CH2)3Cl
R
6
a
b
c
d
CH3
Ph
CH2Cl
(CH2)3Cl
MeO
Scheme 3
CN
MeO
NH2
S
3
ZnCl2
120-130 °C
2.5 h
O
O
ZnCl2
120-130 °C
3 h
heat
170-180 °C
8-10 h
ZnCl2
120-130 °C
2 h
O
RCONH2
11a-11d
(CH2)n
MeO
MeO
H2N
MeO
H2N
H2N
MeO
MeO
H2N
N
(CH2)n
MeO
MeO
MeO
R
N
N
N
S
10
N
S
S
S
7 n=1
8 n=2
9
12a-12d
12 Entry Amide
R
11a-11d
a
b
c
d
HCONH2
H3CCONH2
PhCONH2
H
CH3
Ph
NCCH2
NCCH2CONH2
group, can also react with electrophilic reagents to give new
polycyclic pyrimidine derivatives.
the same position reacted faster and furnished high yields
of pure product. Compounds 6a–6d were purified by col-
umn chromatography eluting with chloroform–methanol
(8:2) and were characterized by analytical and spectral
data. Reaction of 2-amino-3-carbonitrile 3 with cyclic
ketones in the presence of anhydrous ZnCl2 at 120–130 °C
yielded pentacyclic amines 7–9, and with ethyl methyl
ketone it furnished tetracyclic 6,7-dimethoxy-2,3-dimethyl-
9H-indeno[10,20:4,5]thieno[3,2-e]pyridin-4-amine (10) in
good yield. Anhydrous ZnCl2 as a Lewis acid catalyst
activates the C=O group and the high temperature
Structures of compounds 2–4 were assigned by spec-
troscopic and analytical characterizations as shown in the
‘‘Experimental’’ section.
Acid-catalyzed bis-nucleophilic cyclocondensation of
o-aminocarboxamide 4 with acid chloride in acetic acid
furnished pyrimidone derivatives 6a–6d in 70–80% yields
(Scheme 2). Acid chlorides having an electron-withdraw-
ing group a to the carbonyl reacted slowly and gave low
yields, whereas those with an electron-donating group at
123

Expedient approach for the synthesis of novel indenothiophene derivatives
319
Scheme 4
MeO
MeO
MeO
MeO
MeO
MeO
O
S
N
N
CN
CN
HCOOH
CH(OEt)3
Ac2O
reflux
3 h
reflux
8 h
NH2
N
CHOC2H5
H
S
S
15
13
3
NH2NH2.H2O
EtOH
reflux
3 h
POCl3
reflux
4 h
MeO
MeO
Cl
NH2
HN
MeO
MeO
N
N
N
N
S
S
14
16
(120–130 °C) facilitates carbanion formation a to the car-
bonyl group. Unsymmetrical ketones react via the more
acidic a-methylene group yielding compounds 9 and 10 as
sole products (Scheme 3). It was observed that cyclohex-
anone gave a clean reaction product with higher yield
compared with other ketones.
indenothienopyridine and indenothienopyrimidine deriva-
tives. The new compounds may have biological activity.
All reactions reported here are clean with simple workup,
yield single products, and require inexpensive chemicals
and reagents.
Compounds 7–10 were purified by column chromatog-
raphy using chloroform–methanol (9:1) as an eluent to
afford 50–60% yields. A facile reaction occurred when
o-aminocarbonitrile 3 was heated with neat aromatic/
aliphatic amides to afford aminothienopyrimidine deriva-
tives 12a–12e in good yields. Here steric hindrance of the
group a to the carbonyl affects the yield, e.g., formamide
gave 60% yield, whereas the yield decreases with the
introduction of a bulky group. Cyanoacetamide gave a low
yield and required a longer reaction time.
Experimental
Melting points were determined on a Gallenkamp melting
point apparatus. The 1H (300 MHz) and 13C (75 MHz)
NMR spectra were recorded on a Varian XL-300 spec-
trometer. Chemical shifts are reported in ppm relative to
tetramethylsilane (TMS) and multiplicities are given as s
(singlet), br s (broad singlet), d (doublet), t (triplet), q
(quartet), or m (multiplet). The solvents for NMR spectra
were dimethyl sulfoxide (DMSO)-d6 and CDCl3 unless
otherwise stated. Infrared spectra were recorded as KBr
disks on a Shimadzu FTIR-408 spectrophotometer. Mass
spectra were recorded on a Shimadzu GC–MS QP 2010A
mass spectrometer with an ionization potential of 70 eV.
Elemental analyses were performed on a Thermo Quest
Flash 1112 Series EA analyzer. The reactions were moni-
tored by thin-layer chromatography (TLC), carried out on
0.2-mm silica gel 60 F254 (Merck) plates using UV light
(254 and 366 nm) for detection. Common reagent-grade
chemicals are either commercially available and were used
without further purification or were prepared by standard
literature procedures.
In order to build a fused tricyclic pyrimidine ring,
compound 3 was reacted with triethyl orthoformate to
introduce a replaceable ethoxy group, which underwent a
nucleophilic substitution reaction in the presence of acetic
anhydride furnishing intermediate 15 in excellent yield.
Compound 15 on Knoevenagel reaction with hydrazine
hydrate in ethanol yielded novel 4,9-dihydro-4-imino-6,7-
dimethoxy-3H-indeno[10,20:4,5]thieno[2,3-d]pyrimidin-3-
amine (16) in 75% yield. Similarly, compound 3 on
refluxing in formic acid furnished compound 13 in 65%
yield, which on further refluxing in POCl3 gave chloro-
pyrimidine derivative 14 in 78% yield (Scheme 4).
The formation of compound 13 was rationalized by acid
hydrolysis of the nitrile moiety of 3 to an amide in formic
acid followed by condensation of the amine and amide with
the carbonyl group of formic acid, i.e., here formic acid
acts as reagent, catalyst, and solvent.
2-(2,3-Dihydro-5,6-dimethoxy-1H-inden-1-ylidene)-
malononitrile (2, C14H12N2O2)
The reaction mixture of 19.20 g 5,6-dimethoxyindan-1-one
(0.1 mol), 6.6 g malononitrile (0.1 mol), and 2 cm3 piper-
idine in 100 cm3 ethanol was stirred at room temperature
for 2 h (TLC monitoring, chloroform–methanol 9:1). The
solvent was distilled off under vacuum and the residue was
stirred in cold ethanol. The product was filtered, washed
with cold ethanol, dried, and recrystallized from N,N-
dimethylformamide (DMF)–ethanol 1:4 to afford a yellow
Conclusion
2-Aminoindenothiophene-3-carbonitrile and -3-carboxam-
ide are new synthons for bis-electrophilic and bis-
nucleophilic reactions to yield novel fused polycyclic
123

320
S. P. Patil et al.
amorphous solid 2. Yield 19.22 g (80%); m.p.: 215–
217 °C; Rf = 0.57 (chloroform–methanol 9:1); IR (KBr):
acid for 2 h (TLC monitoring, chloroform–methanol 9:1).
After cooling the reaction mixture was poured into
100 cm3 ice-cold water. The separated solid was filtered,
washed with water, dried, and recrystallized from a suitable
solvent. The product was purified by column chromato-
graphy eluting with chloroform.
1
m = 2,240, 1,620, 1,595, 1,160 cm-1; H NMR (CDCl3): d
ꢀ
= 3.47 (t, J = 6.5 Hz, 2H, CH2), 3.54 (t, J = 6.5 Hz, 2H,
CH2), 3.61 (s, 3H, OCH3), 3.58 (s, 3H, OCH3), 7.14 (s, 1H,
ArH), 7.17 (s, 1H, ArH) ppm; 13C NMR (75 MHz, CDCl3):
d = 32.4, 38.6, 62.2, 80.9, 111.2, 120.3, 121.8, 142.3,
146.7, 149.0, 152.1, 172.5 ppm; MS (ESI): m/z = 240
(M?).
3,9-Dihydro-6,7-dimethoxy-2-methyl-4H-indeno-
[10,20:4,5]thieno[2,3-d]pyrimidin-4-one
(6a, C16H14N2O3S)
2-Amino-5,6-dimethoxy-8H-indeno[2,1-b]thiophene-3-
carbonitrile (3, C14H12N2O2S)
Recrystallized from DMF–methanol 1:4; brown amorphous
solid. Yield 2.51 g (80%); m.p.: 298–300 °C; Rf = 0.54
To the stirred solution of 24.02 g 2-(2,3-dihydro-5,6-
dimethoxy-1H-inden-1-ylidene)malononitrile 2 (0.1 mol)
and 3.2 g elemental sulfur (0.1 mol) in 50 cm3 DMF 5 cm3
triethylamine was added dropwise over a period of 5 min
and the resulting reaction mixture was stirred for 3 h at
room temperature (TLC monitoring, chloroform–methanol
9:1). The solvent was removed under reduce pressure and
the residue was stirred in 500 cm3 ice-cold water. The
separated solid was filtered, washed with water, dried, and
recrystallized from 1,4-dioxane to afford a faint brown
amorphous solid. Yield 20.4 g (75%); m.p.: 231–233 °C;
ꢀ
(chloroform–methanol 9:1); IR (KBr): m = 3,350, 1,670,
1,620, 1,120 cm-1; 1H NMR (DMSO-d6): d = 2.23 (s, 3H,
CH3), 3.78 (s, 2H, CH2), 3.80 (s, 3H, OCH3), 3.81 (s, 3H,
OCH3), 7.18 (s, 1H, ArH), 7.26 (s, 1H, ArH), 11.80 (br s,
1H, NH) ppm; 13C NMR (DMSO-d6): d = 22.4, 34.5, 55.6,
55.7, 83.7, 102.0, 109.8, 114.3, 129.4, 134.0, 138.5, 139.7,
147.4, 148.0, 152.2, 168.3 ppm; MS (ESI): m/z = 314
(M?).
3,9-Dihydro-6,7-dimethoxy-2-phenyl-4H-indeno-
[10,20:4,5]thieno[2,3-d]pyrimidin-4-one
(6b, C21H16N2O3S)
ꢀ
Rf = 0.51 (chloroform–methanol 9:1); IR (KBr): m = 3,400,
Recrystallized from DMF–methanol 1:4; brown amorphous
3,325, 2,880, 2,210, 1,595, 1,095 cm-1; 1H NMR (DMSO-
d6): d = 3.61 (s, 2H, CH2), 3.77 (s, 3H, OCH3), 3.78 (s, 3H,
OCH3), 7.06 (s, 1H, ArH), 7.20 (s, 1H, ArH), 7.30 (br s,
2H, NH2) ppm; 13C NMR (DMSO-d6): d = 32.6, 55.5, 55.6,
101.6, 108.5, 109.7, 116.1, 122.7, 127.7, 130.6, 138.1,
140.4, 146.7, 147.8 ppm; MS (ESI): m/z = 272 (M?).
solid. Yield 3.01 g (80%); m.p.: 308–310 °C; Rf = 0.52
ꢀ
(chloroform–methanol 9:1); IR (KBr): m = 3,355, 1,672,
1
1,618, 1,595, 1,118 cm-1; H NMR (DMSO-d6): d = 3.70
(s, 2H, CH2), 3.77 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 7.20
(s, 1H, ArH), 7.25 (s,1H, ArH), 7.30–7.52 (m, 5H, ArH),
11.70 (br s, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 34.5, 64.3, 116.2, 118.1, 122.3, 125.9, 126.1, 127.4,
127.6, 132.6, 135.4, 137.0, 139.2, 139.4, 141.6, 152.1,
160.4, 172.4 ppm; MS (ESI): m/z = 376 (M?).
2-Amino-5,6-dimethoxy-8H-indeno[2,1-b]thiophene-3-
carboxamide (4, C14H14N2O3S)
2-Amino-5,6-dimethoxy-8H-indeno[2,1-b]thiophene-3-car-
bonitrile 3 (27.23 g, 0.1 mol) was stirred in 50 cm3 conc.
H2SO4 for 8 h at room temperature (TLC monitoring,
chloroform–methanol 9:1). The reaction mixture was
poured over 500 cm3 crushed ice and neutralized with
saturated aqueous Na2CO3 solution. The solid product was
filtered, dried, and recrystallized from DMF–methanol 1:4
to afford a colorless solid. Yield 24.6 g (85%); m.p.: 243–
245 °C; Rf = 0.49 (chloroform–methanol 9:1); IR (KBr):
2-(Chloromethyl)-3,9-dihydro-6,7-dimethoxy-4H-indeno-
[10,20:4,5]thieno[2,3-d]pyrimidin-4-one
(6c, C16H13ClN2O3S)
Purified by column chromatography (silica gel) eluting
with chloroform; faint brown amorphous solid. Yield
2.64 g (76%); m.p.: 256–260 °C; Rf = 0.57 (chloroform–
methanol 9:1); IR (KBr): ꢀm = 3,345, 1,665, 1,621,
1,126 cm-1 1H NMR (DMSO-d6): d = 3.71 (s, 2H,
;
-1
;
1H
ꢀ
m = 3,440, 3,310, 3,210, 1,666, 1,612, 1,110 cm
CH2), 3.76 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.87 (s, 2H,
CH2), 7.17 (s, 1H, ArH), 7.24 (s, 1H, ArH), 11.78 (br s, 1H,
NH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 33.7, 52.1,
63.5, 115.8, 117.4, 126.1, 131.6, 137.4, 137.7, 142.5,
149.9, 148.2, 155.3, 165.2, 171.9 ppm; MS (ESI): m/z =
348 (M?), 350 ([M ? 2]?).
NMR (DMSO-d6): d = 3.40 (s, 2H, CH2), 3.69 (s, 3H,
OCH3), 3.72 (s, 3H, OCH3), 5.90 (br s, 2H, CONH2), 6.86
(s, 1H, ArH), 7.00 (s, 1H, ArH), 7.30 (br s, 2H, NH2) ppm;
13C NMR (DMSO-d6): d = 32.5, 55.4, 55.5, 109.1, 116.4,
122.4, 127.6, 138.1, 139.8, 141.4, 146.9, 147.7, 156.3,
169.9 ppm; MS (ESI): m/z = 290 (M?).
2-(3-Chloropropyl)-3,9-dihydro-6,7-dimethoxy-4H-indeno-
[10,20:4,5]thieno[2,3-d]pyrimidin-4-one
(6d, C18H17ClN2O3S)
General procedure for the synthesis of 6a–6d
A mixture of 2.72 g compound 4 (0.01 mol) and acid
chlorides 5a–5d (0.01 mol) was refluxed in 10 cm3 acetic
Faint brown amorphous solid; purified by column chroma-
tography (silica gel) eluting with chloroform–methanol 9:1.
123

Expedient approach for the synthesis of novel indenothiophene derivatives
321
Yield 2.63 g (70%); m.p.: 243–245 °C; Rf = 0.55 (chloro-
form–methanol 9:1); IR (KBr): m = 3,320, 1,666, 1,618,
2,3,4,7-Tetrahydro-9,10-dimethoxy-4-methyl-1H-indeno-
[10,20:4,5]thieno[2,3-b]quinolin-12-amine
(9, C21H22N2O2S)
ꢀ
1,120 cm-1; 1H NMR (DMSO-d6): d = 2.01 (m, 2H, CH2),
2.48 (t, 2H, J = 6.5 Hz, CH2), 3.62 (t, 2H, J = 6.9 Hz,
CH2), 3.71 (s, 2H, CH2), 3.78 (s, 3H, OCH3), 3.79 (s, 3H,
OCH3), 7.21 (s, 1H, ArH), 7.23 (s,1H, ArH), 11.42 (br s,
1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 22.8,
24.1, 33.4, 49.5, 63.2, 112.8, 116.7, 126.1, 132.4, 137.4,
138.1, 138.5, 141.2, 148.3, 148.7, 154.2, 162.3, 169.9 ppm;
MS (ESI): m/z = 376 (M?), 378 ([M ? 2]?).
Purified by colomn chromatography (silica gel) eluting
from chloroform–methanol 9:1); brown amorphous solid.
ꢀ
Yield 1.83 g (50%); m.p. 197–199 °C; IR (KBr): m = 3,335,
3,295, 1,610, 1,105 cm-1; Rf = 0.27 (chloroform–methanol
1
9:1); H NMR (DMSO-d6): d = 1.30 (d, J = 6.9 Hz, 3H,
CH3), 1.70–1.80 (m, 2H, CH2), 1.92–195 (m, 2H, CH2),
2.54 (t, J = 5.4 Hz, 2H, CH2), 2.86–2.92 (m, 1H, CH), 3.80
(s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.88 (s, 2H, CH2), 5.77
(br s, 2H, NH2), 7.25 (s, 1H, ArH), 7.60 (s,1H, ArH) ppm;
13C NMR (75 MHz, DMSO-d6): d = 20.7, 22.7, 22.9, 25.4,
31.8, 62.5, 114.4, 116.2, 121.0, 121.8, 126.7, 130.4, 133.4,
134.7, 146.3, 149.0, 151.2, 153.1, 158.2 ppm; MS (ESI):
m/z = 366 (M?).
General procedure for the synthesis of 7–10
A mixture of 2.72 g 3 (0.01 mol), cyclic/alicyclic ketone
(0.01 mol), and anhydrous ZnCl2 (0.005 mol) was heated
at 120–130 °C for 2–3 h (TLC monitoring, chloroform–
methanol 9:1). After cooling, the reaction mixture was
stirred in 100 cm3 ice-cold water and neutralized with
aqueous NaOH solution. The separated solid was collected
by filtration, washed with water, and recrystallized from a
suitable solvent.
6,7-Dimethoxy-2,3-dimethyl-9H-indeno[10,20:4,5]-
thieno[3,2-e]pyridin-4-amine (10, C18H18N2O2S)
Purified by column chromatography (silica gel) eluting
from chloroform–methanol 9:1; brown amorphous solid.
Yield 1.66 g (51%); m.p.: 298–300 °C; Rf = 0.29 (chlo-
ꢀ
1,2,3,6-Tetrahydro-8,9-dimethoxy-cyclopenta[b]indeno-
[10,20:4,5]thieno[3,2-e]pyridin-11-amine
(7, C19H18N2O2S)
roform–methanol 9:1); IR (KBr): m = 3,360, 3,305, 1,618,
1
1,122 cm-1; H NMR (DMSO-d6): d = 1.24 (s, 3H, CH3),
1.97 (s, 3H, CH3), 3.68 (s, 3H, OCH3), 3.70 (s, 3H, OCH3),
3.82 (s, 2H, CH2), 5.20 (br s, 2H, NH2), 7.21 (s, 1H, ArH),
7.33 (s, 1H, ArH) ppm; 13C NMR (75 MHz, DMSO-d6): d
= 17.1, 22.9, 30.1, 60.7, 115.4, 117.4, 120.8, 122.0, 127.4,
132.4, 133.8, 135.1, 145.3, 147.0, 150.4, 157.1 ppm; MS
(ESI): m/z = 326 (M?).
Purified by column chromatography (silica gel) eluting
from chloroform–methanol 9:1; brown amorphous solid.
Yield 2.18 g (58%); m.p.: 227–229 °C; Rf = 0.34 (chloro-
form–methanol 9:1); IR (KBr): ꢀm = 3,345, 3,305, 1,616,
1,110 cm-1; 1H NMR (DMSO-d6): d = 2.25 (t, J = 7.5 Hz,
2H, CH2), 2.88 (t, J = 7.5 Hz, 2H, CH2), 3.09 (t, J =
7.5 Hz, 2H, CH2), 3.82 (s, 2H, CH2), 3.95 (s, 3H, OCH3),
3.97 (s, 3H, OCH3), 4.58 (br s, 2H, NH2), 7.51 (s, 1H,
General procedure for the synthesis of 12a–12d
ArH), 7.00 (s, 1H, ArH) ppm; 13C NMR (DMSO-d6): d =
22.4, 27.1, 33.6, 35.1, 55.4, 55.8, 106.3, 109.5, 114.4,
117.8, 131.9, 137.1, 137.3, 137.9, 146.3, 146.4, 147.4,
162.1, 164.7 ppm; MS (ESI): m/z = 338 (M?).
A mixture of 2.72 g compound 3 (0.01 mol) and
formamide (11a)/acetamide (11b)/benzamide (11c)/cya-
noacetamide (11d) (0.01 mol) was heated in an oil bath for
8–10 h at 170–180 °C with constant stirring (TLC check,
toluene–acetone 9:1). After cooling, the reaction mixture
was poured into 10 cm3 ice-cold methanol and stirred at
room temperature for 30 min. The precipitated solid was
collected by suction filtration, washed with cold ethanol,
and dried to afford analytical grade 12a–12d in good
yields. These compounds did not require purification.
2,3,4,7-Tetrahydro-9,10-dimethoxy-1H-indeno-
[10,20:4,5]thieno[2,3-b]quinolin-12-amine
(8, C20H20N2O2S)
Purified by column chromatography (silica gel) eluting
from chloroform–methanol 9:1; faint brown solid. Yield
2.11 g (60%); m.p.: 240–243 °C; Rf = 0.31 (chloroform–
methanol 9:1); IR (KBr): m = 3,315, 3,285, 1,666,
6,7-Dimethoxy-9H-indeno[10,20:4,5]thieno[2,3-d]-
pyrimidin-4-amine (12a, C15H13N3O2S)
Brown amorphous solid; yield 1.79 g (60%). M.p.: 188–
ꢀ
1,110 cm-1
;
1H NMR (DMSO-d6): d = 1.94 (t, J =
6.5 Hz, 4H, 2 9 CH2), 2.63 (t, J = 6.5 Hz, 2H, CH2), 2.97
(t, J = 6.5 Hz, 2H, CH2), 3.82 (s, 2H, CH2), 3.92 (s, 3H,
OCH3), 3.95 (s, 3H, OCH3), 4.62 (br s, 2H, NH2), 7.13 (s,
1H, ArH), 7.49 (s, 1H, ArH) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 23.4, 23.9, 24.1, 32.4, 61.5, 114.8, 116.4,
120.5, 122.1, 126.2, 131.1, 132.6, 136.8, 147.3, 148.4,
150.4, 154.3, 157.4 ppm; MS (ESI): m/z = 352 (M?).
190 °C; Rf = 0.40 (chloroform–methanol 9:1); IR (KBr):
m = 3,340, 3,310, 1,610, 1,105 cm-1; 1H NMR (DMSO-d6):
ꢀ
d = 3.81 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.94 (s, 2H,
CH2), 7.02 (br s, 2H, NH2), 7.26 (s, 1H, ArH), 7.48 (s, 1H,
ArH), 8.32 (s, 1H, Ar–H) ppm; 13C NMR (DMSO-d6): d =
34.6, 55.6, 55.7, 102.1, 109.3, 110.8, 130.5, 131.8, 136.3,
123

322
S. P. Patil et al.
138.2, 146.5, 147.7, 151.1, 157.4, 159.2 ppm; MS (ESI):
m/z = 299 (M?).
4-Chloro-6,7-dimethoxy-9H-indeno[10,20:4,5]thieno-
[2,3-d]pyrimidine (14, C15H11ClN2O2S)
Compound 13 (3.00 g, 0.01 mol) was refluxed in 10 cm3
POCl3 for 4 h. The excess solvent was removed under
reduced pressure and the reaction mixture was stirred in
1 kg crushed ice. The separated solid was filtered, washed
with water, dried, and recrystallized from ethanol–DMF to
give compound 14 as brown crystalline solid. Yield 2.48 g
6,7-Dimethoxy-2-methyl-9H-indeno[10,20:4,5]thieno-
[2,3-d]pyrimidin-4-amine (12b, C16H15N3O2S)
Brown amorphous solid; yield 1.75 g (56%). M.p.: 280–
ꢀ
282 °C; Rf = 0.37 (chloroform–methanol 9:1); IR (KBr): m
1
= 3,325, 3,290, 1,610, 1,110 cm-1; H NMR (DMSO-d6):
d = 3.93 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 3.99 (s, 2H,
CH2), 4.80 (br s, 2H, NH2), 3.22 (s, 3H, CH3), 7.28 (s, 1H,
ArH), 7.36 (s, 1H, ArH) ppm; 13C NMR (75 MHz, DMSO-
d6): d = 25.4, 30.6, 62.6, 115.0, 117.4, 120.9, 127.7, 132.4,
133.8, 138.1, 146.8, 148.1, 149.1, 159.3, 164.0 ppm; MS
(ESI): m/z = 313 (M?).
(78%); m.p.: 290–293 °C; Rf = 0.56 (chloroform–methanol
1
9:1); IR (KBr): m = 1,620, 1,590, 1,120 cm-1; H NMR
ꢀ
(DMSO-d6): d = 3.80 (s, 3H, OCH3), 3.81 (s, 3H, OCH3),
3.90 (s, 2H, CH2), 7.12 (s, 1H, ArH), 7.28 (s, 1H, ArH),
8.60 (s, 1H, ArH) ppm; 13C NMR (75 MHz, DMSO-d6): d
= 31.2, 60.4, 113.4, 115.5, 124.8, 130.2, 134.3, 136.6,
141.2, 147.9, 148.6, 149.5, 151.5, 160.2 ppm; MS (ESI):
m/z = 318 (M?), 320 ([M ? 2]?).
6,7-Dimethoxy-2-phenyl-9H-indeno[10,20:4,5]thieno-
[2,3-d]pyrimidin-4-amine (12c, C21H17N3O2S)
2-(Ethoxymethyleneamino)-5,6-dimethoxy-8H-indeno-
[2,1-b]thiophene-3-carbonitrile (15, C17H16N2O3S)
Brown amorphous solid; yield 2.06 g (55%). M.p.: 250 °C;
ꢀ
Rf = 0.43 (chloroform–methanol 9:1); IR (KBr): m = 3,320,
A mixture of 2.72 g compound 3 (0.01 mol) and 1.64 cm3
triethyl orthoformate (0.01 mol) was refluxed in 15 cm3
acetic anhydride for 3 h. After cooling the reaction mixture
was poured into 200 cm3 cold water. The precipitated solid
was collected by filtration, washed with water, dried, and
recrystallized from methanol to afford a brown crystalline
solid. Yield 2.52 g (80%); m.p.: 175–177 °C; Rf = 0.58
1
3,200, 1,618, 1,122 cm-1; H NMR (DMSO-d6): d = 3.86
(s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.02 (s, 2H, CH2), 4.65
(br s, 2H, NH2), 7.01–7.30 (m, 5H, ArH), 7.36 (s, 1H,
ArH), 7.40 (s, 1H, ArH) ppm; 13C NMR (75 MHz, DMSO-
d6): d = 30.2, 60.2, 113.5, 116.8, 122.9, 127.9, 128.4,
129.4, 130.1, 132.9, 134.7, 139.1, 141.5, 147.2, 148.5,
149.7, 160.0, 162.3 ppm; MS (ESI): m/z = 375 (M?).
ꢀ
(chloroform–methanol 9:1); IR (KBr): m = 2,245, 1,610,
1
1,630, 1,115 cm-1; H NMR (DMSO-d6): d = 1.40 (t, J =
4-Amino-6,7-dimethoxy-9H-indeno[10,20:4,5]thieno-
[2,3-d]pyrimidin-2-acetonitrile (12d, C17H14N4O2S)
Brown amorphous solid; yield 1.52 g (45%). M.p.: 277–
7.2 Hz, CH3), 3.87 (s, 3H, OCH3), 3.91 (s, 3H, OCH3),
4.92 (s, 2H, CH2), 4.37 (q, J = 7.2 Hz, 2H, OCH2), 7.28 (s,
1H, ArH), 7.30 (s, 1H, ArH) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 20.4, 30.4, 58.4, 60.4, 113.5, 117.5, 119.3,
129.9, 136.5, 140.2, 144.3, 146.1, 149.6, 157.1, 165.2 ppm;
MS (ESI): m/z = 328 (M?).
ꢀ
279 °C; Rf = 0.37 (chloroform–methanol 9:1); IR (KBr): m
= 3,320, 3,200, 2,255, 1,610, 1,120 cm-1 1H NMR
;
(DMSO-d6): d = 3.71 (s, 2H, CH2), 3.80 (s, 3H, OCH3),
3.84 (s, 3H, OCH3), 3.98 (s, 2H, CH2), 4.60 (br s, 2H,
NH2), 7.32 (s, 1H, ArH), 7.36 (s, 1H, ArH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 26.1, 30.2, 63.1, 110.2, 114.1,
116.2, 123.8, 129.9, 131.5, 135.9, 141.2, 146.2, 147.7,
149.3, 157.2, 164.2 ppm; MS (ESI): m/z = 338 (M?).
4,9-Dihydro-4-imino-6,7-dimethoxy-3H-indeno-
[10,20:4,5]thieno[2,3-d]pyrimidin-3-amine
(16, C15H14N4O2S)
Hydrazine hydrate (0.98 cm3, 0.01 mol) was added to a
stirred solution of 3.16 g 15 (0.01 mol) in 12 cm3 ethanol.
The reaction was refluxed for 3 h. After cooling the
reaction mixture was poured into 100 cm3 ice-cold water
under stirring. The precipitated solid was filtered, dried,
and recrystallized from benzene to yield compound 16 as
an off-white amorphous solid. Yield 2.35 g (75%); m.p.:
195–197 °C; Rf = 0.47 (chloroform–methanol 9:1); IR
1,9-Dihydro-6,7-dimethoxy-4H-indeno[10,20:4,5]-
thieno[2,3-d]pyrimidin-4-one (13, C15H12N2O3S)
A mixture of 2.72 g 3 (0.1 mol) and 10 cm3 formic acid
was refluxed for 8 h. The solvent was removed under
reduced pressure and the separated solid was filtered and
recrystallized from ethanol to give 13 as a brown crystal-
line solid. Yield 2.05 g (65%); m.p.: 284–286 °C; Rf = 0.44
-1
ꢀ
(chloroform–methanol 9:1); IR (KBr): m = 3,338, 1,671,
ꢀ
(KBr): m = 3,350, 3,325, 3,240, 1,616, 1,112 cm
;
1H
1,616, 1,110 cm-1; 1H NMR (DMSO-d6): d = 3.77 (s, 3H,
OCH3), 3.78 (s, 2H, OCH3), 3.79 (s, 2H, CH2), 7.15 (s, 1H,
ArH), 7.25 (s, 1H, ArH), 8.42 (s, 1H, ArH), 12.15 (br s, 1H,
NH) ppm; 13C NMR (DMSO-d6): d = 35.1, 55.6, 55.7,
106.1, 109.4, 110.8, 130.6, 136.8, 138.2, 138.4, 146.8,
147.5, 152.8, 158.8, 171.2 ppm; MS (ESI): m/z = 300
(M?).
NMR (DMSO-d6): d = 3.79 (s, 3H, OCH3), 3.81 (s, 3H,
OCH3), 3.86 (s, 2H, CH2), 5.69 (br s, 2H, NH2), 7.19 (s,
1H, ArH), 7.26 (s, 1H, ArH), 7.97 (s, 1H, ArH), 8.84 (br s,
1H, NH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 33.4,
57.2, 57.4, 110.1, 114.4, 129.6, 134.3, 138.1, 138.8,
139.1, 144.6, 146.7, 150.8, 154.9, 165.7 ppm; MS (ESI):
m/z = 314 (M?).
123

Expedient approach for the synthesis of novel indenothiophene derivatives
323
Acknowledgments We gratefully acknowledge financial support
for this research by CSIR New Delhi, the University of Pune for
spectral analysis, and the Principal, KTHM College, Nashik-02 for
facilities.
16. Miki S, Fukuoka K, Akita M, Kawakami J, Furuya S, Isshimaru
Y (1999) PCT Int Appl WO 99,09,033
17. Miki S, Fukuoka K, Akita M, Kawakami J, Furuya S, Isshimaru
Y (1999) Chem Abstr 130:196644h
18. Suzuki N, Matsumoto H, Furuya S (1997) Eur Pat Appl 781,774
19. Suzuki N, Matsumoto H, Furuya
127:135807e
20. Furuya S, Choh N, Suzuk N, Imada T (2000) PCT Int Appl WO
00,00,493
S (1997) Chem Abstr
References
1. Torrance C, Agarwal V, Vogelstein B, Kinzler K (2001) Nat
Biotechnol 19:940
2. Hanahan D, Weinberg R (2000) Cell 100:57
3. Levine A (1997) Cell 88:323
21. Furuya S, Choh N, Suzuk N, Imada T (2000) Chem Abstr
132:64179s
22. Furuya S, Matsumoto H, Hayase Y, Suzuki N, Imada T (1997)
PCT Int Appl WO 97,41,26
4. Patil C, Sadana G (1991) J Ind Chem Soc 68:169
5. Sharaideh Z, Sallal A (1997) Bioorg Med Chem Lett 54:233
6. Bompart J, Giral L, Malicorne G, Puygreneir M (1987) Eur J Med
Chem 22:139
7. Sohda T, Makino H, Baba A (1996) PCT Int Appl WO 96,14,319
8. Sohda T, Makino H, Baba A (1996) Chem Abstr 125:114583x
9. Manhas M, Sharma S, Amin S (1972) J Med Chem 15:106
10. Adachi I, Yamomori T, Hiramatsu Y, Sakai K, Mihara S,
Kawakami M, Masui M, Uno O, Ueda M (1988) Chem Pharm
Bull 36:4389
23. Furuya S, Matsumoto H, Hayase Y, Suzuki N, Imada T (1998)
Chem Abstr 128:13211f
24. Haadsma-Svensson S, Cleek K, Dinh D, Duncan J, Haber C, Huff
R, Lajiness M, Nichols N, Smith M, Svensson K, Zaya M (2001)
J Med Chem 44:4716
25. Ladduwahetty T, MacLeod A, Merchant K, Sternfeld F (2004)
US Patent 2004/6226
26. Chordia M, Murphree L, Macdonald T, Linden J, Olsson R
(2002) Bioorg Med Chem Lett 12:1563
27. Ho C, Ludovici D, Maharoof U, Mei J, Sechler J, Tuman R,
Strobel E, Andraka L, Yen H, Leo G, Li J (2005) J Med Chem
48:8163
11. Blackburn T, Davies D, Forbes I, Hayward C, Johnson C, Martin
R, Piper D, Thomas D, Thompson M, Upton N, Ward R (1995)
Bioorg Med Chem Lett 5:2589
28. Sabnis R (1994) J Sulfur Chem 16:1
12. Jennings L, Kincaid L, Wang D, Krishnamurti G, Beyer C,
McGinnis J, Miranda M, Discafani C, Rabindran S (2005) Bioorg
Med Chem Lett 15:4731
13. Furuya S, Choh N, Kato K, Hinuma S (1995) PCT Int Appl WO
95,28,405
29. Morwick T, Berry A, Brichwood J, Carodoza M, Catron K,
Deturi M, Emeigh J, Homon C, Hrapchak M, Jacober S, Jakes S,
Kaplita P, Kelly T, Ksiazek J, Liuzzi M, Magolda R, Mao C,
Marshall D, McNeil D, Prokopowicz A, Sarko C, Scouten E,
Sledziona C, Sun S, Watrous J, Wu J, Cywin C (2006) J Med
Chem 49:2898
14. Furuya S, Choh N, Kato K, Hinuma S (1996) Chem Abstr
124:202226t
30. Tsai L, Miwa T, Newman M (1957) J Am Chem Soc 79:2530
15. Cho N, Harada M, Imeada T, Matsumoto H, Hayase Y, Sasaki S,
Furuya S, Suzuki N, Okubo S, Ogi K, Endo S, Onda H, Fujino M
(1998) J Med Chem 41:4190
123