Polyfunctional fused heterocyclic compounds via indene-1,3-diones

Article abstract of DOI:10.1002/hc.10166

2-Dimethylaminomethylene- and 2-ethoxymethylene-1,3-indendione 1a,b react with 6-amino-2-thioxopyrimidin-4(3H)-one 2 in boiling acetic acid to give 2-thioxo-1,3-dihydroindeno[3,2-d]pyrimidino[4,5-b]pyridine-4,9-dione (4). The latter compound reacts with h

Full text of DOI:10.1002/hc.10166

Heteroatom Chemistry
Volume 14, Number 6, 2003
Polyfunctional Fused Heterocyclic
Compounds via Indene-1,3-diones
Hamdi M. Hassaneen,1 Tayseer A. Abdallah,1 Hyam A. Abdelhadi,1
Huwaida M. E. Hassaneen,1 and Richard M. Pagni2
1Department of Chemistry, Faculty of Science, University of Cairo, Giza, Egypt
2Department of Chemistry, University of Tenneesse, Knoxville, Tenneesse 37996-1600
Received 3 March 2003
pounds from readily obtainable starting materials
ABSTRACT: 2-Dimethylaminomethylene- and 2-
such as 1a and 1b. In the following work, we report
a novel synthesis of 2-thioxo-1,3-dihydroindeno[3,2-
d]pyrimidino[4,5-b]pyridine-4,9-dione (4) and its
utility for the synthesis of fused heterocyclic com-
pounds 12. We also report the reaction of 1a or 1b
with heterocyclic amines.
ethoxymethylene-1,3-indendione 1a,b react with 6-
amino-2-thioxopyrimidin-4(3H)-one
2 in boiling
acetic acid to give 2-thioxo-1,3-dihydroindeno[3,2-
d]pyrimidino[4,5-b]pyridine-4,9-dione (4). The latter
compound reacts with hydrazonoyl chlorides 5a–c to
afford products 12a–c. Formamidine 15 reacts with
indene-1,3-dione in boiling ethanol to give acyclic
compound 16, which cyclizes to 12a in boiling glacial
acetic acid. Also, enaminone 1a reacts with hetero-
cyclic amines 17a–e in boiling ethanol, affording the
corresponding substitution products 18a–c, respec-
tively. The latter products 18a–c cyclize in glacial
acetic acid to give 19a–c, respectively. The struc-
tures of the newly synthesized compounds are estab-
lished on the basis of chemical and spectroscopic ev-
RESULTS
We have found that 1a or 1b, obtained via
condensation of the indene-1,3(2H)-dione with
dimethylformamide dimethylacetal (DMFDMA) or
triethyl orthoformate (TEOF), respectively, as has
been described earlier [1,3], readily condenses with
6-amino-2-thioxopyrimidin-4(3H)-one [4] in acetic
acid to give 2-thioxo-1,3-dihydro-indeno[3,2-d]pyri-
midino[4,5-b]pyridine-4,9-dione (4) (Scheme 1).
It may be assumed that initially formed 3 cy-
clized to give 4 (Scheme 1). The structure of com-
pound 4 is based on its elemental analysis and spec-
ꢀ
C
idence. 2003 Wiley Periodicals, Inc. Heteroatom Chem
14:491–497, 2003; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.10166
1
troscopic data (IR, H NMR, and MS). The mass
INTRODUCTION
spectrum showed an intense peak at m/z 281 corr-
1
esponding to its molecular ion peak. The H NMR
Even though 2-dimethylaminomethylene- and 2-
ethoxymethylene-1,3-indendione 1a,b were synthe-
sized long ago, their utility in the synthesis of fused
heterocyclic compounds has received little attention
[1–3]. The objective of our program is to develop the
synthesis of functionally fused heteroaromatic com-
spectrum of 4 displayed three singlets at δ 8.09 (s,
1H, pyridine-H), 12.89 (s, 1H, NH), and 13.62 (s, 1H,
NH) in addition to the multiplet in the aromatic re-
gion at δ 7.60–7.81 (4H). Its IR spectrum showed
four absorption bands at 1682, 1716, 3350, and 3421,
corresponding to two carbonyl and two NH groups,
respectively.
Correspondence to: H. M. Hassaneen; e-mail: tiseer123@
Treatment of 4 with hydrazonoyl chlorides 5a–c
[5–7] in chloroform in the presence of triethylamine
hotmail.com.
c
ꢀ
2003 Wiley Periodicals, Inc.
491

492 Hassaneen et al.
SCHEME 1
yields products that can be formulated as 12a–c
or their isomeric structures 13a–c (Scheme 2). The
reaction pathway that seems reasonable to account
for the formation of 12 or 13 is outlined in Scheme 2.
It is proposed that the reaction involves an initial nu-
cleophilic substitution to give thiohydrazonate esters
7, which undergo an S → N migration via the spiro
intermediates 8 to give the thiohydrazides 9. The
spiro intermediates 8 may be also formed via 1,3-
dipolar cycloaddition of nitrilimines 6a–c, generated
in situ from the reaction of hydrazonoyl chlorides
5a–c with triethylamine, to the thione C S group of
compound 4. The latter intermediates 9 undergo cy-
clization via elimination of hydrogen sulfide to give
final products that may have structure 12 or 13 acc-
ording to which cyclization step is followed (route a
or b in Scheme 2). Isomers 12 and 13 will, of course,
yield identical elemental analyses and mass spectra.
These data thus cannot be used to determine the ex-
act structure of the product; conclusive evidence for
the structures were obtained by the synthesis of 12
by an alternative method.
Thus, treatment of 7-amino-1,3-diphenyl-1,2,4-
triazolo[4,5-a]pyrimidin-5-one (14) [8], prepared via
1,3-dipolar cycloaddition reaction of 2 [4], with N-
phenylbenzohydrazonoyl chloride (5a) [5] in boil-
ing acetonitrile in the presence of triethylamine,
with DMFDMA yields the corresponding formami-
dine compound 15 [9] (Scheme 3). Treatment of
compound 15 with indene-1,3(2H)-dione in boil-
ing ethanol leads to the formation of acyclic struc-
ture 16 (Scheme 3). Elemental analysis and spectro-
scopic data confirmed the structure 16. Its 1H NMR
spectrum displayed two singlets at δ 6.19 (N CH)
and 11.18 (OH), which disappeared upon shaking
with deuterium oxide, in addition to a multiplet of
aromatic protons. Also, its mass spectrum gave an
intense peak at m/z 459 corresponding to the molec-
ular ion peak. Boiling of compound 16 in glacial
acetic acid led to the formation of the cyclized
product, via elimination of water, which was iden-
1
tical in all respects (mp, mmp, H NMR, and MS)
with compound 12a that was prepared previously
(Scheme 2).
Treatment of 1a or 1b with 5-aminotriazole 17a
in boiling ethanol affords the substitution product
18a or 21a having a molecular formula C12H8N4O2
(Scheme 4). The resulting product gave an intense
molecular ion peak at m/z 240 in its mass spec-
trum. Boiling of the resulting substitution product
in glacial acetic acid results in formation of the
cyclized product 19a or its isomer 22a via elimi-
nation of water (Scheme 4). The elemental analy-
sis and spectral data (IR and MS) of the product
agreed with either 19a or 22a. Conclusive evidence
for the structure was obtained by an alternative syn-
thesis. Thus, condensation of triazolylformamidine
20a [10], prepared by reaction of 5-aminotriazole
17a with DMFDMA, with indene-1,3-dione in boil-
ing acetic acid leads to the formation of compound
19a via elimination of dimethylamine and water
molecules (Scheme 4).
Similarly, treatment of 1a or 1b with heterocyclic
amines 17b–e in boiling ethanol yields the substi-
tution products 18b–e or 21b–e. The latter prod-
ucts are cyclized in boiling glacial acetic acid via

Polyfunctional Fused Heterocyclic Compounds Via Indene-1,3-diones 493
SCHEME 2
elimination of water to give 19b–e or 22b–e. The
structures of 19b–e are established for the prod-
ucts based on the identity reaction of formamidines
20b–e [10], prepared by condensation of 17b–e
with DMFDMA, with 1,3-indenedione (Scheme 4).
The structures were confirmed from spectral
data and elemental analyses (see Experimental
section).

494 Hassaneen et al.
SCHEME 3
EXPERIMENTAL
(DMSO-d6) δ 7.60–7.81 (m, 4H), 8.09 (s, 1H), 12.89 (s,
1H), 13.62 (s, 1H); MS m/z: 281, 252, 237, 222, 138,
137, 110, 81, 59.
Anal. Calcd for C14H7N3O2S: C, 59.78; H, 2.51; N,
14.94; S, 11.40. Found: C, 59.48; H, 2.19; N, 14.65; S,
11.08%.
Melting points were determined on a Gallenkamp
electrothermal apparatus and are uncorrected. In-
frared spectra were recorded as KBr pellets with
a Pye Unicam SP-3000 infrared spectrophotome-
1
ter. H NMR spectra were determined on a Varian
Gemini 200 spectrometer (200 MHz) in DMSO-d6
as solvent and TMS as internal standard. Chemical
shifts δ are reported in ppm. Mass spectra were mea-
sured at 70 eV using a Shimadzu GCMS-QP 1000EX.
Microanalyses were performed on a Perkin-Elmer
2400 CHN Elemental Analyzer at the microanalyt-
ical center, University of Cairo. Compounds 1a [3],
1b [1], 2 [4], 5a–c [5–7], 14 [8], 15 [9], 20a [10],
20b [10], and 20e [10] were prepared as previously
described.
Synthesis of 12a–c
Method A. To a stirred solution of the appro-
priate hydrazonoyl chlorides 5a–c (5 mmol) and 4
(1.40 g, 5 mmol) in chloroform (40 ml) was added tri-
ethylamine (0.7 ml, 5 mmol). The reaction mixture
was refluxed until the hydrogen sulfide gas ceased
to evolve (8 h) as indicated by TLC analysis. The
solvent was evaporated under reduced pressure and
the residue was treated with methanol (10 ml). The
solid formed was collected and crystallized from
dimethylformamide to give the corresponding prod-
ucts 12a–c, respectively.
Synthesis of 2-Thioxo-1,3-dihydroindeno[3,2-d]-
pyrimidino[4,5-b]pyridine-4,9-dione (4)
A solution of compound 1a or 1b (5 mmol) and
2 (0.72 g, 5 mmol) in acetic acid was refluxed for
2 h. The excess solvent was evaporated under re-
duced pressure and the residue was treated with
methanol (10 ml). The solid that formed was col-
lected and crystallized from dimethylformamide to
give 4 in 90% yield; mp 311◦C; IR (KBr) ν 3421 (NH),
3350 (NH), 1716 (C O), 1682 (C O) cm−1; 1H NMR
Method B. A solution of compound 16 (2.29 g,
5 mmol) in acetic acid (30 ml) was refluxed for 2 h.
The excess solvent was evaporated under reduced
pressure and the residue was treated with methanol
(10 ml). The solid that formed was collected and crys-
tallized from dimethylformamide to give compound
identical in all respects (mp, mmp and spectral data)
with 12a obtained by method A.

Polyfunctional Fused Heterocyclic Compounds Via Indene-1,3-diones 495
SCHEME 4
cm−1; MS m/z: 408, 407, 406, 364, 310, 248, 193, 165,
138, 77.
Anal. Calcd for C23H13N5O3: C, 67.81; H, 3.22; N,
17.19. Found: C, 67.59; H, 3.11; N, 16.95%.
1,3-Diphenyl-13-hydroindeno[3,2-d]1,2,4-
triazolino[4ꢁ,5ꢁ-2,1]pyrimidino[4,5-b]pyridine-
7,12-dione (12a)
The compound was obtained in 89% yield; mp 303◦C;
IR (KBr) ν 1719 (C O), 1675 (C O) cm−1; MS,
m/z: 442, 441, 384, 339, 233, 204, 193, 103, 91,
77.
1-Ethoxycarbonyl-3-phenyl-13-hydroindeno[3,2-
d]1,2,4-triazolino[4ꢁ,5ꢁ-2,1]pyrimidino[4,5-
b]pyridine-7,12-dione (12c)
Anal. Calcd for C27H15N5O2: C, 73.46; H, 3.43; N,
15.87. Found: C, 73.16; H, 3.25; N, 15.53%.
The compound was obtained in 91% yield; mp
265◦C; IR (KBr) ν 1714 (C O), 1669 (C O), 1648
(C O) cm−1; 1H NMR (DMSO-d6) δ 1.41 (t, J = 7 Hz,
3H) 4.59 (q, J = 7 Hz, 2H), 7.52–8.10 (m, 9H), 8.39
(s, 1H); MS m/z: 438, 437, 364, 324, 248, 205, 165,
138, 77.
1-Acetyl-3-phenyl-13-hydroindeno[3,2-d]1,2,4-
triazolino[4ꢁ,5ꢁ-2,1]pyrimidino[4,5-b]pyridine-
7,12-dione (12b)
The compound was obtained in 90% yield; mp 315◦C;
Anal. Calcd for C24H15N5O4: C, 65.90; H, 3.46; N,
16.01. Found: C, 65.62; H, 3.13; N, 15.86%.
IR (KBr) ν 1708 (C O), 1678 (C O), 1652 (C O)

496 Hassaneen et al.
(C O) cm−1; 1H NMR (DMSO-d6) δ 6.92 (s, 1H),
7.41–7.72 (m, 9H), 8.34 (s, 1H), 11.20 (s, 1H), 13.21
(s, 1H); MS m/z: 316, 315, 270, 185, 157, 143, 102, 77.
Anal. Calcd for C19H13N3O2: C, 72.37; H, 4.16; N,
13.33. Found: C, 72.19; H, 3.99; N, 13.05%.
Synthesis of 2-[(1,3-Diphenyl-7-amino-1,2,4-
triazolo[4,3-a]pyrimidin-5-one)methylene]-1,3-
indenedione (16)
An equimolecular amount of 15 (1.79 g, 5 mmol)
and 1,3-indene-dione (0.73 g, 5 mmol) was refluxed
in boiling ethanol (30 ml) for 2 h. The excess sol-
vent was evaporated under reduced pressure and
the residue was treated with methanol (10 ml). The
solid that formed was collected and crystallized from
dimethylformamide to give 16 in 90% yield; mp
317◦C; IR (KBr) ν 3440 (OH), 1717 (C O), 1643
(C O) cm−1; 1H NMR (DMSO-d6) δ 6.19 (s, 1H), 7.41–
8.09 (m, 14H), 8.52 (s, 1H), 11.18 (s, 1H); MS m/z:
459, 383, 355, 303, 178, 163, 91, 76.
2-[(4-Phenylpyrazol-3-ylamino)methylene]-1,3-
indenedione (18d)
The compound was obtained in 82% yield; mp 263◦C;
IR (KBr) ν 3428 (NH), 3199 (NH), 1698 (C O), 1656
1
(C O) cm−1; H NMR (DMSO-d6) δ 7.31–7.72 (m,
9H), 8.11 (s, 1H), 8.42 (s, 1H), 11.30 (s, 1H), 13.21 (s,
1H); MS m/z: 316, 315, 314, 181, 143, 102, 50.
Anal. Calcd for C19H13N3O2: C, 72.37; H, 4.16; N,
13.33. Found: C, 72.24; H, 3.94; N, 13.15%.
Anal. Calcd for C27H17N5O3: C, 70.58; H, 3.73; N,
15.24. Found: C, 70.45; H, 3.56; N, 14.98%.
2-[(Benzimidazol-2-ylamino)methylene]-1,3-
indenedione (18e)
Synthesis of 18a–e: General Method
A mixture of compound 1a or 1b (5 mmol) and one
of 17a–e (5 mmol) in ethanol (30 ml) was refluxed
for 2 h and left to cool. The solid product was col-
lected by filtration and crystallized from dimethyl-
formamide to give compounds 18a–e, respectively.
The compound was obtained in 80% yield; mp 209◦C;
IR (KBr) ν 3369 (NH), 3187 (NH), 1690 (C O), 1651
(C O) cm−1; 1H NMR (DMSO-d6) δ 6.21 (s, 2H), 6.82–
7.13 (m, 8H), 7.60 (s, 1H); MS m/z: 290, 289, 271, 243,
203, 146, 134, 86, 52.
Anal. Calcd for C17H11N3O2: C, 70.58; H, 3.83; N,
14.53. Found: C, 70.29; H, 3.62; N, 14.35%.
2-[(Triazol-5-ylamino)methylene]-1,3-
indenedione (18a)
The compound was obtained in 70% yield; mp 230◦C;
IR (KBr) ν 3325 (NH), 3201 (NH), 1665 (C O), 1643
(C O) cm−1; MS m/z: 240, 201, 186, 159, 144, 101,
75, 53.
Anal. Calcd for C12H8N4O2: C, 60.00; H, 3.36; N,
23.32. Found: C, 59.70; H, 3.06; N, 23.10%.
Synthesis of 19a–e
Method A. A mixture of compound 1a or 1b
(5 mmol) and one of 18a–e (5 mmol) in acetic acid
(30 ml) was refluxed for 4 h and left to cool. The solid
product was collected by filtration and crystallized
from dimethylformamide to give compounds 19a–e,
respectively.
2-[(3-Methylpyrazol-5-ylamino)methylene]-1,3-
indenedione (18b)
Method B. A mixture of each compound 20a–e
(5 mmol) and 1,3-indene-dione (0.73 g, 5 mmol) in
acetic acid (30 ml) was refluxed for 1 h and left to
cool. The solid product was collected by filtration and
crystallized from dimethylformamide to give com-
pounds which were identical in all respects (mp,
mmp, and spectral data) with 19a–e obtained by
Method A.
The compound was obtained in 85% yield; mp 270◦C;
IR (KBr) ν 3202 (NH), 3140 (NH), 1697 (C O), 1656
(C O) cm−1; 1H NMR (DMSO-d6) δ 2.63 (s, 3H),
6.29 (s, 1H), 7.89 (s, 4H), 8.33 (s, 1H), 11.12 (s,
1H), 12.53 (s, 1H); MS m/z: 254, 253, 225, 196, 157,
129, 101, 76, 67; 13C NMR (DMSO-d6) δ 12.49, 77.22,
95.84, 123.13, 135.69, 141.33, 142.28, 144.96, 157.02,
177.36.
Anal. Calcd for C14H11N3O2: C, 66.39; H, 4.38; N,
16.59. Found: C, 66.23; H, 4.12; N, 16.42%.
11-Hydroindeno[2,3-e]1,2,4-triazolo[1,5-a]-
pyrimidin-6-one (19a)
The compound was obtained in 77% yield; mp 281◦C;
IR (KBr) ν 1711 (C O) cm−1; MS m/z: 223, 222, 194,
167, 142, 126, 111, 91, 53.
Anal. Calcd for C12H6N4O: C, 64.86; H, 2.72; N,
25.22. Found: C, 64.65; H, 2.55, N, 24.96%.
2-[(3-Phenylpyrazol-5-ylamino)methylene]-1,3-
indenedione (18c)
The compound was obtained in 87% yield; mp 299◦C;
IR (KBr) ν 3289 (NH), 3223 (NH), 1698 (C O), 1654

Polyfunctional Fused Heterocyclic Compounds Via Indene-1,3-diones 497
refluxed for 1 h. The reaction mixture was left to
cool and triturated with ethanol (10 ml). The solid
product, so formed, was collected by filtration and
crystallized from ethanol to give products 20c,d
respectively.
2-Methyl-11-hydroindeno[2,3-e]pyrazolo[1,5-a]-
pyrimidin-6-one (19b)
The compound was obtained in 80% yield; mp 225◦C;
1
IR (KBr) ν 1712 (C O) cm−1; H NMR (DMSO-d6)
δ 2.61 (s, 3H), 6.72 (s, 1H), 7.72–7.75 (m, 4H), 8.60
(s, 1H); MS m/z: 236, 235, 207, 142, 81, 69.
Anal. Calcd for C14H9N3O: C, 71.48; H, 3.86; N,
17.86. Found: C, 71.39; H, 3.81; N, 17.67%.
5-Phenyl-1H-pyrazol-3-yl-
dimethylaminoformamidine (20c)
The compound was obtained in 80% yield; mp 180◦C;
1
IR (KBr) ν 3189 (NH) cm−1; H NMR (DMSO-d6)
2-Phenyl-11-hydroindeno[2,3-e]pyrazolo[1,5-a]-
pyrimidin-6-one (19c)
δ 2.91 (s, 3H), 3.09 (s, 3H), 6.33 (s, 1H), 7.21–7.79
(m, 5H), 8.14 (s, 1H), 12.32 (s, 1H); MS m/z: 215,
214, 213, 172, 104, 83, 57.
Anal. Calcd for C12H14N4: C, 67.26; H, 6.59; N,
26.15. Found: C, 67.15; H, 6.42; N, 26.04%.
The compound was obtained in 75% yield; mp 280◦C;
1
IR (KBr) ν 1713 (C O) cm−1; H NMR (DMSO-d6)
δ 7.31 (s, 1H), 7.41–8.32 (m, 9H), 8.53 (s, 1H); MS
m/z: 298, 297, 268, 221, 148, 142, 88, 77.
Anal. Calcd for C19H11N3O: C, 76.75; H, 3.73; N,
14.13. Found: C, 76.44; H, 3.44; N, 13.86%.
4-Phenyl-1H-pyrazol-3-yl-
dimethylaminoformamidine (20d)
The compound was obtained in 80% yield; mp 184◦C;
3-Phenyl-11-hydroindeno[2,3-e]pyrazolo[1,5-a]-
pyrimidin-6-one (19d)
1
IR (KBr) ν 3186 (NH) cm−1; H NMR (DMSO-d6)
δ 3.03 (s, 6H), 7.14–7.83 (m, 6H), 8.02 (s, 1H), 12.11
(s, 1H); MS m/z: 215, 214, 213, 172, 142, 115, 89,
57.
Anal. Calcd for C12H14N4: C, 67.26; H, 6.59; N,
26.15. Found: C, 67.11; H, 6.52; N, 26.09%.
The compound was obtained in 91% yield; mp 260◦C;
1
IR (KBr) ν 1713 (C O) cm−1; H NMR (DMSO-d6)
δ 7.31–8.42 (m, 9H), 8.91 (s, 1H), 9.20 (s, 1H); MS
m/z: 298, 297, 296, 139, 107, 102, 73, 63, 51, 50.
Anal. Calcd for C19H11N3O: C, 76.75; H, 3.73; N,
14.13. Found: C, 76.54; H, 3.34; N, 13.96%.
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The compound was obtained in 78% yield; mp 315◦C;
IR (KBr) ν 1712 (C O) cm−1; MS m/z: 272, 271, 243,
215, 189, 139, 126, 102, 55.
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15.49. Found: C, 75.08; H, 3.05; N, 15.19%.
Synthesis of 20c,d: General Method
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A mixture of the appropriate 17c,d (5 mmol) and
DMFDMA (0.66 g, 5 mmol) in dioxan (25 ml) was