Synthesis and molluscicidal activity of new chromene and pyrano[2,3-c]pyrazole derivatives

Article abstract of DOI:10.1002/ardp.200700157

The chromene derivative 4 reacts with acetic anhydride, phenylisothiocyanate and ethyl orthoformate to afford the N-acetyl derivative 6, the chromenopyrimidine 8 and the formimidate 9, respectively. 2-(1H-Indol-3-ylmethylene)-malononitrile 10b reacts with

Full text of DOI:10.1002/ardp.200700157

Arch. Pharm. Chem. Life Sci. 2007, 340, 543–548
F. M. Abdelrazek et al.
543
Full Paper
Synthesis and Molluscicidal Activity of New Chromene and
Pyrano[2,3-c]pyrazole Derivatives
Fathy M. Abdelrazek1,2, Peter Metz1, Olga Kataeva1, Anne Jꢀger1, and Sherif F. El-Mahrouky3
1 Department of Chemistry, Technische Universitꢀt Dresden, Dresden, Germany
2 Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
3
Research Institute for Tropical Medicine, Cairo, Egypt
The chromene derivative 4 reacts with acetic anhydride, phenylisothiocyanate and ethyl ortho-
formate to afford the N-acetyl derivative 6, the chromenopyrimidine 8 and the formimidate 9,
respectively. 2-(1H-Indol-3-ylmethylene)-malononitrile 10b reacts with 1,3-cyclohexanedione and
dimedone 11a, b to afford the 4(3-indolyl)-chromene derivatives 12a, b respectively, and with the
pyrazolone derivatives 13a–d to afford the arylidene exchange derivatives 14a–c and the pyra-
nopyrazole derivative 15, respectively. The arylidene derivatives 10a, b react also with indane-
1,3-dione 16 to afford the arylidene exchange derivatives 18a, b. The molluscicidal activity of the
synthesized compounds towards Biomphalaria alexandrina snails, the intermediate host of Schis-
tosoma mansoni, was investigated and most of them showed weak to moderate activity.
Keywords: Arylidene exchange / Chromenes / Molluscicidal activity / Pyrano[2,3-c]pyrazoles /
Received: June 6, 2007; accepted: July 28, 2007
DOI 10.1002/ardp.200700157
pin A 2, and ricchiocarpin B 3 [3], the chromene deriv-
ative 4 [4] and the pyranopyrazole 5 [5] (Fig. 1); all have
shown a considerable molluscicidal activity. The furan
and the pyran rings as well as the methyl groups are com-
mon features in these compounds.
Is is known that the mollusc's soft tissues are rich in
sterols contents which are highly lipophilic, and it seems
that the molluscicides action is to chelate with some met-
als essential for vital processes in the organism [6]. There-
fore, the more lipophilicity the compound has, the more
its ability to merge and chelate with these metals. In the
present work, we tried to introduce groups to increase
the lipophilicity and / or the chelating ability of com-
pounds 4 and 5.
Based on the above discussion it was decided to modify
compounds 4 by exploring its enaminonitrile moiety in
order to obtain some new derivatives, while preserving
the features to which the activity is attributed, the two
geminal methyl groups on the cyclohexanone and the 3-
furanyl moiety in the 4-position of the pyran [4]. Further-
more, it is well known that the indole system is con-
tained in a variety of synthetic pharmaceuticals as well
as naturally occuring alkaloids [7]. Therefore, we thought
that substituting the 3-furanyl by a 3-indolyl ring system
Introduction
Schistosomiasis is one of the most wide-spread endemic
diseases in Egypt as well as in most of the tropical coun-
tries, and represents one of the serious problems due to
its destructive health consequences. Great national and
international efforts are made to combat this disease
through hygienic awareness, chemotherapeutic treat-
ment of infected persons, or through cutting the life
cycle of the parasite through killing of the water snail
Biomphalaria alexandrina, the intermediate hosts of the
infective phase of Schistosoma mansoni, named cercaria.
Although chemotherapy proved to be successful, the ina-
voidable contact with polluted water, however, leads to
repeated infection. Therefore, snail control through mol-
luscicides, is considered essential in Schistsomal control.
Naturally occuring compounds containing the fused
pyran (or pyranone) ring were found to exhibit mollusci-
cidal activity. For example Bergapten 1 [1, 2]; ricchiocar-
Correspondence: Fathy Mohamed Abdelrazek, Chemistry Department,
Faculty of Science, Cairo University, Giza, Egypt.
E-mail: prof_fmrazek@yahoo.com
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544
F. M. Abdelrazek et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 543–548
Scheme 1. Synthesis of compounds 6, 8, and 9.
Figure 1. Chemical structures of compounds 1–5.
might enhance the molluscicidal activity of the chro-
mene 4 as well as the pyranopyrazole 5 by virtue of the
extra NH of the indole which affords more chance for
chelation.
Results and discussion
Chemistry
Compound 4, prepared as previously reported [4],
smoothly underwent N-acetylation upon reflux with ace-
tic anhydride in pyridine. It was expected to obtain the
cyclized chromenopyrimidine derivative 7, however,
spectral data showed that our product is the N-acetyl
derivative 6 (Scheme 1).
Figure 2. Crystal structure of formimidate 9 [9, 10].
the compound was obtained in analytically pure state
without further purification (mp 225–2268C; reported:
219–2208C [12], 221–2238C [13], 228–2308C [14]). Com-
pound 10b reacted with cyclohexa-1,3-dione 11a and
with dimedone 11b (Scheme 2) to afford the chromene
derivatives 12a and 12b, respectively, similar to the
behavior of 10a towards the same diketones [4].
Compound 10b interacted with the pyrazolone deriv-
atives 13a–d in two different ways depending on the sub-
stituents of the pyrazolone nucleus. Thus, all pyrazolones
bearing a phenyl substituent (1,3-diphenyl 13a, 3-methyl-
1-phenyl 13b, or 3-phenyl 13c) reacted with 10b to afford
the arylidene exchange products 14a–c, respectively. The
3-methylpyrazolone 13d, however, reacted with 10b to
give the expected pyranopyrazole 15, similar to the
behavior of 10a towards the same substrate [5]. Analytical
and spectral data are in complete agreement with the
depicted structures (Scheme 2) (see section 3, Experimen-
tal). The reaction of 13a–d with 10b is assumed to take
place via the intermediacy of an acyclic Michael adducts,
which either eliminate malononitrile (in case of 13a–c)
to afford 14a–c, or undergo cyclization (in case of 13d)
Compound 4 reacted with phenylisothiocyanate in
refluxing acetone to afford the chromenopyrimidine thi-
one derivative 8 apparently via a thiourea intermediate.
Treatment of compound 4 with triethyl orthoformate in
refluxing acetic anhydride afforded the formimidate 9.
The structures of compounds 6, 8, and 9 were all con-
firmed by spectral and analytical data (see section 3,
Experimental). Similar results have been reported with
analogous chromenes [8] previously. Structure 9 was fur-
ther confirmed by an X–ray crystallographic analysis
(Fig. 2; also see Experimental). The X-ray picture shows
the pyran ring fused to the cyclohexanone ring, and that
both are in the chair conformation. This also affords a
further evidence of all our chromene derivatives pub-
lished earlier [4, 5].
On the other hand, (1H-indol-3-ylmethylene)-malononi-
trile 10b (Scheme 2) was prepared by condensation of
indole-3-carbaldehyde with malononitrile using sodium
ethoxide as the catalyst. This improved method gave a
higher yield (95%) than reported before (85%, [11]), and
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Arch. Pharm. Chem. Life Sci. 2007, 340, 543–548
Bioactive Fused-Pyran Derivatives
545
Scheme 3. Synthesis of compounds 18.
the same chemical shifts (l25–28 ppm) except for com-
pound which showed this carbon downfield
6
(41.48 ppm). This down-field shift is apparently due to
the presence of the acetyl group which causes deshield-
ing as an electron withdrawing group. A similar effect
was observed in a related system in which the C-1 signal
should appear at l26 ppm in the parent compound,
while this signal is down-shifted to 37.3 ppm in the o-ace-
tyl derivative [16].
Scheme 2. Synthesis of compounds 12, 14, and 15.
Molluscicidal activity
The toxicity of compounds 6, 8, 9, 12a, b, 14a–c, 15, and
18a, b toward Biomphalaria alexandrina snails was eval-
uated. The tenth-, quarter-, half-, and sub-lethal doses
(LC10, LC25, LC50, and LC90 in ppm/lM) for each com-
pound were determined and is shown in Table 1.
through addition of the hydroxyl group of the enol tauto-
mer to one of the cyano groups to give 15. It seems that
the presence of a phenyl group in the pyrazolone com-
pounds facilitates the elimination of malononitrile
rather than enolization. A conclusive evidence of struc-
tures 14a–c was obtained from the condensation reac-
tion of the pyrazolones 13a, 13b, and 13c with indole-3-
carbaldehyde. The products obtained were found to be
identical to 14a, 14b, and 14c, respectively in all respects.
It should be noted that compound 14b was reported in
the literature to be obtained also by an arylidene
exchange reaction between 3-methyl-1-phenylpyrazol-5-
one 13b and ethyl indol-3-ylidene cyanoacetate [15].
As an extension of this work, 1,3-indanedione 16
(Scheme 3) was allowed to react with the dinitriles 10a, b
aiming at the formation of indeno[1,2-b]pyran derivatives
17, similar to the behavior of the ß-diketones 11a and 11b
towards 10a, b. However, we only obtained the products
of arylidene exchange 18a, b, respectively. It seems that
due to the presence of the benzene moiety again the elim-
ination of malononitrile from the intermediate is facili-
tated rather than enolization followed by cyclization. For
rigorous structural proof, compounds 18a, b were also
prepared through the reaction of 16 with furan-3-carbal-
dehyde and indole-3-carbaldehyde, respectively.
Inspection of the results listed in Table 1 shows that
most of the tested compounds have moderate to low
effects on the snails relative to bayluscide as a reference,
and generally show very weak activity below 3 ppm. The
most effective of them are 9 and 12b (LC90 = 6 and 7 ppm,
respectively). Compounds 14a-c and 18a, b did not show
any activity at all. These results confirm our previous
observations [4]; that the presence of gem-dimethyl sub-
stituents in the cyclohexanone ring and the fused pyran
ring are prerequisits for enhanced activity. The 3-indolyl
moiety in 12b accomplished more activity (LC50 = 4 ppm;
Table 1) than 3-furyl moiety in 4 (LC50 = 5 ppm [4]) perhaps
due to the fact that the NH of the indolyl moiety affords a
better condition for chelation (cf. Introduction, section
1). However, the formimidate side chain apparently
increases the lipophilicity of 9, which made it slighty
superior to 12b (LC90 = 6 and 7 ppm, respectively). A com-
parison of the molluscicidal activity of the new com-
pounds reported here with the international standard
2‘,5-dichloro-4-nitrosalicylanilide (bayluscide) (LC100
=
1 ppm) [17, 18] showed that our compounds are still infe-
rior as molluscicidal agents. However, compounds 9 and
12b look promising after further structural modifica-
tion, which will be considered in a future study.
A comparative study of the 13C-NMR spectra of all the
chromene compounds 6, 8, 9, 12b, and the pyranopyra-
zole compound 15 showed the pyran C-4 signal almost at
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F. M. Abdelrazek et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 543–548
Table 1. Molluscicidal activity of the synthesized compounds
expressed as LC10, LC25, LC50, and LC90 in ppm (lM).
overnight. The contents of the flask were then poured on ice
cold water and acidified with conc. HCl. The solid precipitate
thus obtained was collected by filtration and recrystallized from
ethanol to afford compound 6 (2.45 g, 75%) as pale yellow crys-
tals; mp 190–1928C (EtOH); C18H18N2O4 (M = 326.35); MS (LC/MS)
m/z 327 [M+H+]; IR 3151, 3111 (NH), 2206 (CN), 1694 (C=O), 1665
(C=O) cm– 1; 1H-NMR (CDCl3) d 1.07 (s, 3H, CH3), 1.15 (s, 3H, CH3),
2.32 (s, 2H, CH2), 2.36 (s, 3H, CH3), 2.57 (s, 2H, CH2), 5.41 (s, 1H,
pyran 4-H), 6.26 (dd, J = 0.8 Hz, J = 1.7 Hz, 1H, furan-4H), 7.30–
7.40 (m, 2H, furan-2H,5H), 11.79 (s, 1H, D2O exchangeable, NH);
13C-NMR (CDCl3) d 27.58 (q), 28.04 (q), 28.75 (q), 32.47 (s), 39.95 (t),
41.48 (d), 50.41 (t), 72.22 (s), 108.19 (d), 112.93 (s), 117.13 (s),
125.11 (s), 140.01 (d), 144.18 (d), 160.91 (s), 163.19 (s) 194.36 (s),
195.74 (s).
Compd. No LC10 ppm
LC25 ppm
LC50 ppm
LC90 ppm
(lM)
(lM)
(lM)
(lM)
Control
–
–
–
–
Bayluscide a2(a6.12)
a2 (a6.12)
a2(a6.12)
a2(a6.12)
6
7 (21.45)
4 (9.54)
2 (5.88)
9.5 (29.11) >10 (>30.64) >10 (>30.64)
8
9
6 (14.30)
a3 (a8.81)
8 (19.07) >10 (23.84)
4 (11.75) 6 (17.63)
7 (22.93) >10 (>32.75)
4 (12.00) 7 (21.00)
12a
12b
14a
14b
14c
15
4 (13.10) a6 (a19.65)
2 (6.00)
a3 (a9.00)
–
–
–
–
–
–
–
–
–
–
–
–
3 (10.30) >4 (>13.73)
6 (20.60) 10 (34.33)
10-Furan-3-yl-4-amino-7,7-dimethyl-3-phenyl-2-thioxo-
1,2,3,4,6,7,8,10-octahydro-9-oxa-1,3-diazaanthracen-5-
18a
18b
–
–
–
–
–
–
–
–
one 8
To a solution of compound 4 (2.84 g, 10 mmol) in dry pyridine
(20mL) was added phenylisothiocyanate (1.35 g, 10 mmol), and
the reaction mixture was refluxed for 2 h, after which it was left
to cool to room temperature. The reaction mixture was then
poured on crushed ice and acidified with HCl until just neutral
to pH paper. The formed paste soon solidified to give an apricot
colored solid, which was filtered off and recrystallized from
ethanol to afford compound 8 (2.90 g, 69%); mp 1838C (EtOH);
C23H21N3O3S (M = 419.50); MS (LC/MS) m/z 420 [M+H+]; IR 3382-
3206 (NH2), 1681 (C=O) cm– 1; 1H-NMR d 0.95 (s, 3H, CH3), 1.05 (s,
3H, CH3), 2.18 (d, J = 16.1 Hz, 1H), 2.28 (d, J = 16.1 Hz, 1H), 2.47 (br
s, 2H, CH2), 4.19 (s, 1H, pyran 4-H), 6.25 (d, J = 0.8 Hz, 1H, furan-
4H), 7.00 (s, 2H, NH2), 7.30–7.60 (m, 7H, furan + phenyl H); 13C-
NMR d 25.88 (d), 26.70 (q), 28.26 (q), 31.67 (s), 39.64 (t), 49.94 (t),
56.80 (s), 109.52 (d), 112.33 (s), 123.55 (d), 125.84 (d), 127.90 (d),
128.54 (s), 138.87 (d), 139.38 (s), 143.22 (d), 149.22 (s), 159.09 (s),
162.40 (s), 179.58 (s), 195.58 (s).
We thank the Alexander-von-Humboldt Foundation (Germany)
for granting a research fellowship to F. M. Abdelrazek from
July to September 2006; during this time, the synthetic part of
this work has been carried out.
Experimental
Melting points were measured on a digital Electrothermal 9100
apparatus (Kleinfeld, Gehrden, Germany) and are uncorrected.
FT-IR spectra (KBr) were obtained on a Nicolet 205 spectropho-
tometer (Nicolet, Madison, WI, USA). 1H-NMR and 13C-NMR spec-
tra were obtained on a Bruker AC 300 P (1H: 300 MHz, 13C: 75.5
MHz; Bruker, Rheinstetten, Germany) in DMSO-d6 if not men-
tioned otherwise. Chemical shifts are expressed in d values. 13
C
Ethyl-N-(3-cyano-4-furan-3yl-7,7-dimethyl-5-oxo-5,6,7,8-
multiplicities were determined using DEPT pulse sequences.
Mass spectra were recorded with a Hewlett Packard Esquire-LC
(LC/MS; Hewlett Packard, Palo Alto, CA, USA). Elemental analyses
were carried out in the microanalytical laboratory of the Depart-
ment of Chemistry, Technische Universitꢀt Dresden. Satisfactory
elemental analysis results (l 0.35%) have been obtained for all
compounds. X-ray data were collected using a Bruker Nonius
5622 diffractometer (Bruker) and were corrected by SADABS fac-
tors and emperical absorption. The structure was solved by
direct methods and expanded using Fourier technique. SCHA-
KAL 99 program system was used in the graphic representation
of the structure [9]. The nonhydrogen atoms are refined aniso-
tropically and the hydrogen atoms were refined according to
theoretical models. Molluscicidal activity tests were conducted
in the Research Institute for Tropical Medicine, Cairo, Egypt. 3-
Furfurylidene malononitrile derivative 10a and the chromene
derivative 4 were prepared according to the methods reported
previously [4].
tetrahydro-4H-chromen-2-yl)formimidate 9
To a solution of compound 4 (2.84 g, 10 mmol) in acetic anhy-
dride (20 mL) was added an excess of triethyl orthoformate
(4.45 g, 30 mmol), and the mixture was heated for 6 h under effi-
cient reflux and then left to cool to room temperature. The sol-
vent was evaporated under vacuum to half of its original vol-
ume, then the flask was left at room temperature for 3 d,
whereby colorless cubic crystals appeared. These were filtered
off and washed thoroughly with cold ethanol to give 9 (2.65 g,
78%); mp 133–1348C (EtOH); C19H20N2O4 (M = 340.37); MS (LC/MS)
m/z 341 [M+1]+; IR 2208 (CN), 1664 (C=O), 1605 (N=C) cm– 1; H-
1
NMR d 0.98 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.31 (t, J = 7.1 Hz, 3H,
CH3), 2.20 (d, J = 16.1 Hz, 1H), 2.30 (d, J = 16.1 Hz, 1H), 2.51 (br s,
2H, CH2), 4.33 (q, J = 7.1 Hz, 2H, CH2), 4.42 (s, 1H, pyran 4-H), 6.36
(s, 1H, furan-H), 7.50–7.60 (m, 2H, furan), 8.54 (s, 1H, N=CH); 13C-
NMR d 13.87 (q), 26.96 (q), 27.59 (q), 28.23 (d), 31.91 (s), 39.98 (t),
50.06 (t), 64.14 (t), 81.17 (s), 109.85 (d), 111.16 (s), 117.40 (s),
126.94 (s), 139.92 (d), 143.65 (d), 156.84 (s), 162.00 (d), 162.95 (s),
195.76 (s). X-ray crystallographic data: light yellow crystals,
C19H20N2O4 (Mr = 340.37 g/mol), triclinic, space group P-1(2), a =
Chemistry
´
´
´
8.041 (1) ꢁ, b = 9.720 (1) ꢁ, c = 12.999 (1) ꢁ, a [O] = 73.52 (1), b [O] =
N-(3-Cyano-4-furan-3-yl-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromen-2-yl)-acetamide 6
Compound 4 (2.84 g, 10 mmol) was refluxed in a mixture of ace-
tic anhydride and pyridine (25 mL; 1 : 1) for 2 h, then left to cool
´
72.25 (1), c [O] = 65.78 (1); V [ꢁ3] = 867.61 (16), Z = 2, Dcalc .= 1.303 g/
cm3, F (000) = 360 e, l (Mo Ka) = 0.092 nm– 1; the final difference
´
Fourier q = 0.30 (–0.27) e ꢁ– 3.crystal dimensions = 0.33 nm N 0.23
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Arch. Pharm. Chem. Life Sci. 2007, 340, 543–548
Bioactive Fused-Pyran Derivatives
547
´
nm N 0.20 nm. Max. resolution [sin h/k] = 0.7 ꢁ– 1/99.1%. Data
were collected using a Bruker Nonius area detector at T (8C) =
198 (2), with graphite monochromator with Mo Ka radiation (k =
Reaction of 10b with the pyrazolones 13a–d; Preparation
of 14a–c and 15
To a refluxing mixture of 2-(1H-indol-3-ylmethylene)-malononi-
trile 10b (1.93 g, 10 mmol) and each of the pyrazolone deriv-
atives 13a–d (10 mmol) in ethanol (25 mL) was added piperidine
(0.5 mL), whereby a homogeneous solution was obtained. Reflux
was continued for about 15 min until colored precipitates
appeared. The mixture was left to cool to room temperature,
and the solids were filtered off and recrystallized from ethanol
to afford the pure products.
´
0.71073 ꢁ) using the CCD data collection and SADABS absorp-
tion correction method; min. 91.5%; max 98.2%. Total independ-
ent reflections are 5044 were counted with observed reflections
3511. Rint = 0.0518. The final R and R2W = 0.0450 and 0.1078,
respectively.
2-(1H-Indol-3-ylmethylene)-malononitrile 10b
A mixture of indole-3-carbaldehyde (7.25 g, 50 mmol) and malo-
nonitrile (3.30 g, 50 mmol) in absolute ethanol (100 mL) was
warmed until complete dissolution. To this solution were added
five drops of a sodium ethoxide solution prepared by dissolving
sodium metal (0.1 g) in dry ethanol (10 mL) while shaking. After
a vigorous exothermic reaction and boiling of the contents of
the flask, a canary yellow precipitate instantly formed. The mix-
ture was left to cool down, triturated with cold ethanol, and the
solid was filtered off and washed thoroughly with cold ethanol
to afford 10b (9.2 g, 95% yield); mp 225–2268C (EtOH); C12H7N3
(M = 193.20); 1H-NMR d 7.20–7.35 (m, 2H), 7.58 (d, J = 7.3 Hz, 1H),
8.03 (d, J = 7.3 Hz, 1H), 8.50 (s, 1H, olefinic H), 8.65 (s, 1H, indole
2-H), 12.70 (br s, 1H, NH); 13C-NMR d 69.26 (s), 110.97 (s), 113.03
(d), 115.91 (s), 115.95 (s), 119.01 (d), 122.55 (d), 123.93 (d), 126.72
(s), 133.23 (d), 136.17 (s), 152.45 (d).
4-(1H-Indol-3-ylmethylene)-2,5-diphenyl-2,4-
dihydropyrazol-3-one 14a
Bright orange cotton like crystals, yield 3.40 g (93%); mp 283–
2848C (EtOH/DMF); C24H17N3O (M = 363.41); MS (LC/MS) m/z 364
[M+H+]; IR 3232–3136 (NH), 1655 (C=O) cm-1; 1H-NMR d 7.20–8.15
(m, 15H, aromatic + olefinic H), 9.90 (br s, 1H, indole 2-H), 12.80
(br s, 1H, NH);13C-NMR 112.54 (s), 113.21 (d), 116.38 (s), 117.96 (d),
118.70 (d), 122.59 (d), 123.81 (d), 124.55 (d), 128.09 (s), 128.69 (d),
128.84 (d), 129.05 (d), 129.47 (d), 131.40 (s), 136.53 (s), 138.56 (d),
138.81 (s), 139.01 (d), 152.17 (s), 162.93 (s).
4-(1H-Indol-3-ylmethylene)-5-methyl-2-phenyl-2,4-
dihydropyrazol-3-one 14b
Reddish-orange crystals, yield 2.16 g (72%); mp 228–2298C
(EtOH/DMF); C19H15N3O (M = 301.34); MS (LC/MS) m/z 302 [M+H+];
IR 3245–3144 (NH), 1651 (C=O) cm– 1; 1H-NMR d 2.40 (s, 3H, CH3),
7.10–8.20 (m, 10H, aromatic + olefinic H), 9.83 (s, 1H, indole 2-
H), 12.70 (s, 1H, NH). 13C-NMR 13.09 (q), 112.34 (s), 113.01 (d),
118.11 (d), 118.41 (s), 118.73 (d), 122.20 (d), 123.62 (d), 124.01 (d),
128.22 (d), 128.79 (d), 136.49 (s), 137.36 (d), 138.32 (d), 138.98 (s),
151.04 (s), 162.88 (s).
2-Amino-4-(1H-indol-3-yl)-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile 12a
To a solution of cyclohexa-1,3-dione 11a (1.12 g, 10 mmol) in tet-
rahydrofuran (25 mL) was added 2-(1H-indol-3-ylmethylene)-
malononitrile 10b (1.93 g, 10 mmol) followed by a few drops of
piperidine. The reaction mixture was stirred at room tempera-
ture for 2 h and then left to stand overnight. The white-pale to
yellow precipitate formed was filtered off and recrystallized
from ethanol to afford the chromene derivative 12a (2.20 g, 72%)
as pale yellow fine crystals; mp 188–1898C (EtOH); C18H15N3O2
(M = 305.33); IR 3460, 3385, 3324, 3214 (NH2, NH), 2192.5 (CN),
4-(1H-Indol-3-ylmethylene)-5-phenyl-2,4-dihydropyrazol-
3-one 14c
Yellow fine needle crystals, yield 2.50g (87%); mp 220–2228C
(MeOH); C18H13N3O (M = 287.32); MS (LC/MS) m/z 288 [M+H+], 310
1
1682.5 (C=O); H-NMR d 1.70–1.85 (m, 2H, CH2), 2.16–2.22 (m,
1
[M+Na+]; IR 3268–3181 (NH), 1660 (C=O) cm-1; H-NMR d 7.25–
2H, CH2), 2.44– 2.54 (m, 2H, CH2), 4.40 (s, 1H, pyran-4H), 6.80 (s,
2H, NH2), 6.85–7.40 (m, 5H, Ph + indole 2H), 10.8 (s, 1H, NH).
8.08 (m, 9H, aromatic H), 8.54 (s, 1H, olefinic H), 8.72 (s, 1H, pyra-
zole NH), 9.87 (s, 1H, indole 2H), 11.60 (s, 1H, indole NH).
2-Amino-4-(1H-indol-3-yl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile 12b
6-Amino-4-(1H-indol-3-yl)-3-methyl-1,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile 15
To a mixture of dimedone 11b (1.4 g, 10 mmol) and 2-(1H-indol-
3-ylmethylene)-malononitrile 10b (1.93 g, 10 mmol) in ethanol
(25 mL) was added a catalytic amount of triethylamine (5 drops).
The mixture was refluxed for 5 min, whereby a coagulated white
precipitate appeared. Heating was stopped, and the flask was
left to cool overnight. The solid was collected by filtration and
recrystallized from dioxane to afford 12b (2.60 g, 79% yield); mp
178–1798C (dioxane); C20H19N3O2 (M = 333.38); MS (LC/MS) m/z
Pale yellow powder, yield 1.8 g (62%); mp 205–2068C (dioxane);
C16H13N5O (M = 291.31); MS (LC/MS) m/z 292 [M+H+]; IR 3371–3132
(NH2, NH), 2178 (CN) cm– 1; 1H-NMR d 1.75 (s, 3H, CH3), 4.85 (s, 1H,
pyran 4-H), 6.75 (s, 2H, NH2), 6.84–7.35 (m, 5H, Ph + indole 2-H),
10.85 (s, 1H, NH), 12.03 (s, 1H, NH); 13C-NMR 9.68 (q), 28.24 (d),
57.80 (s), 97.63 (s), 111.77 (d), 116.94 (s), 118.34 (d), 118.62 (d),
120.97 (d), 121.24 (s), 123.01 (d), 125.41 (s), 135.72 (s), 137.00 (s),
154.98 (s), 160.67 (s).
+
351 [M+NH4 ], 356 [M+Na+]; IR 3405-3153 (NH2, NH), 2186 (CN),
1683 (C=O); 1H-NMR d 0.86 (s, 3H, CH3), 1.02 (s, 3H, CH3), 2.06 (d,
J = 16.1 Hz, 1H), 2.23 (d, J = 16.1 Hz, 1H), 2.46–2.56 (m, 2H, CH2),
4.48 (s, 1H, pyran 4-H), 6.89 (s, 2H, NH2), 6.93–7.35 (m, 5H, Ph +
indole 2H), 10.86 (s, 1H, NH); 13C-NMR 26.78 (q), 27.31 (d), 28.57
(q), 31.75 (s), 39.66 (d or t), 39.82 (d or t), 50.18 (t), 58.57 (s), 111.74
(d), 112.8 (s), 117.62 (s), 118.39 (d), 118.45 (d), 120.28 (s), 120.83
(d), 123.23 (d), 125.38 (s), 136.65 (s), 158.68 (s), 161.76 (s), 195.85
(s).
Reaction of arylidene malononitriles 10a, b with 1,3-
indanedione 16
To a solution of 3-furfurylidenemalononitrile 10a (1.44 g,
10 mmol) or 3-indolylidenemalononitrile 10b (1.93 g, 10 mmol)
in ethanol (25 mL) was added 1,3-indanedione 16 (1.46 g,
10 mmol). To the refluxing mixture were added a few drops of
triethylamine, whereby a precipitate appeared, and the color
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548
F. M. Abdelrazek et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 543–548
turned to dark violet. After cooling to room temperature, the
product was filtered off, washed thoroughly with cold ethanol,
and was then recrystallized to afford the arylidene exchange
products 18a and 18b, respectively. Exactly the same products
were obtained upon reacting 1,3-indanedione 16 with furan-3-
carbaldehyde or indole-3-carbaldehyde, respectively. The iden-
tity of the products was deduced from the mp, 1H-NMR, and ele-
mental analyses.
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canals) to get a homogeneous suspension with the requisite con-
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few drops of Tween 20 and 2 mL of DMSO. Bayluscide was used
as a reference molluscicidal agent. These bioassays are in accord-
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