Synthesis and molluscicidal activity of 5-oxo-5,6,7,8-tetrahydro-4H- chromene derivatives

Article abstract of DOI:10.1002/ardp.200400881

Furfurylidenemalononitriles and thienylidenemalononitriles were treated with 1,3-cyclohexanediones to afford 2-amino-4-hetaryl-5-oxo-5,6,7,8-tetrahydro- 4H-chromene-3-carbonitrile derivatives. The molluscicidal activity of these compounds was investigated.

Full text of DOI:10.1002/ardp.200400881

482 Abdelrazek et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 482−485
Fathy M. Abdelrazeka,
Peter Metza,
Synthesis and Molluscicidal Activity of 5-oxo-
5,6,7,8-Tetrahydro-4H-Chromene Derivatives
Ebtehal K. Farragb
a Institut für Organische
Chemie, Technische
Universität Dresden,
Dresden, Germany
b Medicinal Chemical
Department, National
Research Center, Dokki,
Giza, Egypt
Furfurylidenemalononitriles and thienylidenemalononitriles were treated with
1,3-cyclohexanediones to afford 2-amino-4-hetaryl-5-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile derivatives. The molluscicidal activity of these
compounds was investigated.
Keywords: Furfurylidenemalononitriles; Thienylidenemalononitriles; 1,3-cyclo-
hexanediones; 2-Amino-4-hetaryl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-car-
bonitriles
Received: February 25, 2004; Accepted: June 24, 2004 [FP881]
DOI 10.1002/ardp.200400881
Introduction
Schistosomiasis (bilharziasis) is one of the major
national health problems in Egypt. One approach to
combat this disease is to kill the water snail Biomphal-
aria alexandrina which is the intermediate host of the
infective phase of Schistosoma mansoni in endemic
areas.
Figure 1.
Ricciocarpin A (1) and ricciocarpin B (2) (Figure 1) iso-
lated from the liverwort Ricciocarpos natans were
found to exhibit high molluscicidal activity against the
water snail Biomphalaria glabrata (LC100 = 11 and 43
ppm, respectively) [1]. Metz et al. have reported an
enantioselective synthesis of the molluscicides 1 and
2 via ring closing metathesis [2]. Previously, Abdelra-
zek et al. have reported the synthesis of several
furo[2,3-d]pyrimidine and furo[2,3-b]pyridine deriva-
tives. From those compounds, 3a,b (Figure 1) showed
a moderate molluscicidal activity against Biomphalaria
alexandrina (LC50 = 10 ppm for both compounds) [3].
A common feature of structures 1 and 3a,b is the pres-
ence of the furan moiety. Furthermore, we have also
reported that some pyran derivatives exhibit also a
moderate molluscicidal activity down to LC50 = 10 ppm
[4]. In the light of these data, it was planned to rapidly
construct structural analogs of 1 and/or 2 incorporating
a furan subunit with the aim of obtaining related com-
pounds that might possess potent molluscicidal ac-
tivity.
dimedone (5a) reacts with arylidenemalononitriles to
afford tetrahydrobenzo[b]pyran (chromene) derivatives
[5Ϫ7]. Therefore, it was envisioned that 5a can serve
as a suitable candidate to supply the gem-dimethylcy-
clohexane part, and ,by virtue of its active methylene
and carbonyl groups, it seemed to be a good precursor
for a fused pyran through its reaction with 3-furfuryl-
idenemalononitrile as well. Furthermore, in order to
verify whether the activity (if found) is attributed to the
position of attachment, to the nature of the five-mem-
bered heterocyclic ring, or to the presence of the gem-
dimethyl group at the cyclohexane, the reaction was
carried out with 3- and 2-furfurylidene- as well as 3-
and 2-thienylidenemalononitriles on the one hand and
dimedone (5a) as well as 1,3-cyclohexanedione (5b)
on the other hand.
Results and discussion
Synthesis
Compounds 1 and 2 are essentially assembled from a
pyran fused to a gem-dimethyl-substituted cyclo-
hexane with a 3-furyl substituent (or oxidized deriva-
tive) attached to the pyran. It has been reported that
Furfurylidene- and thienylidenemalononitriles 4aϪd
were prepared via Knoevenagel condensation of the
corresponding aldehydes with malononitrile in the
presence of a basic catalyst as reported in the litera-
ture [5Ϫ10]. These arylidene compounds were al-
lowed to react with both dimedone (5a) and 1,3-cyclo-
hexanedione (5b) to afford a 1:1 adduct in each case
Correspondence: Fathy Mohamed Abdelrazek, Chemistry
Department, Faculty of Science, Cairo University, Giza,
Egypt. Phone: +20 2 330-1651 or +20 2 567-6601, e-mail:
prof fmrazek@yahoo.com
Ϫ
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 482−485
Synthesis of Biologically Active 4H-Chromenes 483
Molluscicidal activity
The toxicity of compounds 6aϪh to Biomphalaria alex-
andrina snails, the intermediate host of Schistosoma
mansoni in Egypt was evaluated as shown in Table 1.
The half lethal dose (LC50 in ppm/nM) for each com-
pound was determined and is shown in Table 2. An
insight inspection of the results listed in Table 2 shows
that the presence of a 3-furanyl substituent along with
a gem-dimethyl group (6a) gives the relatively best re-
sults (5 ppm; 17.6 nM), while a 2-furanyl substituent
with the two methyl groups present (6e) is lower in
activity (8 ppm; 28.17 nM). 3-Furanyl and 2-furanyl
substituents are associated with nearly equal, but
lower, activities in the absence of methyl groups at the
cyclohexane ring (6c, 6g) (11 and 12 ppm; 42.97 and
46.88 nM, respectively). Thiophene derivatives are
generally less active than their furan analogs. 3-Thi-
enyl and 2-thienyl derivatives with methyl groups at
the cyclohexane ring (6b, 6f) show also nearly equal
activities (10 and 11 ppm; 33.33 and 36.66 nM, resp.),
whereas both thienyl derivatives in the absence of
cyclohexane methyl groups are completely inactive
even in concentrations above 17 ppm; 62.50 nM (6d,
6h). In comparison with ricciocarpin A (1) having
LC100 = 11ppm, and with our previous compounds 3a,
b having LC50 = 10ppm; our new compound 6a is
superior in activity. LC50 = 5ppm means that half the
number of the snails die at this concentration and that
any slight increase in the concentration (approx. 6Ϫ7
ppm, not necessarily double the value) will lead to the
death of all snails, which is LC100. A comparison of the
molluscicidal activity of our compounds with an inter-
national standard: 2,5-dichloro-4-nitrosalicylanilide
which is reported to possess LC100 = 1ppm [13, 14]
showed that our compounds are still far inferior as
molluscicidal agents. Thus, the combination of 3-fu-
ranyl substitution at the pyran and a cyclohexane
bearing a gem-dimethyl group is the most promising
Scheme 1.
(Scheme 1). Elemental analyses and spectral data
proved these reaction products to be the tetrahydro-
4H-chromene compounds 6aϪh, respectively (see
Experimental). The 2-furanyl and 2-thienyl derivatives
are generally darker in colour than the 3-substituted
analogs presumably due to the longer conjugation in
the former compounds which causes a shift of the
wave length to the visible region [11]. Formation of
these heterocycles is assumed to proceed via Michael
addition of the active methylene group in 5a or 5b to
the electron-deficient double bond of the ylidenes
4aϪd followed by intramolecular addition of an enol
hydroxyl group to one of the nitrile functions under the
reaction conditions to give the isolated products. A
support of this plausible mechanism has been recently
reported [12].
Table 1. The mean number of snails killed 1 after an exposure time of 24 h at the given concentration.
Compd. No.
1 ppm
3 ppm
5 ppm
7 ppm
9 ppm
11 ppm
13 ppm
15 ppm
17 ppm
6a
6b
6c
6d
6e
6f
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
2
5
8
1
Ϫ
Ϫ
3
Ϫ
Ϫ
Ϫ
10
3
2
Ϫ
8
3
1
Ϫ
10
7
5
Ϫ
10
5
10
10
8
Ϫ
10
10
8
10
10
10
Ϫ
10
10
10
Ϫ
10
10
10
Ϫ
10
10
10
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
2
Ϫ
Ϫ
Ϫ
6g
6h
3
Ϫ
Ϫ
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

484 Abdelrazek et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 482−485
120.99 (s), 145.96 (d), 150.02 (d), 150.14 (d). Anal. calcd. for
C8H4N2O: C, 66.67; H, 2.80; N, 19.44. Found C, 66.32; H,
2.73; N, 19.25.
Table 2. Molluscicidal activity of compounds 6aϪh
expressed as LC50 in ppm.
1,1-Dicyano-2-thien-3-ylethylene (4b)
Compound
LC50
Compound
LC50
(nM)
Yield 90%; pale yellowish crystalline solid, mp 63Ϫ64°C
1
(EtOH); IR 2224 (CN) cmϪ1; H NMR δ 7.51 (dd, J = 2.9 Hz,
6a
6b
6c
6d
5 (17.61)
10 (33.33)
11 (42.97)
>17 (62.50)
6e
6f
6g
6h
8 (28.17)
11 (36.66)
12 (46.88)
>17 (62.50)
J = 4.9 Hz, 1H), 7.70-7.85 (m, 2H), 8.18 (d, J = 1.5 Hz, 1H);
13C NMR δ 80.74 (s), 113.03 (s), 113.77 (s), 126.88 (d),
128.45 (d), 134.02 (s), 136.72 (d), 152.20 (d). Anal. calcd. for
C8H4N2S: C, 59.98; H, 2.52; N, 17.49; S, 20.02. Found C,
60.08; H, 2.54; N, 17.41; S, 20.13.
1,1-Dicyano-2-furan-2-ylethylene (4c) and 1,1-Dicyano-2-
thien-2-ylethylene (4d)
structural feature. Modifications on the basis of this
lead scaffold might further improve molluscicidal activi-
ty, which should be taken into consideration in future
studies.
Yield 4c: 87%, yield 4d: 91%. The data of these two com-
pounds were found to be identical to those reported in the
literature [4Ϫ9].
Reaction of arylidenemalononitriles 4aϪd with dimedone (5a)
and 1,3-cyclohexanedione (5b) (general procedure)
Acknowledgments
To a solution of dimedone (5a) (1.4 g, 10 mmol) or 1,3-cyclo-
hexanedione (5b) (1.12 g, 10 mmol) in dry ethanol (20 mL)
the appropriate arylidene derivative (10 mmol) was added, as
well as 5 drops of morpholine as catalyst. The reaction mix-
ture was heated gently until the contents of the flask dis-
solved and then stirred at room temperature until a precipitate
appeared (usually 1 h). Otherwise, the reaction mixture was
refluxed for 30 min, after which the products precipitated. In
any case, the reaction mixture was allowed to cool to room
temperature, poured on ice-cold water and neutralized by
dropwise addition of conc. HCl. The precipitated solids were
filtered off and recrystallized from ethanol to afford the pure
products.
We are indebted to the Alexander von Humboldt Foun-
dation (Germany) for granting a research fellowship to
F. M. Abdelrazek from July to September 2003; during
this time the synthetic part of this work has been car-
ried out.
Experimental
Melting points were measured on an Electrothermal 9100 ap-
paratus (Kleinfeld, Gehrden, Germany) and are uncorrected.
FT-IR spectra (KBr) were obtained on a Nicolet 205 spectro-
photometer (Nicolet, Madison, WI, USA). 1H NMR and 13C
NMR spectra were obtained on a Bruker AC 300 P (1H: 300
MHz, 13C: 75.5 MHz; Bruker, Rheinstetten, Germany) in
CDCl3 unless mentioned otherwise using TMS as internal ref-
2-Amino-4-furan-3-yl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (6a)
Yield 91%; yellow granules, mp 181Ϫ183°C (EtOH); IR
erence. Chemical shifts are expressed in δ (ppm) values. 13
C
3400, 3330, 3216 (NH2), 2196 (CN), 1657 (CO) cmϪ1 1H
;
multiplicities were determined using DEPT pulse sequences.
Elemental analyses were carried out in the microanalytical
laboratory of the Institut für Organische Chemie, Technische
Universität Dresden. Molluscicidal activity tests were conduc-
ted in the Medicinal Chemical Department, Laboratory of
Parasitology, National Research Center of Egypt.
NMR δ 1.03 (s, 3H), 1.11 (s, 3H), 2.26 (s, 2H), 2.40 (s, 2H),
4.43 (s, 1H), 4.70 (s, 2H, D2O exchangeable, NH2), 6.27 (d,
J = 0.8 Hz, 1H), 7.25-7.35 (m, 2H); 13C NMR δ 26.07 (d),
27.52 (q), 28.88 (q), 32.12 (s), 40.73 (t), 50.75 (t), 62.08 (s),
109.58 (d), 113.88 (s), 118.62 (s), 127.52 (s), 139.71 (d),
143.06 (d), 158.28 (s), 161.61 (s), 195.80 (s). Anal. calcd. for
C
16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found C, 67.41; H,
Furfurylidene and thienylidene derivatives 4aϪd (general
procedure)
5.62; N, 9.83.
2-Amino-4-thien-3-yl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (6b)
To the appropriate aldehyde (10 mmol) in dry ethanol (20 mL)
malononitrile (0.66 g, 10 mmol) and 2Ϫ3 drops of sodium
ethoxide solution in dry ethanol were added, whereupon the
content of the flask boiled vigorously. After allowing the mix-
ture to cool to room temperature, crystalline products precipi-
tated, which were filtered off and washed several times with
cold ethanol to afford analytically pure compounds.
Yield 93%; fine white needles, mp 214Ϫ215°C (EtOH); IR
3370, 3320, 3206 (NH2), 2196 (CN), 1656 (CO) cmϪ1 1H
;
NMR δ 1.03 (s, 3H), 1.11 (s, 3H), 2.25 (s, 2H), 2.42 (s, 2H),
4.56 (s, 1H), 4.58 (s, 2H), 6.95 (dd, J = 1.3 Hz, J = 5.0 Hz,
1H), 7.09 (dd, J = 1.3 Hz, J = 2.9 Hz, 1H), 7.21 (dd, J = 2.9
Hz, J = 5.0 Hz, 1H); 13C NMR δ 27.63 (q), 28.87 (q), 30.36
(d), 32.16 (s), 40.69 (t), 50.68 (t), 62.93 (s), 114.13 (s), 118.68
(s), 125.88 (d), 126.74 (d), 127.75 (d), 143.84 (s), 157.86 (s),
161.44 (s), 195.84 (s). Anal. calcd. for C16H16N2O2S: C,
63.98; H, 5.37; N, 9.33; S, 10.67. Found C, 64.09; H, 5.32;
N, 9.28; S, 10.63.
1,1-Dicyano-2-furan-3-ylethylene (4a)
Yield 85%; grey solid crystals, mp 119Ϫ120°C (EtOH); IR
2232, 2222 (CN) cmϪ1 1H NMR δ 7.19 (d, J = 2.1 Hz, 1H),
;
7.59 (apparent t, J = 1.4 Hz, 1H), 7.69 (s, 1H), 8.06 (s, 1H);
13C NMR δ 81.65 (s), 108.08 (d), 112.66 (s), 113.42 (s),
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 482−485
Synthesis of Biologically Active 4H-Chromenes 485
2-Amino-4-furan-3-yl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (6c)
centrations (nine) ranging from 1 ppm to 17 ppm of each
compound under investigation was prepared. The required
amount of the compound under investigation was mixed thor-
oughly with few drops of Tween 20 followed by addition of
the appropriate volume of untreated raw water (taken direcly
from the River Nile or its subsidary branches/canals) to get a
homogeneous suspension with the necessary concentration;
it was poured in glass jar vessels 15 ϫ 25 ϫ 20 cm dimen-
sions fitted with air bubblers. Ten snails having the same size
and diameter (ca. 7 mm) were used in each experiment and
maintained in the test solution under laboratory conditions at
ambient temperature for 24 h. Each experiment was repeated
three times and the mean number of killed snails was taken
for each concentration as shown in Table 1. A control group
was taken by placing 10 snails in water containing few drops
of Tween 20. These bioassays are in accordance with the
W.H.O. guidelines [15].
Yield 73%; fine yellow crystals, mp 187Ϫ189°C (EtOH); IR
3460, 3337 (NH2), 2199 (CN), 1651 (CO) cmϪ1 1H NMR δ
;
1.90Ϫ2.10 (m, 2H), 2.30-2.60 (m, 4H), 4.45 (s, 1H), 4.57 (s,
2H, D2O exchangeable, NH2), 6.29 (s, 1H), 7.27-7.33 (m,
2H). Anal. calcd. for C14H12N2O3: C, 65.62; H, 4.72; N, 10.93.
Found C, 65.62; H, 4.67; N, 10.85.
2-Amino-4-thien-3-yl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (6d)
Yield 75%; cotton white hairy needles, mp 213Ϫ215°C
(EtOH); IR 3307, 3165 (NH2), 2188 (CN), 1647 (CO) cmϪ1
;
1H NMR δ 1.90-2.10 (m, 2H), 2.30-2.50 (m, 2H), 2.53-2.60
(m, 2H), 4.56 (s, 1H), 4.60 (s, 2H, D2O exchangeable, NH2),
6.97 (dd, J = 1.3 Hz, J = 5.0 Hz, 1H), 7.09 (dd, J = 1.3 Hz,
J = 3.0 Hz, 1H), 7.21 (dd, J = 3.0 Hz, J = 5.0 Hz, 1H); 13C
NMR δ 20.09 (t), 27.01 (t), 30.30 (d), 36.77 (t), 62.75 (s),
115.33 (s), 118.68 (s), 121.78 (d), 125.85 (d), 126.88 (d),
143.92 (s), 157.83 (s), 163.13 (s), 195.92 (s). Anal. calcd. for
C14H12N2O2S: C, 61.75; H, 4.44; N, 10.29; S, 11.77. Found
C, 61.79; H, 4.34; N, 10.11; S, 11.49.
References
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2565Ϫ2568; G. Wurzel, H. Becker, T. Eicher, K. Tiefen-
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2-Amino-4-furan-2-yl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (6e)
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Yield 74%; fine brownish needles, mp 210Ϫ211°C (EtOH)
(Ref. [5] 209Ϫ210°C, Ref. [6] 200Ϫ202°C).
2-Amino-4-thien-2-yl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (6f)
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Yield 76%; dark buff fine needles, mp 214Ϫ215°C (EtOH)
(ref [6] 214Ϫ216°C).
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3-carbonitrile (6g)
[5] X. S. Wang, D. Q. Shi, S. J. Tu, C. S. Yao, Synth. Com-
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Yield 70%; reddish brown powder, mp 232Ϫ233°C (EtOH);
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IR 3462, 3224 (NH2), 2197 (CN), 1675 (CO) cmϪ1 1H NMR
;
(DMSO-d6) δ 1.90-2.07 (m, 2H), 2.32-2.58 (m, 4H), 4.50 (s,
1H), 7.10 (s, 2H, D2O exchangeable, NH2), 6.25-7.35(m, 3H).
Anal. calcd. for C14H12N2O3: C, 65.62; H, 4.72; N, 10.93.
Found C, 65.48; H, 4.54; N, 10.71.
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3-carbonitrile (6h)
H. W. Scheeren, Tetrahedron 1988, 44, 6491Ϫ6504.
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869Ϫ876.
Yield 72%; brownish needles, mp 204Ϫ205°C (EtOH); IR
3327, 3265 (NH2), 2198 (CN), 1670 (CO) cmϪ1 1H NMR
;
(DMSO-d6)
δ 1.90Ϫ2.05 (m, 2H), 2.32Ϫ2.40 (m, 2H),
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2.51Ϫ2.58 (m, 2H), 4.53 (s, 1H), 6.85 (apparent dt, Jd = 3.4
Hz, Jt = 0.8 Hz, 1H), 6.91 (dd, J = 3.4 Hz, J = 5.0 Hz, 1H),
7.09 (s, 2H, D2O exchangeable, NH2), 7.31 (dd, J = 1.4 Hz,
J = 5.0 Hz, 1H). Anal. calcd. for C14H12N2O2S: C, 61.75; H,
4.44; N, 10.29; S, 11.77. Found C, 61.68; H, 4.34; N, 10.41;
S, 11.72.
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192Ϫ198.
Molluscicidal activity tests
[12] T.-S. Jin, A.-Q. Wang, X. Wang, J.-S. Zhang, T.-S. Li,
The molluscicidal activity tests were carried out by determi-
nation of the half lethal dose LC50 of each compound under
investigation. Biomphalaria alexandrina snails were collected
from the field (water canals) and maintained under laboratory
conditions for a period of 45 days before the test and fed daily
with lettuce leaves. Then, the snails were examined to ensure
that they were free from parasitic infection. A series of con-
Synlett 2004, No.5, 871Ϫ873.
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 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim