Synthesis and molluscicidal evaluation of some new pyrazole, isoxazole, pyridine, pyrimidine, 1,4-thiazine and 1,3,4-thiadiazine derivatives incorporating benzofuran moiety

Article abstract of DOI:10.1016/j.ejmech.2010.07.043

Chalcone derivative 3 was synthesized via the base catalyzed Claisen-Schmidt condensation and was used as a precursor for synthesizing pyrazoline 11, isoxazoline 12, pyrazoline carbothioamide 13, 5,6-dihydropyrimidine-2-(1H)-thione 14 and aminopyridinecarbonitrile derivative 15. Bromination of 3 afforded the dibromo derivative 4. Monobromo derivative 5 obtained by boiling 4 in dry benzene in the presence of triethylamine. Fused thiadiazines 9a,b and 1,4-thiazine 9c derivatives were synthesized upon treatment of α-bromopropenone derivative 5 with 4-amino-4H-1,2,4-triazole- 3-thiol (6) or 1-amino-2-mercapto-5-methylpyrimidin-4(1H)-one (7) or with 2-aminothiophenol (8) in ethanolic potassium hydroxide solution. The newly synthesized compounds were screened for their molluscicidal activities, whereas compounds 3, 4, 9a, 11 and 15 exhibited promising molluscicidal activities. On the other hand compounds 5, 9b, 9c, 12, 13 and 14 showed a moderate effect as compared to the standard molluscicidal agent (Bayluscide).

Full text of DOI:10.1016/j.ejmech.2010.07.043

European Journal of Medicinal Chemistry 45 (2010) 4783e4787
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and molluscicidal evaluation of some new pyrazole, isoxazole, pyridine,
pyrimidine, 1,4-thiazine and 1,3,4-thiadiazine derivatives incorporating
benzofuran moiety
,
M.F. El Shehry a, R.H. Swellem a, Sh.M. Abu-Bakr b, E.M. El-Telbani a
*
a National Research Centre, Green Chemistry Department, El-Tahrir Street, 12622 Dokki, Cairo, Egypt
b National Research Centre, Chemistry of Natural and Microbial Products Department, 12622 Dokki, Cairo, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Chalcone derivative 3 was synthesized via the base catalyzed ClaiseneSchmidt condensation and was
used as a precursor for synthesizing pyrazoline 11, isoxazoline 12, pyrazoline carbothioamide 13,
5,6-dihydropyrimidine-2-(1H)-thione 14 and aminopyridinecarbonitrile derivative 15. Bromination of 3
afforded the dibromo derivative 4. Monobromo derivative 5 obtained by boiling 4 in dry benzene in the
presence of triethylamine. Fused thiadiazines 9a,b and 1,4-thiazine 9c derivatives were synthesized upon
Received 20 March 2010
Received in revised form
10 July 2010
Accepted 27 July 2010
Available online 4 August 2010
treatment of a-bromopropenone derivative 5 with 4-amino-4H-1,2,4-triazole-3-thiol (6) or 1-amino-2-
mercapto-5-methylpyrimidin-4(1H)-one (7) or with 2-aminothiophenol (8) in ethanolic potassium
hydroxide solution. The newly synthesized compounds were screened for their molluscicidal activities,
whereas compounds 3, 4, 9a, 11 and 15 exhibited promising molluscicidal activities. On the other hand
compounds 5, 9b, 9c, 12, 13 and 14 showed a moderate effect as compared to the standard molluscicidal
agent (Bayluscide).
Keywords:
Chalcone
Benzofuran
Pyrazole
1,3,4-Thiadiazine
1,4-Thiazine
Molluscicidal agents
Ó 2010 Elsevier Masson SAS. All rights reserved.
1. Introduction
optical brighteners. Moreover, many of the natural benzo[b]furans
have physiological, pharmacological and toxic properties [11].
Schistosomiasis (bilharziasis) is an endemic disease caused by
helminthes belonging to the genus schistosoma. This disease
affects more than 200 million people and places with more than
600 million inhabitants are at risk of infection in more than 70
countries in the tropics WHO [1]. In view of its prevalence and
morbidity this disease is a serious public health problem in many
countries especially Egypt and one of the great efforts made to
combat this disease is combating the water snails Biomphlaria
alexandrina, the intermediate host of the infective phase of schis-
tosoma mansoni, through molluscicides to control the vector snails
with easy and cheap procedures.
Chalcones are natural biocides [2] and well known as interme-
diates for synthesizing of various heterocycles which have
impressive array of biological activities [3e5]. In addition, benzo-
furan derivatives are nowadays an important class of organic
compounds that occur in a great number of natural products [6],
used in cosmetics [7] and as synthetic pharmaceuticals [8,9]. Benzo
[b]furans build blocks for fluorescent sensors [10], and are used as
In the present study we are just making the so called prelimi-
nary blind screening until we find the suitable effective lead
compounds, then we can modifying its properties, evaluate its
biodegradability stability as well as its effect on the other water
living organisms.
2. Results and discussion
2.1. Chemistry
2-Acetylbenzofuran (1) and 3-(benzofuran-2-yl)-1-phenyl-1H-
pyrazole-4-carbaldehyde (2) [12] reacted in the presence of
aqueous sodium hydroxide yielded the 1,3-disubstituted prop-2-
en-1-one derivative 3. Bromonation of 3 with bromine in chloro-
form yielded 2,3-dibromo-1,3-disubstituted propan-1-one 4 in
good yield. Compound 4 undergoes dehydrobromonation by using
triethylamine in dry benzene yielded 2-bromo-1,3-disubstituted
prop-2-en-1-one 5. The 1H, 13C NMR and mass spectrum of 5
supported the structure. (cf. Scheme 1).
In a one pot reaction between 4 and 6 or 7 or with 8 in the
presence of triethylamine in absolute ethanol, there are three
possibilities for that reaction. The first is the attack at C2 to give
* Corresponding author. Tel.: þ202 333 711211 1428; fax: þ202 33370931.
E-mail address: e_misbah@yahoo.co.uk (E.M. El-Telbani).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.07.043

4784
M.F. El Shehry et al. / European Journal of Medicinal Chemistry 45 (2010) 4783e4787
9aec were confirmed by 1H NMR, mass and elemental analysis
(cf. Scheme 3).
Ar
Ar`
O
O
aq. NaOH
EtOH
+
Ar`
O
O
Ar
H
Various interesting heterocycle skeletons were synthesized via
reaction of 3 with hydrazine hydrate or with hydroxylamine
hydrochloride in refluxing ethanol afforded the corresponding 4,5-
dihydropyrazole derivative 11 and 4,5-dihydroisoxazole derivative
12 respectively. On the other hand, when compound 3 was
condensed with thiosemicarbazide or with thiourea in boiling
ethanolic alkaline medium yielded 4,5-dihydropyrazole carbo-
thioamide derivative 13 and 5,6-dihydropyrimidine-2-(1H)-thione
derivative 14 respectively. Moreover, when compound 3 reacted
with malononitrile in boiling ethanol in the presence of a catalytic
amount of ammonium acetate yielded aminopyridinecarbonitrile
derivative 15. Spectral data (1H, 13C NMR, mass and elemental
analysis) of all the newly synthesized compounds were in full
agreement with the proposed structures (cf. experimental and
Scheme 4).
3
1
2
Br2 / CHCl3
Br
Br
Ar
Ar`
Ar
Ar`
Et3N
dry benzene
O
Br
5
4
O
Ar =
Ar` =
N
N
O
Ph
Scheme 1. The reaction sequences of the formation of
a
-bromopropenone derivative 5.
thiadiazines 9a,b and thiazine 9c derivatives, the second is the
attack at C3 to yield the fused thiadiazepines 10a,b and thiazepine
10c derivatives, finally dehydrobromonation may take place to
afford 5. On the other hand, the unexpected chalcone derivative 3
obtained as the major product, which was confirmed by spectro-
scopic and analytical data. This could be attributed to dehydro-
bromination of two molecules of hydrogen bromide under mild
basic condition.
It worthily mentioned that, the above reaction was carried out in
two steps. Initially, triethylamine was added to dibromo derivative
4 in absolute ethanol and refluxed for 1 h. To this reaction mixture
compound 6 or 7 or 8 was added and refluxed for further 6 h, which
yielded 9aec rather than 10aec, respectively. Compounds 9aec
were also synthesized by an alternate route to confirm their
2.2. Molluscicidal activity
The mortality of compounds 3, 4, 5, 9aec, 11, 12, 13, 14 and 15
toward B. alexandrina snails was screened. An insight inspection of
the results listed in Table 1 shows that compounds 3, 9a, 11 and 15
have high effect but all the other compounds have moderate to low
effect, they all showed very weak activity below 5 ppm. The data
obtained showed promising result especially the compounds that
possess triazolo and pyrazolo residues, this data was in a good
agreement with our previous reports [13,14]. The comparison of the
molluscicidal activity of the tested compounds reported here with
the international standard 20,5-dichloro-4-nitrosalicylanilide
(Bayluscide) [15,16] showed that our compounds are still far infe-
rior as molluscicidal agents.
formation, when a-bromopropenone derivative 5 was treated with
6 or 7 or with 8 in the presence of potassium hydroxide in ethanol,
compounds 9aec were obtained as a sole products rather than
10aec. (cf. Scheme 2).
3. Material and methods
A mechanism for the formation of 9aec involves the formation
of 5 at first by refluxing 4 with triethylamine in absolute ethanol.
When compounds 6, 7 or 8 were added to the reaction mixture
Schiff base was formed, further nucleophlic attack at C2 resulted
in cyclization and subsequent dehydrobromonation yielding fused
thiadiazines 9a,b and thiazine 9c derivatives rather than fused
thiadiazepines 10a,b or thiazepine 10c derivatives. Compounds
3.1. General
All melting points were determined on an Electrothermal 9100
digital melting point apparatus. NMR and mass spectra were
recorded on: 1H, 13C NMR spectra were determined using Jeol JMS-
AX 500 MHz, Jeol GLM EX 270 MHz FT NMR spectrophotometer,
DMSO-d6, TMS as internal standard, chemical shift in d (ppm). Mass
spectra were recorded on Varian MAT 311 A at 70 ev. Elemental
analysis (in accord with the calculated values) was carried out in
the microanalytical unit, Faculty of Science, Cairo University. Pre-
coated silica gel 60 F254 plats with a layer thickness 0.25 nm from
Merck were used for thin layer chromatography. Yields are not
optimized.
C1
N
Ar
Y
X
Br
Z
Br
Ar`
Ar
Ar`
W
C2
S
9a-c
Ar
Ar`
C3
O
Br
4
5
O
attack at C2
attack at C3
attack at C2
attack at C3
Et3N/
KOH
+
+
EtOH
EtOH
3.2. 1-(Benzofuran-2-yl)-3-(3-(benzofuran-2-yl)-1-phenyl-1H-
pyrazol-4-yl) prop-2-en-1-one (3)
6 or 7 or 8
6 or 7 or 8
Ar
C1
N
Y
Z
W
X
To a solution of 1 (10 mmol) in absolute ethanol (20 mL) and
aqueous solution of 10% NaOH (10 mL) the aldehyde 2 (10 mmol)
was added with constant stirring and the resulting solution was
heated to 80 ꢀC for 4 h, cooled to room temperature, and was stand
overnight. The solid obtained was separated, collected by filtration,
dried and recrystallized from ethanol. Yield, 80%; m.p. 190e192 ꢀC;
C2
Ar =
O
O
S
C3
Ar`
10a-c
N
Ar` =
a: X = Z = W = N. Y = CH
b: X = Z = W = N, Y = (CMe)CO
c: X = CH = CH, Z = W = Y = CH
N
Ph
1H NMR (DMSO-d6)
1H, furan H-3), 7.25e8.10 (m, 15H, Ar-H, furan H-3 and olefinic
eCH]), 9.50 (s, 1H, pyrazole H-5). 13C NMR (DMSO-d6)
: 98.5,
d
: 7.10 (d, 1H, J ¼ 12.5 Hz, olefinic CH]), 7.15 (s,
O
NH2
NH2
SH
NH2
SH
Me
N
N
d
;
6 =
;
7 =
8 =
N
N
107.0, 111.5, 115.9, 119.3, 121.1, 123.3, 123.5, 123.7, 126.2, 127.5, 128.8,
129.4, 129.5, 131.1, 139.5, 141.0, 145.2, 150.0, 155.0, 161.7, 177.4. MS,
m/z (%): 430 [Mþ] (25.8), 353 (1.2), 313 (1.42), 285 (100), 145 (10.9),
SH
N
N
Scheme 2. Synthesis of thiadiazines and thiazine derivatives 9aec.

M.F. El Shehry et al. / European Journal of Medicinal Chemistry 45 (2010) 4783e4787
4785
Scheme 3. A plausible mechanism for the formation of 9aec.
117 (4.1), 89 (60.3), 77 (67.7). Anal. Calcd. For C28H18N2O3 (430.46):
C, 78.13; H, 4.21; N, 6.51. Found: C, 78.23; H, 4.15; N, 6.46.
room temperature for 24 h. After removal of the separated trie-
thylamine hydrobromide, the filtrate was concentrated under
reduced pressure. The residue was recrystallized from ethanol.
Yield, 65%; m.p. 204e206 ꢀC; 1H NMR (DMSO-d6)
d
: 7.10e7.90 (m,
14H, Ar-H and olefinic eCH]Ce), 8.50, 8.80 (2s, 2H, benzofuran
H-3), 9.60 (s, 1H, pyrazole H-5). 13C NMR (DMSO-d6)
: 98.7, 113.4,
3.3. 1-(Benzofuran-2-yl)-3-(3-(benzofuran-2-yl)-1-phenyl-1H-
pyrazol-4-yl)-2,3-dibromopropan-1-one (4)
d
118.2, 120.3, 121.1, 121.3, 122.3, 122.9, 123.1, 124.1, 126.8, 127.5,
129.4, 130.3, 131.8, 134.3, 135.6, 141.1, 152.9, 156.2, 158.1, 172.5. MS,
m/z (%): 508 [Mþ] (12.5), 431 (35), 428 (12.9), 363 (17.8), 259 (45),
248 (18.9), 145 (12.6), 117 (64.6), 77 (100). Anal. Calcd. For
C28H17BrN2O3 (509.35): C, 66.03; H, 3.36; N, 5.50. Found: C, 66.10;
H, 3.28; N, 5.46.
Bromine (10 mmol) was added dropwise with vigorous stirring
to a solution of 3 (10 mmol) in (30 mL) chloroform at room
temperature over 30 min. After complete addition, the reaction
mixture was allowed to stand for an hour. The precipitate formed
was filtered off, washed with ether to remove the excess of
bromine and recrystallized from ethanol. Yield, 85%; m.p.
170e172 ꢀC; 1H NMR (DMSO-d6)
d: 5.40 (d, 1H, eCHeCHe,
J ¼ 9.2 Hz), 5.80 (d, 1H, eCHeCHe, J ¼ 8.3 Hz), 7.20e7.90 (m, 13H,
3.5. General procedure for synthesis of thiadiazines (9a,b) and
thiazine (9c)
Ar-H), 8.00, 8.10 (2s, 2H, benzofuran H-3), 9.00 (s, 1H, pyrazole H-
5). 13C NMR (DMSO-d6)
d: 48.8, 54.7, 98.4, 110.8, 113.4, 119.4, 120.3,
121.1, 121.6, 122.3, 123.4, 123.5, 124.6, 127.5, 129.4, 135.6, 143.1,
150.9, 153.5, 156.7, 158.9, 179.1. MS, m/z (%): 589 [Mþ] (37), 509
(12.5), 470 (24.5), 259 (100), 236 (45), 145 (3.6), 117 (5.9), 77 (85).
Anal. Calcd. For C28H18Br2N2O3 (590.26): C, 56.97; H, 3.07; N, 4.75.
Found: C, 56.88; H, 3.13; N, 4.66.
Method A: A mixture of compound 4 (10 mmol) and triethyl-
amine (20 mmol) in absolute ethanol (50 mL) was refluxed for 1 h.
To the resulting reaction mixture (10 mmol) compounds 6, 7 and 8
were added individually and refluxed for 6 h. The resulting solid
was filtered off, washed with water and recrystallized to give 9a, 9b
and 9c respectively.
3.4. 1-(Benzofuran-2-yl)-3-(3-(benzofuran-2-yl)-1-phenyl-1H-
pyrazol-4-yl)-2-bromoprop-2-en-1-one (5)
Method B: A mixture of compound 5 (10 mmol) and compounds
6, 7, 8 (10 mmol) were added individually in alcoholic potassium
hydroxide solution (15 mmol) and refluxed in absolute ethanol
(30 mL) for 6 h. The precipitated solid was filtered off, washed with
water and recrystallized to yield 9aec.
Triethylamine (40 mmol) in dry benzene (30 mL) was added to
a solution of 4 (10 mmol) in dry benzene (50 mL) with stirring at
Ar
Ar
NH2OH . HCl
NH2NH2 . H2O
N
Ar
Ar`
N
Ar`
Ar`
O
N
H
O
3
12
11
NH2NHCSNH2
Ar
CH2(CN)2
NH2CSNH2
Ar
Ar`
Ar
Ar`
N
N
S
Ar`
N
N
CN
HN
NH2
15
NH2
S
14
13
O
Ar =
Ar` =
N
N
O
Ph
Scheme 4. 1,3-Addition to chalcone derivative 3 to form compounds 11e15.

4786
M.F. El Shehry et al. / European Journal of Medicinal Chemistry 45 (2010) 4783e4787
Table 1
The solid product was filtered off and recrystallized from ethanol.
Yield, 70%; m.p. 180e182 ꢀC; 1H NMR (DMSO-d6)
: 3.10 (dd, 1H,
Molluscicidal activity of compounds 3e15 on Biomphlaria alexandrina snails (10
snails by concentrations) under laboratory conditions and after 24 h exposure.
d
CH2 pyrazoline, J ¼ 16.3, 12.3 Hz), 3.70 (dd, 1H, CH2 pyrazoline,
J ¼ 10.7, 8.7 Hz), 5.30 (dd, 1H, CH pyrazoline, J ¼ 12.4, 9.6 Hz), 6.80
(br s, 1H, NH), 7.10e7.90 (m, 13H, Ar-H), 8.10, 8.70 (2s, 2H, benzo-
Compd. no.
Different concentration used in (ppm)
1
5
10
furan H-3), 8.80 (s, 1H, pyrazole H-5). 13C NMR (DMSO-d6)
d: 39.4,
3
4
5
9a
9b
9c
11
12
0
0
0
0
0
0
0
0
0
0
0
7
5
2
6
1
0
3
0
1
0
3
10
8
5
9
4
3
7
3
4
55.2, 97.9, 105.3, 111.3, 111.5, 115.1, 118.0, 119.2, 119.4, 122.1, 123.0,
123.6, 124.2, 124.5, 126.3, 128.5, 129.4, 139.5, 140.0, 145.2, 150.0,
155.4, 156.1. Anal. Calcd. For C28H20N4O2 (444.49): C, 75.66; H, 4.54;
N, 12.60. Found: C, 75.58; H, 4.47; N, 12.67.
3.7. 3-(Benzofuran-2-yl)-4-(3-(benzofuran-2-yl)-4,5-
dihydroisoxazol-5-yl)-1-phenyl-1H-pyrazole (12)
13
14
15
3
8
To a solution of 3 (5 mmol) in absolute ethanol (15 mL),
hydroxylamine hydrochloride (0.3 g) and freshly fused anhydrous
sodium acetate (3.0 g) were added and the reaction mixture was
heated under reflux for 7 h on a water bath. The content of the flask
was poured onto ice water with stirring. The separated solid was
filtered off, washed with water and dried. Further purification was
done by recrystallization from ethanol. Yield, 55%; m.p.175e177 ꢀC;
Bayluscide
10
10
10
3.5.1. 6-(Benzofuran-2-yl)-7-((3-(benzofuran-2-yl)-1-phenyl-1H-
pyrazol-4-yl)methylene)-7H-[1,2,4] triazolo [3,4-b][1,3,4]
thiadiazine (9a)
The compound 9a was obtained from the reaction of 4-amino-
4H-1,2,4-triazole-3-thiol (6) (10 mmol), recrystallized from (EtOH/
1H NMR (DMSO-d6)
d
: 3.80 (dd, 1H, CH2 isoxazoline, J ¼ 13.1,
10.3 Hz), 4.00 (dd, 1H, CH2 isoxazoline, J ¼ 9.2, 7.8 Hz), 6.20 (dd, 1H,
isoxazoline H-5, J ¼ 13.4, 8.5 Hz), 7.10e7.80 (m, 13H, Ar-H), 7.90,
8.30 (2s, 2H, benzofuran H-3), 8.90 (s, 1H, pyrazole H-5). 13C NMR
DMF). Yield, 55%; m.p. 257e259 ꢀC; 1H NMR (DMSO-d6)
d: 6.80 (s,
1H, ]CHe), 7.10e7.90 (m, 14H, Ar-H and triazole H-3), 8.40, 8.80
(2s, 2H, benzofuran H-3), 9.00 (s,1H, pyrazole H-5). 13C NMR
(DMSO-d6) d: 38.7, 59.8, 98.7, 105.1, 111.2, 111.5, 114.3, 118.4, 119.2,
(DMSO-d6) d: 97.1, 111.7, 113.4, 118.8, 119.9, 120.3, 120.6, 122.3, 123.1,
119.3, 122.3, 122.6, 123.6, 124.4, 125.0, 128.5, 129.4, 129.5, 139.7,
140.1, 145.2, 155.1, 156.3, 164.2. MS, m/z (%): 445 [Mþ] (31.7), 428
(14.6), 337 (31.4), 321 (40.6), 295 (11.6), 257 (13.2), 285 (59.8), 115
(23.8), 89 (26.5), 77 (100). Anal. Calcd. For C28H19N3O3 (445.48): C,
75.49; H, 4.30; N, 9.43. Found: C, 75.40; H, 4.38; N, 9.37.
123.5, 123.8, 125.1, 125.9, 127.5, 129.4, 134.1, 140.5, 143.3, 147.7,
152.9, 154.4, 155.2, 157.2, 159.5, 159.9. MS, m/z (%): 526 [Mþ] (12.5),
411 (43.4), 407 (11.8), 267 (21.4), 260 (13), 117 (14.2), 113 (7.7), 77
(100). Anal. Calcd. For C30H18N6O2S (526.51): C, 68.43; H, 3.45; N,
15.96. Found: C, 68.36; H, 3.51; N, 15.83.
3.8. 3-(Benzofuran-2-yl)-5-(3-(benzofuran-2-yl)-1-phenyl-1H-
pyrazol-4-yl)-4,5-dihydropyrazole-1-carbothioamide (13)
3.5.2. 3-(Benzofuran-2-yl)-2-((3-(benzofuran-2-yl)-1-phenyl-1H-
pyrazol-4-yl)methylene)-7-methylpyrimido[2,1-b][1,3,4]thiadiazin-
8(2H)-one (9b)
The compound 9b was obtained from the reaction of 1-amino-2-
mercapto-5-methylpyrimidin-4(1H)-one (7) (10 mmol), recrystal-
lized from (EtOH/DMF). Yield, 45%; m.p. 200e202 ꢀC; 1H NMR
To a mixture of compound 3 (10 mmol) and thiosemicarbazide
(10 mmol) in ethanol (50 mL), NaOH (20 mmol) in 5 mL of water
was added and refluxed for 10 h. The reaction mixture was poured
onto crushed ice, the resulting solid was filtered, dried and
recrystallized from DMF. Yield, 45%; m.p. 228e230 ꢀC; 1H NMR
(DMSO-d6)
13H, Ar-H), 8.00, 8.20 (2s, 2H, benzofuran H-3), 8.80 (s, 1H, pyrazole
H-5). 13C NMR (DMSO-d6)
: 97.4, 109.3, 110.8, 112.1, 113.4, 118.8,
d: 1.60 (s, 3H, CH3), 6.40 (s, 1H, ]CHe), 7.20e7.90 (m,
(DMSO-d6)
d
: 3.80 (dd, 1H, CH2 pyrazoline, J ¼ 14.7, 9.6 Hz), 4.20
d
(dd, 1H, CH2 pyrazoline, J ¼ 10.1, 8.8 Hz), 6.20 (dd, 1H, pyrazoline H-
5, J ¼ 13.4, 9.4 Hz), 7.10e7.90 (m, 13H, Ar-H), 8.10, 8.60 (2s, 2H,
benzofuran H-3), 8.80 (s, 2H, thioamide NH2), 9.60 (s, 1H, pyrazole
119.5, 120.1, 120.3, 120.5, 120.6, 123.1, 125.1, 127.6, 129.4, 129.5,
140.5, 145.2, 147.7,152.9, 155.7,158.3, 159.9,165.5,170.3. Anal. Calcd.
For C32H20N6O3S (568.55): C, 67.59; H, 3.55; N, 14.78. Found: C,
67.66; H, 3.62; N, 14.87.
H-5). 13C NMR (DMSO-d6)
d: 32.6, 52.5, 95.1, 104.2, 107.6, 109.5,
113.4, 118.3, 119.2, 119.3, 122.3, 123.1, 123.8, 125.1, 127.5, 127.9, 129.4,
137.4, 140.6, 150.4, 151.8, 151.9, 154.5, 161.7. Anal. Calcd. For
C29H21N5O2S (503.52): C, 69.17; H, 4.20; N,13.91. Found: C, 69.23; H,
4.28; N, 13.85.
3.5.3. 3-(Benzofuran-2-yl)-2-((3-(benzofuran-2-yl)-1-phenyl-1H-
pyrazol-4-yl)methylene)-2H-benzo[b][1,4] thiazine (9c)
The compound 9c was obtained from the reaction of 2-amino-
thiophenol (8) (10 mmol), recrystallized from (EtOH/DMF). Yield,
3.9. 6-(Benzofuran-2-yl)-4-(3-(benzofuran-2-yl)-1-phenyl-1H-
pyrazol-4-yl)-5,6-dihydropyrimidine-2(1H)-thione (14)
60%; m.p. 218e220 ꢀC; 1H NMR (DMSO-d6)
d
: 5.80 (s, 1H, CH),
7.10e7.90 (m, 19H, Ar-H and benzofuran H-3), 8.80 (s, 1H, pyrazole
H-5). 13C NMR (DMSO-d6)
: 97.9, 110.6, 113.4, 118.8, 120.3, 120.4,
d
To a solution of 3 (10 mmol) and thiourea (30 mmol) in ethanol
(20 mL), ethanolic KOH (20 mmol, 5 mL) was added. The reaction
mixture was refluxed. TLC (EtOAc:Pet-ether, 2:1) showed that the
reaction was completed in 5 h. The reaction mixture was poured in
cold solution of 10% HCl (50 mL) and the precipitate was filtered off,
washed with water and recrystallized from C6H6/EtOH. Yield, 45%;
122.3, 123.1,123.5, 123.8, 124.4,125.1, 127.7, 129.4, 130.3, 130.7, 132.2,
141.7, 145.3, 147.7, 153.2, 155.6, 158.5, 159.3, 183.8. Anal. Calcd. For
C34H21N3O2S (535.56): C, 76.24; H, 3.95; N, 7.85. Found: C, 76.31; H,
3.88; N, 7.76.
3.6. 3-(Benzofuran-2-yl)-4-(3-(benzofuran-2-yl)-4,5-dihydro-1H-
m.p. 249e251 ꢀC; 1H NMR (DMSO-d6)
d: 3.40 (dd, 1H, CH2 pyrim-
pyrazol-5-yl)-1-phenyl-1H-pyrazole (11)
idine), 4.00 (dd, 1H, CH2 pyrimidine), 5.80 (dd, 1H, pyrimidine H-5),
7.10e7.80 (m, 13H, Ar-H), 8.00, 8.70 (2s, 2H, benzofuran H-3), 9.20
To an ethanolic solution of 3 (10 mmol), hydrazine hydrate
(15 mmol) was added dropwisely. The reaction mixture was heated
under reflux for 6 h and then cooled and poured onto crushed ice.
(s, 1H, pyrazole H-5), 10.30 (br s, 1H, NH). 13C NMR (DMSO-d6)
d:
47.1, 59.7, 98.8, 104.7, 112.0, 119.1, 119.3, 122.2, 123.8, 125.3, 125.4,
125.9, 126.5, 127.4, 128.4, 128.7, 129.0, 130.2, 139.5, 141.0, 148.7,

M.F. El Shehry et al. / European Journal of Medicinal Chemistry 45 (2010) 4783e4787
4787
149.7, 154.4, 154.6, 175.7. Anal. Calcd. For C29H20N4O2S (488.50): C,
71.29; H, 4.13; N, 11.47. Found: C, 71.21; H, 3.06; N, 11.39.
with the WHO guidelines [17] slightly modified by using two mixed
solvents to dissolve the compounds.
3.10. 2-Amino-6-(benzofuran-2-yl)-4-(3-(benzofuran-2-yl)-1-
5. Conclusions
phenyl-1H-pyrazol-4-yl) pyridine-3-carbonitrile (15)
In summary, an interesting fused ring systems containing
benzofuran residue were synthesized and evaluated for their
molluscicidal activities. All the screened compounds did not exhibit
any effect bellow 5 ppm concentration. Compounds 3, 4, 9a, 11 and
15 showed potent molluscidal activities while compounds 5, 9b, 9c,
12, 13 and 14 showed a moderate effect as compared to the stan-
dard molluscicidal agent (Bayluscide). This obtained results,
showed that our compounds are still far inferior as molluscicidal
agents.
A solution of 3 (10 mmol) in absolute ethanol (40 mL) contain-
ing excess of ammonium acetate and malononitrile (10 mmol) was
heated under reflux for 5 h. The reaction mixture was then cooled,
poured onto crushed ice and the resulting solid was filtered off,
washed with water, dried and recrystallized from EtOH. Yield, 65%;
m.p. 305e307 ꢀC; 1H NMR (DMSO-d6)
d
: 5.10 (br s, 2H, NH2),
7.20e8.20 (m, 16H, Ar-H, pyridyl H-5 and benzofuran H-3), 9.20 (s,
1H, pyrazole H-5). 13C NMR (DMSO-d6)
: 92.5, 98.4, 104.1, 106.2,
d
112.2, 113.1, 120.5, 120.9, 121.4,122.3, 122.9, 123.5, 124.7, 125.2, 127.5,
128.9,129.2,135.2,136.7,139.3,144.4,154.4,155.1,159.2,168.2,171.4.
Anal. Calcd. For C31H19N5O2 (493.52): C, 75.44; H, 3.88; N, 14.19.
Found: C, 75.51; H, 3.93; N, 14.11.
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