Synthesis of polyfunctional substituted pyrazoles

Article abstract of DOI:10.3184/030823409X12523423287039

Synthesis of pyrazoles incorporating substituted derivatives of 2, 4-dichloroacetic acid residues is described. Reactions with different reagents afford fused and polyfunctional substituted pyrazoles.

Full text of DOI:10.3184/030823409X12523423287039

JOURNAL OF CHEMICAL RESEARCH 2009
OCTOBER, 625–629
RESEARCH PAPER 625
Synthesis of polyfunctional substituted pyrazoles
Mohamed F. El-Shehry, Emad M. El-Telbani* and Randa H.Swellem
Green Chemistry Department, National Research Centre, Dokki 12622, Cairo, Egypt
Synthesis of pyrazoles incorporating substituted derivatives of 2, 4-dichloroacetic acid residues is described.
Reactions with different reagents afford fused and polyfunctional substituted pyrazoles.
Keywords: b-ketoester, pyrazole, pyran, oxime
Pyrazole derivatives have received more and more attention in
the recent years. Pharmaceutical research into such compounds
has been reported, including a potent cyclin dependent kinase
1 (CDK1) inhibitors,1 HIV reverse transcriptase inhibitors,2
CCR1 antagonists,3 protein kinase inhibitors4 and inhibitors
of cGMP degradation. In addition, they show a wide range of
pharmacological activities5,6 together with several herbicidal,
fungicidal7 and molluscicidal activities.8 Recently, we reported
a simple and versatile route for preparing a new b-ketoester
1 starting from 2, 4-dichlorophenoxyacetic acid which
possesses an excellent herbicidal activity.9 This reaction is
widely applicable for the preparation of different substituted
heterocyclic compounds having a 2, 4-D residue as possible
molluscicidal agents.8 In an effort to extend the scope of this
method, we attempted to prepare further interesting bioactive
compounds having 2, 4-D residue, which may show potential
pharmaceutical activities in addition to molluscicidal and
herbicidal activities.
at d = 10.30 ppm with a lack of the peak attributed to the
ylidine proton detected in the parent 3c.
Furthermore, 2a reacted with phosphoryl chloride in
dimethyl formamide under Vilsmier–Haack chloroformylation
conditions to afford the pyrazol-4-carbaldehyde derivative 5
1
in good yield. The H NMR spectrum of 5 revealed a signal
at d = 8.45 ppm characteristic for the aldehydic proton.8,10
Moreover, 13C NMR revealed a signal at d = 183.70 ppm
characteristic for the aldehydic CHO group.
Bromonation of 2a with N-bromosuccinimide (NBS) in
chloroform afforded two isolable products 4-bromopyrazol-
3-one 6 and the 4, 4-dibromo derivativese 7 in 2:1 ratio.
Structures 6 and 7 were based on both spectral and
microanalytical data, 1H NMR of 6 revealed a signal at
d = 5.25 ppm (one proton), attributed to the pyrazolone H-4
with disappearance of the signal at d = 5.50 ppm (two protons)
characteristic for the pyrazolone CH2 protons. Moreover, the
mass spectrum was in accord with the proposed structure.
On the other hand, the mass spectrum of 7 showed at m/z =
417 which was in accord with the calculated molecular weight
Results and discussion
1
(C10H6Br2Cl2N2O2), while, the H and 13C NMR supported
We successfully transformed ethyl-4-(2, 4-dichlorophenoxy)-
3-oxo-butanoate (1) which was recently prepared by us in
high yield8 into 3-((2, 4-dichlorophenoxy) methyl)-2, 4-
dihydopyrazol-5-one (2a) through reaction with hydrazine
hydrate in the presence of an acidic medium. Also, 3-((2,
4-dichlorophenoxy) methyl)-1-phenyl-1, 5-dihydropyrazol-
5-one (2b) was prepared when, 1 was treated with phenyl
hydrazine in the presence of acetic acid.8 Compound 2a
the suggested dibromo structure 7 (cf. Experimental).
From a biological view, it seemed a good idea to form the
N-glucosylated derivative of the pyrazolone 2a to enhance its
solubility thereby enhancing the rate of adsorption. To this
purpose, 2a was coupled with 2, 3, 4, 6-tetra-O-acetyl-a-D-
glucopyranosyl bromide in dimethylformamide in the presence
of sodium hydride to yield the N-glucoside derivative 8a. The
1H NMR of 8a revealed the absence of the NH and presence
of the all protons characteristic for the tetraacetyl glucose
moiety (cf. Experimental). Deprotection of the tetraacetyl
groups of 8a could be achieved by passing ammonia into the
methanolic solution of 8a to give the deprotected product 8b.
(cf. Scheme 1).
1
showed in its H NMR spectrum a new methylene protons
signal at d = 5.50 ppm characteristic for the pyrazolone
CH2-protons. Moreover, the 13C NMR revealed a signal at
d = 152.87 ppm attributed to the pyrazolone CO.
Compound 2a was nitrosated with sodium nitrite in acetic
acid to give the corresponding oxime 3a. Its mass spectrum
showed at m/z = 288, which was in accord with the calculated
molecular weight C10H7Cl2N3O3. 1H NMR showed the
hydroximino proton as a broad singlet at d = 7.70 ppm as
(D2O exchangeable), along with the other protons at their
expected locations. Compound 2a was also coupled with the
diazonium salt of aniline, affording the phenylazo derivative
3b in moderate yield. Its 1H NMR spectrum showed two (D2O
exchangeable) at d = 9.05 and 10.11 ppm assigned to both NH
groups, while the M+ was detected at m/z = 362.
Acetylation of 2a and 2b using acetyl chloride in dioxane in
thepresenceofcalciumhydroxide, gavetheacetylatedproducts
9a and 9b, respectively. Both elemental and spectroscopic data
of 9a and 9b supported the suggested structures. The 1H NMR
of 9a revealed the presence of two acetyl groups at d = 2.20
and 2.36 ppm and the pyrazolone 4-H at d = 6.37 ppm with
a lack of the pyrazole CH2 protons detected in the parent 2a,
and the 13C NMR revealed a signal at d = 167.80 and 170.32
ppm attributed to two acetyl CO groups. Moreover, the mass
spectrum was in accord with the calculated molecular weight
1
(C14H12Cl2N2O4).The H NMR of 9b showed a signal at d =
Compound 2a was condensed with anisaldehyde in the
presence of triethylamine as catalyst to give the condensed
product 3c. Both elemental and spectroscopic data was in
2.23 ppm attributed to the COCH3 protons with la ack of the
pyrazole CH2 detected in the parent 2b. Moreover, its mass
spectrum was in accord with the calculated molecular weight
(C18H14Cl2N2O3).
1
accord with the suggested structure 3c. H NMR showed a
new ylidene CH-proton at d = 8.70 ppm with a disappearance
of the pyrazolone CH2 proton detected in the parent 2a.
Upon treating 3c with hydrazine hydrate in ethanol, the
corresponding pyrazolopyrazole derivative 4 was obtained in
low yield. The mass spectrum of compound 4 showed at m/z
= 388 while, the 1H NMR spectrum revealed a new NH signal
Better success was achieved in synthesising a fused bicyclic
compounds with 2, 4-dichlorophenoxy residue using 9b as a
synthon. To this aim, 9b was reacted with benzaldehyde in
the presence of methanolic potassium hydroxide to give 10 in
1
moderate yield. In the H NMR of 10 appeared new doublet
signals at d = 7.40 and 7.80 ppm characteristic for the olefenic
double bond with a lack of the acetyl proton detected in the
parent 9b. Furthermore, 10 was cyclised using piperidine in
* Correspondent. E-mail: e_misbah@yahoo.co.uk

626 JOURNAL OF CHEMICAL RESEARCH 2009
OCH3
Br
R
R
CHO
Cl
R
N
N
O
N
H
N
H
R
N
NH
6
+
5
Br
N
Br
O
N
H
4
N
POCl3 / DMF
NBS
3c,
N
H
NH2NH2 . H2O
7
OAc
R
R'
R
R
O
AcO
AcO
+
-
Br
O
HONO or
N Cl
PhN
OAc
N
O
N
N
O
O
OCH3
or OHC
NaH / DMF
N
H
OR'
N
N
H
O
O
R'
R'
3 a: R' = N-OH
2 a
OR'
b: R' = NNHPh
Cl
Cl
8 a:R' = Ac
OCH3
HC
c: R' =
R =
O
NH3 / MeOH
b:R' = H
Scheme 1
boiling ethanol to afford the pyranopyrazole derivative 11.
The IR spectrum of 11 revealed a new CO group at 1685 cm-1
while the 1H NMR showed a new singlet peak at d = 5.60 ppm
characteristic of a pyran H-2 11 with disappearance of olefinic
protons detected in the parent 10.
yields, respectively. All elemental and spectral data of
compounds 14a and 14b were in accord with the suggested
structures. The 1H NMR of compound 14a as a representative
example showed a coumarin H-5 at d = 5.80 ppm with the
disappearance of the CH2 of pyrazole detected in the parent
2a. Moreover, the 13C NMR showed the coumarin CO at
d = 170.55 ppm and the mass spectrum showed m/z = 486,
which was in accord with the calculated molecular weight
(C20H12Cl4N2O4) (cf Experimental). Biological activities of
products will be studied.
9b was reacted with acetone in the presence of pyrrolidine
using a Dean–Stark apparatus to afford the pyranopyrazole
derivative 12 in a moderate yield. The IR spectrum showed the
1
pyranone CO group at 1670 cm-1 and the H NMR spectrum
showed a characteristic singlet peak at d = 3.80 ppm for the
COCH2 group12 (cf. Experimental and Scheme 2)
When the reaction of 2a with anisaldehyde was carried out
in the presence of an excess of triethylamine another product
13a was obtained. 13a might be formed through formation of
3c followed by addition of another molecule of 2a and finally
by subsequent elimination of a molecule of water to give the
pyran derivative 13a. The mass spectrum of 13a showed at
m/z = 617 which is in accord with the calculated molecular
weight and its 1H NMR revealed a new signal at d = 4.80 ppm
characteristic for the pyran H-4.13
Experimental
Melting points were determined on an Electrothermal 9100 digital
melting point apparatus. IR, NMR and mass spectra were recorded
on: IR spectra (KBr): Pye-Unicam SP-1100. H, 13C NMR spectra:
1
Bruker AMX400 MHz, Jeol 500 and Jeol GLM EX 270 MHz FT
NMR spectrophotometer, DMSO-d6, TMS as internal standard,
chemical shift in d (ppm). Mass spectra: 70 eV, Varian MAT 311 A.
Elemental analysis (in accord with the calculated values) were carried
out in the Microanalytical Unit, Faculty of Science, Cairo University.
Precoated silica gel 60 F254 plates with a layer thickness 0.25 nm
from Merck were used for thin layer chromatography. Yields are not
optimised.
Similarly, when compound 2a was reacted with
benzaldehyde in the presence of an excess of triethylamine
the same previous result was obtained whereby the pyran
derivative 13b afforded directly without isolation the
5-((2, 4-Dichlorophenoxy) methyl)-2, 4-dihydropyrazol-3-one (2a):
To a solution of 1 (2.90 g, 10 mmol) in acetic acid (20 mL), hydrazine
hydrate (0.75 g, 15 mmol) was added dropwise within 30 min.
After the addition was completed, the reaction mixture was stirred
at room temperature; for another 3 h. A solid product precipitated
during stirring was filtered off, washed with hot water (20 mL),
dried and recrystallised from ethanol to give 2a as a white solid,
m.p.168–170°C; (2 g, 77% yield). IR (KBr): nmax 3360 (NH), 1693
1
condensed adduct. The H NMR of 13b showed the pyran
H-4 proton at d = 4.90 ppm, which supported the suggested
structure 13b.
To elucidate the mechanism of the reaction pathway, the
same reaction was performed on another substituted N-
phenyl pyrazolone namely, 3-(2, 4-dichlorophenoxymethyl)-
1-phenyl-1, 5-dihydropyrazol-5-one (2b) under the same
reaction conditions. In a similar manner, the substituted pyran
derivative 13c was obtained as a complex with a molecule of
water14 (cf. Experimental).
Compound 2a was condensed with some b-ketoesters
namely, ethyl-4-(2, 4-dichlorophenoxy)-3-oxo-butanoate (1)
or ethyl acetoacetate in the presence of a basic medium to
yield the corresponding compounds 14a and 14b in good
(CO), 1599 (C=N)cm-1. H NMR (400 MHz, DMSO-d6): d 4.90 (s,
1
2H, CH2 phenoxy), 5.50 (s, 2H, CH2), 7.10–7.70 (m, 3H, ArH), 10.55
(s, 1H, NH) ppm. 13C NMR (400 MHz, DMSO-d6): d 63.48, 89.54,
115.89, 122.93, 125.14, 128.37, 129.71, 152. 87. MS: m/z (%) = 259
(5%) [M+ ]. Anal. Calcd for C10H8Cl2N2O2 (259.18): C, 46.34; H,
3.11; N, 10.81. Found: C, 46.30; H, 3.20; N, 10.90%.
5-((2, 4-Dichlorophenoxy) methyl)-2H-pyrazol-3, 4-dione-4-oxime
(3a): To a cooled solution of compound 2a (2.85 g, 10 mmol) in
acetic acid (20 mL), aqueous sodium nitrite (1.38 g, 20 mmol) was
added portionwise, with stirring at 0–5°C, over a period of 20 min.
After 2 h, the reaction mixture was poured over water and a precipitate

JOURNAL OF CHEMICAL RESEARCH 2009 627
R
A r
O
R
N
R
N
P h
N
N
O
O
R '
N
N
11
R '
P h
13 a: A r = 4 -C H 3 O P h, R ' = H
b : A r = P h, R ' = H
c: A r = P h, R ' = P h
E tO H / P ip.
A rC H O
E tO H / T E A
O
O
R
C H 3
R
R
P h
9b
A cO C l
N
N
O
N
O
O
C a(O H )2
C H O
N
N
N
R '
P h
R '
9 a:R ' = C O C H 3
b :R ' = P h
10
2 a: R ' = H
b : R ' = P h
O
O
9 b
O
2 a or
O E t
O
C H 3
H 3
C
E tO H / P ip .
R
R '
N
O
R
N
O
P h
N
C l
C l
O
O
R =
12
N
H
14 a: R = R '
b : R ' = C H
3
Scheme 2
was formed, filtered and recrystallised from acetic acid to give 3a
as a white solid, m.p. 165–167°C; (2 g, 71% yield). H NMR (270
MHz, DMSO-d6): d 5.51 (s, 2H, CH2 phenoxy), 7.10–7.81 (m, 4H,
ArH, OH), 10.10 (s, 1H, NH) ppm. MS: m/z (%) = 288 (6%) [M+].
Anal. Calcd for C10H7Cl2N3O3 (288.18): C, 41. 68; H, 2.45; N, 14.58.
Found: C, 41.70; H, 2.40; N, 14.70%.
7.15–7.80 (m, 7H, ArH), 10.10 (s, 1H, NH), 10.30 (s, 1H, NH) ppm.
MS: m/z (%) = 388 [M+ -1]. Anal. Calcd for C18H14Cl2N4O2 (389.33):
C, 55.53; H, 3.62; N, 14.39. Found: C, 55.70; H, 3.70; N, 14.30%.
1
3-((2,
4-Dichlorophenoxy)
methyl)-5-chloro-1H-pyrazole-4-
carbaldehyde (5): To dry DMF (0.73 g, 10 mmol) cooled to 0°C,
POCl3 (2 mL, 13 mmol) was slowly added at such a rate that the
temperature was maintained below 10°C followed by the addition of
2a (2.58 g, 10 mmol) in a small portions. The resulting solution was
stirred at room temperature for 30 min and at 50°C for 1 h. The dark
reaction mixture was then cooled to room temperature and poured
slowly onto ice/H2O and neutralised to pH 6-7 by adding Na2CO3 in
small portions and the resulting solid was filtered off, washed with
water (50 mL) and recrystallised from ethanol to give 5 as yellow
crystals, m.p. 193–195°C; (1.89 g, 62% yield). IR (KBr): n max 3355
(NH), 1680 (CHO), 1523 (C=N) cm-1. 1H NMR (400 MHz, DMSO-
d6): d 4.91 (s, 2H, CH2 phenoxy), 7.11–7.52 (m, 3H, ArH), 8.45 (s,
1H, aldehydic H), 9.55 (s, 1H, NH)) ppm. 13C NMR (400 MHz,
DMSO-d6): 65.74, 104.71, 116.43, 122.9, 125.28, 128.34, 129.68,
154.05, 183.70. MS: m/z (%) = 304 (10%) [M+ –1]. Anal. Calcd for
C11H7Cl3N2O2 (305.69): C, 43.22; H, 2.31; N, 9.16. Found: C, 43.30;
H, 2.50; N, 9.10%.
5-((2, 4-Dichlorophenoxy) methyl)-4-(phenylhydrazono)-2, 4-
dihydropyrazol-3-one (3b): To a stirred cooled solution of 2a (2.85 g,
10 mmol) and sodium acetate (5.1 g, 80 mmole) in dioxane (30 mL),
the diazonium salt of aniline was added and the temperature was kept
at (0–5°C) for about 1 h. After removing the ice bath, stirring was
maintained for 30 min at room temperature. Then water (100 mL)
was added, the precipitated was filtered off, washed with water and
recrystallised from methanol to give 3b as a white solid, m.p. 210–
212°C (1.9 g, 52% yield). 1H NMR (500 MHz, DMSO-d6): d 5.56 (s,
2H, CH2 phenoxy), 7.10–7.78 (m, 8H, ArH), 9.05 (s, 1H, NH), 10.11
(s, 1H, NH) ppm. MS: m/z (%) = 362 (10%) [M+ -1 ]. Anal. Calcd
for C16H12Cl2N4O2 (363.29): C, 52.91; H, 3.33; N, 15.43. Found: C,
52.80; H, 3.50; N, 15.60%.
5 – ((2, 4 – Dichlorophenoxy) methyl) – 4 – (4-methoxybenzylidene)-
2, 4-dihydropyrazol-3-one (3c): A mixture of 2a (2.85 g, 10 mmol)
and anisaldehyde (10 mmol) in ethanol (20 mL) in the presence of
one drop of triethylamine was stirred for 1 h at 70°C. After cooling,
the separated precipitate was filtered off, washed with ethanol, dried
and recrystallised from ethanol to give 3c as yellow crystals, m.p.
176–178°C; (1.4 g, 37% yield). 1H NMR (270 MHz, DMSO-d6):
d 3.70 (s, 3H, OCH3), 4.10 (s, 2H, CH2 phenoxy), 7.00–7.90 (m, 7H,
ArH), 8.70 (s, 1H, ylidene CH), 10.50 (s, 1H, NH) ppm. MS: m/z (%)
= 377 [M+]. Anal. Calcd for C18H14Cl2N2O3 (377.32): C, 57.30; H,
3.74; N, 7.42. Found: C, 57.40; H, 3.60; N, 7.40%.
Preparation of compounds (6) and (7)
To a stirred suspension of 2a (2.58 g, 10 mmol) in anhydrous carbon
tetrachloride (50 mL), N-bromosuccinimide (1.77 g, 10 mmol)
was added in the presence of a catalytic amount of (10 mg) benzoyl
peroxide. The resulting mixture was refluxed for 2.5 h. After
completion, the mixture was diluted with water (30 mL), the two
phases were separated, and the aqueous layer was extracted with
CHCl3 (3 ¥ 20 mL). The organic extracts were evaporated and purified
by column chromatography (silica gel, ethyl acetate/n-hexane, 1/2,
Rf = 0.35) to afford 6 and 7.
4-Bromo-5-((2, 4-dichlorophenoxy) methyl)-2, 4-dihydro-pyrazol-
3-one (6): Pale yellow needles, m.p. 133–135°C; (2.1 g, 62% yield).
1H NMR (500 MHz, DMSO-d6): d 5.01 (s, 2H, CH2 phenoxy), 5.25
(s, 1H, pyrazolone H-4), 7.17–7.66 (m, 3H, ArH), 11.81 (s, 1H, NH)
ppm. MS: m/z (%) = 338 [M+]. Anal. Calcd for C10H7BrCl2N2O2
3-((2,4-Dichlorophenoxy)methyl)-4-(4-methoxyphenyl)-1,6-dihydro
pyrazolo [3, 4-c] pyrazole (4): A mixture of 3c (3.76 g, 10 mmol)
and hydrazine hydrate (0.75 g, 15 mmol) in ethanol (30 mL) was
heated under reflux for 4 h, the solid precipitated after concentration
was filtered off, dried and recrystallised from methanol to give 4 as
1
a white solid, m.p. 130–132°C; (1.2 g, 30% yield). H NMR (270
MHz, DMSO-d6): d 3.80 (s, 3H, OCH3), 4.30 (s, 2H, CH2 phenoxy),

628 JOURNAL OF CHEMICAL RESEARCH 2009
(338.09): C, 35.52; H, 2.09; N, 8.29. Found: C, 35.60; H, 2.20;
N, 8.40%.
3-((2, 4-Dichlorophenoxy) methyl)-1, 6-diphenyl-4-1H-pyrano
[2, 3-c] pyrazol-4-one (11): A solution of 10 (4.6 g, 10 mmol) in
ethanol (40 mL) in the presence of piperidine (5 drops) was boiled
for 6 h. The reaction mixture was concentrated and the colourless
crystals after cooling, were filtered off, washed with a few drops of
ethanol and recrystallised to yield 11 as yellow needles, m.p. 222–
4, 4-Dibromo-5-((2, 4-dichlorophenoxy) methyl)-2, 4-dihydropyrazol
1
-3-one (7): Yellow needles, 143–145°C; (1.7 g, 35% yield). H NMR
(400 MHz, DMSO-d6): d 5.10 (s, 2H, CH2 phenoxy), 7.20–7.65 (m, 3H,
ArH), 10.65 (s, 1H, NH) ppm. 13C NMR (400 MHz, DMSO-d6): 62.09,
116.13, 123.13, 125.53, 125.63, 128.4, 129.81, 152.79. MS: m/z (%) =
417 (4%) [M+]. Anal. Calcd for C10H6Br2Cl2N2O2 (416.98): C, 28.80;
H, 1.45; N, 6.72. Found: C, 28.70; H, 1.30; N, 6.60%.
224°C; (2.5 g, 53% yield). IR (KBr): n
1685 (CO), 1523 (C=N)
cm-1. 1H NMR (270 MHz, CDCl3): d 2.9m1a–x3.05 (m, 2H, pyran CH2),
5.30 (s, 2H, CH2 phenoxy), 5.60 (dd, 1H, pyran H-2), 7.10–7.80 (m,
13H, ArH) ppm. Anal. Calcd for C25H18Cl2N2O3 (465.34): C, 64.53;
H, 3.90; N, 6.02. Found: C, 64.50; H, 3.80; N, 6.20%.
2-(2,3,4,6-Tetra-O-acetyl-b–D-glucopyranosyl)-5-((2,4-dichloro-
phenoxy) methyl)-2, 4-dihydropyrazol-3-one (8a): Compound
2a (2.58 g, 10 mmol) was stirred with an equimolar amount of
sodium hydride in dry dimethylformamide (25 mL) for 2 h at
room temperature. To the formed salt, a solution of 2, 3, 4, 6-tetra-
O-acetyl-a-D-gylcopyranosyl bromide (4.1 g, 10 mmole) in dimethyl-
formamide (20 mL) was added dropwise and stirring was continued
for an additional 2 h at room temperature. The reaction mixture
was acidified with (50%) acetic acid, and then extracted with
ethyl acetate. The organic layer was dried over anhydrous sodium
sulfate, evaporated, and the remaining oily residue was separated
by column chromatography (silica gel, ethyl acetate/pet-ether, 1/3,
Rf = 0.35), to give 8a as colourless needles, m.p. 181–183°C; (1.5 g,
31% yield). 1H NMR (270 MHz, DMSO-d6): d 1.80–2.00 (4 s, 12H,
4 ¥ COCH3), 3.32 (m, 1H, H-6, 6'), 3.41 (s, 2H, pyrazolone CH2),
4.22 (m, 2H, H-4', 5'), 5.02 (m, 2H, H-3'), 5.20 (s, 2H, CH2 phenoxy),
5.42 (m, 1H, H-2'), 5.60 (d, 1H, H-1'), 7.15–7.81 (m, 3H, ArH) ppm.
Anal. Calcd for C20H26Cl2N2O7 (477.43): C, 50.31; H, 5.49; N, 5.87.
Found: C, 50.40; H, 5.40; N, 5.90%.
2-(2,3,4,6-Tetrahydroxy-b-D-glucopyranosyl)-5-((2,4-dichloro-
phenoxy) methyl)-2, 4-dihydropyrazol-3-one (8b): Compound 8a
(4.76 g, 10 mmol) was dissolved in a solution of methanol saturated
with ammonia (30 mL) and stirred for two days at room temperature.
Then the solution was concentrated to dryness and the residue was
recrystallised to yield 8b as colourless needles, m.p. 241–243°C; (1.6 g,
38% yield). 1H NMR (270 MHz, DMSO-d6): d 3.11 (m, 1H, H-6, 6'),
3.80 (s, 2H, pyrazolone CH2), 4.10–4.43 (m, 8H, H-4', H-5', H-2', H-3',
2'-OH, 3'-OH, 4'-OH, 6'-OH), 5.10 (s, 2H, CH2 phenoxy), 5.32 (d, 1H,
H-1'), 7.05-7.80 (m, 3H, ArH) ppm. Anal. Calcd for C16H18Cl2N2O7
(421.23): C, 45.62; H, 4.31; N, 6.65. Found: C, 45.70; H, 4.40;
N, 6.40%.
3-((2,4-Dichlorophenoxy)methyl)-6,6-dimethyl-1-phenyl-5,6-dihydro-
1H-pyrano [2, 3-c] pyrazol-4-one (12): A mixture of 9b (3.76 g,
10 mmol), acetone (0.6 g, 10 mmol) and pyrrolidine (0.7 g, 10
mmol) in dry benzene (100 mL) was refluxed using a Dean–Stark
apparatus. After the calculated amount of water is eliminated, the
reaction mixture was concentrated and left to cool. The solid formed
was washed with petroleum ether, dried and recrystallised to yield
12 as yellow needles, m.p. 189–191°C (2.5 g, 60% yield). IR (KBr):
1
n
1670 (CO), 1600 (C=N) cm-1. H NMR (270 MHz, CDCl3):
max
d 1.50 (s, 3H, CH3), 1.64 (s, 3H, CH3), 3.80 (s, 2H, CH2), 5.10 (s,
2H, CH2 phenoxy), 7.00–7.91 (m, 8H, ArH) ppm. MS: m/z (%) = 417
(20%) [M+]. Anal. Calcd for C21H18Cl2N2O3 (417.30): C, 60.45; H,
4.35; N, 6.71. Found: C, 60.50; H, 4.40; N, 6.50%.
Preparation of compounds (13a-c); general procedure
A mixture of 2a and/or 2b (20 mmol), benzaldehyde and/or
anisalehyde (10 mmol), and triethylamine (1 mL) in ethanol (30 mL)
was stirred for 2 h at 50°C. The solution was evaporated to one-
third volume; the separated precipitate was filtered off, washed with
ethanol, dried, and recrystallised from the appropriate solvent.
3, 5-Bis((2, 4-dichlorophenoxy) methyl)-4-(4-methoxyphenyl)-4, 7-
dihydro-1H-pyrano[2, 3-c; 6, 5-c'] dipyrazole (13a): Yellow needles,
m.p. 240–242°C; (2.8 g, 45% yield). 1H NMR (270 MHz, DMSO-
d6): d 3.75 (s., 3H, OCH3), 4.30 (s, 2H, CH2 phenoxy), 4.80 (s, 1H,
pyran H-4), 5.51 (s, 2H, CH2 phenoxy), 7.10–7.84 (m, 10H, ArH),
10.11 (s, 1H, NH), 10.12 (s, 1H, NH) ppm. MS: m/z (%) = 617 (7%)
[M+ –1]. Anal. Calcd for C28H20Cl4N4O4 (618.31): C, 54.39; H, 3.26;
N, 9.06. Found: C, 54.40; H, 340; N, 9.20%.
3, 5-Bis((2, 4-dichlorophenoxy) methyl)-4-phenyl-4, 7-dihydro-
1H-pyrano[2, 3-c; 6, 5-c'] dipyrazole (13b): Yellow needless, m.p.
198–200°C (2.6 g, 44% yield). 1H NMR (400 MHz, DMSO-d6):
d 4.50 (s, 2H, CH2 phenoxy), 4.72 (s, 2H, CH2 phenoxy), 4.90 (s,
1H, pyran H-4), 7.03–7.75 (m, 11H, ArH), 10.31 (s, 1H, NH), 10.43
(s, 1H, NH) ppm. 13C NMR (400 MHz, DMSO-d6): 61.27, 100.22,
115.65, 120.88, 123.15, 125.5, 127.26, 127.67, 128, 08, 128.36,
128.80, 129.79, 134.18, 144.16, 152.36, 161.17. MS: m/z (%) = 587
(6%) [M+ –1]. Anal. Calcd for C27H18Cl4N4O3 (588.28): C, 55.13; H,
3.08; N, 9.52. Found: C, 55.20; H, 3.20; N, 9.60%.
Preparation of compounds (9a, b); general procedure
A suspension of compound 2a and/or 2b (10 mmol) and calcium
hydroxide powder (1.48 g, 20 mmol) in dioxane (50 mL) was stirred
vigorously and treated with acetyl chloride (0.78 g, 10 mmol) over
30 min. The stirring was continued for another 1 h, and then the
reaction mixture was filtered, and poured into ice-cold water and
finally acidified with 2 N hydrochloric acid (25 mL). A solid product
was filtered off, washed with water, and recrystallised to give 9a or
9b, respectively.
3-((2,4-Dichlorophenoxy)methyl)-1,4-diacetyl-1H-pyrazol-5(4H)-
one (9a): Grey needles, 145–147°C; (2 g, 58% yield). 1H NMR
(400 MHz, DMSO-d6): d 2.20 (s, 3H, COCH3), 2.36 (s, 3H, COCH3),
5.51 (s, 2H, CH2 phenoxy), 6.37 (s, 1H, pyrazolone H-4), 7.00–7.82
(m, 3H, ArH) ppm. 13C NMR (400 MHz, DMSO-d6): 20.60, 22.41,
64.33, 102.40, 115.45, 122.51, 125.20, 128.20, 129.44, 143.41,
152.14, 156.05, 167.80, 170.32. MS: m/z (%) = 343 (60%) [M+].
Anal. Calcd for C14H12Cl2N2O4 (343.16): C, 49.00; H, 3.52; N, 8.16.
Found: C, 49.10; H, 3.50; N, 8.10%.
3,5-Bis((2,4-dichlorophenoxy)methyl)-1,4,7-triphenyl-4,7-dihydro-
1H-pyrano [2, 3-c; 6, 5-c']dipyrazole (13c): Yellow needles, m.p.
1
180–182°C; (2.9 g, 39% yield). H NMR (400 MHz, DMSO-d6): d
5.10 (s, 2H, CH2 phenoxy), 5.22 (s, 2H, CH2 phenoxy), 5.30 (s, 1H,
pyran H-4), 7.13–7.63 (m, 21H, ArH) ppm. 13C NMR (400 MHz,
DMSO-d6): 65.71, 103.43, 115.01, 120.07, 122.54, 124.27, 124.70,
125.18, 127.58, 128.11, 128.78, 128.84, 129.49, 140.72, 144.68,
145.44, 153.20, 158.14. MS: m/z (%) = 759 (100%) [M+ + H2O].
Anal. Calcd for C39H26Cl4N4O3. H2O (758.48): C, 61.76; H, 3.72; N,
7.39. Found: C, 61.80; H, 3.60; N, 7.50%.
3-((2, 4-Dichlorophenoxy) methyl)-4-acetyl-1-phenyl-1H-pyrazol-5-
(4H)-one (9b): Pale yellow needles, m.p. 184–186°C; (2.5 g, 66% yield).
1H NMR (270 MHz, CDCl3): d 2.23 (s, 3H, COCH3), 5.20 (s, 2H, CH2
phenoxy), 6.25 (s, 1H, pyrazolone H-4), 7.10–7.76 (m, 8H, ArH) ppm.
MS: m/z (%) = 377 [M+]. Anal. Calcd for C18H14Cl2N2O3 (377.23): C,
57.31; H, 3.73; N, 7.43. Found: C, 57.40; H, 3.90; N, 7.30%.
5-((2, 4-Dichlorophenoxy) methyl)-2-phenyl-4-(3-phenylacryloyl)-
4, 5-dihydro pyrazol-3-one (10): To a mixture of 9b (3.76 g,
10 mmol) in a 10% solution of sodium hydroxide (10 mL) in an ice
bath, benzaldehyde was added dropwise (1.06 g, 10 mmol) within
15 min and the stirring was continued for another 1/2 hour at room
temperature. The reaction mixture was poured into ice-cooled water
and acidified with diluted hydrochloric acid. The yellow precipitate
which was formed was filtered off, washed with water, dried and
recrystallised to yield 10 as yellow needles, m.p. 163–165°C; (2 g;
43% yield). 1H NMR (270 MHz, DMSO-d6): d 4.80 (s, 2H, CH2
phenoxy), 5.21 (s, 1H, pyrazolone H-4), 7.00–7.65 (m, 14H, ArH and
olefinic-H), 7.80 (d, 1H, olefinic-H) ppm. MS: m/z (%) = 465 (5%)
[M+]. Anal. Calcd for C25H18Cl2N2O3 (465.34): C, 64.53; H, 3.90; N,
6.02. Found: C, 64.60; H, 3.70; N, 6.10%.
Preparation of compounds (14a, b); general procedure
A solution of 2a (2.85 g, 10 mmol) and the b-ketoester (10 mmol)
in ethanol (30 mL) in the presence of piperidine (three drops) was
refluxed for 4–6 h. The reaction mixture was concentrated to half of its
volume and cooled. The solid product was precipitate, filtered off and
recrystallised from methanol to give 14a and/or 14b, respectively.
3,4-Bis((2,4-dichlorophenoxy)methyl)-1H-pyrano[2,3-c]-pyrazol-
6-one (14a): Pale yellow needles, m.p. 230–232°C; (2.7 g, 60%
yield). 1H NMR (400 MHz, DMSO-d6): d 4.87 (s, 2H, CH2 phenoxy),
5.00 (s, 2H, CH2 phenoxy), 5.80 (s, 1H, coumarin H-5) 7.02–7.61
(m, 6H, ArH), 10.30 (s, 1H, NH) ppm. 13C NMR (400 MHz, DMSO-
d6): 60.41, 111.58, 115.72, 118.06, 122.77, 123.53, 125.43, 127.40,
128.41, 128.52, 129.72, 130.04, 140.36, 151.41, 152.56, 170.55. MS:
m/z (%) = 486 (6%) [M+]. Anal. Calcd for C20H12Cl4N2O4 (486.13):
C, 49.41; H, 2.49; N, 5.76. Found: C, 49.40; H, 2.60; N, 5.90%.
3-((2, 4-Dichlorophenoxy) methyl)-4-methyl-1H-pyrano [2, 3-c]
pyrazol-6-one (14b): Pale yellow needles, m.p. 142–144°C; (2 g,
1
65% yield). H NMR (400 MHz, DMSO-d6): d 1.82 (s, 1H, CH3),
5.11 (s, 2H, CH2 phenoxy), 5.98 (q, 1H, coumarin H-5) 7.00–7.60

JOURNAL OF CHEMICAL RESEARCH 2009 629
4
G. Chiu, S. Li, J.P. Connolly, A.S. Middleton, L.S. Emanuel, S. Huang,
R. Lin and Y. Lu, PCT Int.Appl. WO 2006130673, Janssen Pharmaceutica,
N.V., Belgium.
(m, 3H, ArH), 10.30 (s, 1H, NH) ppm. Anal. Calcd for C14H10Cl2N2O3
(325.15): C, 51.72; H, 3.10; N, 8.62. Found: C, 51.70; H, 3.20;
N, 8.50%.
5
6
7
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We thank Professor Galal A.M. Nawwar (Head of Chemical
Industries Research Division, National Research Centre) for
invaluable and helpful discussions.
Received 17 June 2009; accepted 31 August 2009
Paper 09/0643 doi: 10.3184/030823409X12523423287039
Published online: 8 October 2009
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