Indian Journal of Chemistry

Vol. 44B, November 2005, pp. 2338-2342

Regioselective one-pot synthesis of 3,5-diarylpyrazoles

P D Lokhande*, B Y Waghamare & S S Sakate
The Centre for Advanced Studies, Department of Organic Chemistry, University of Pune, Pune 4110 07, India
Email: pdlokhande@rediffmail.com
Received 19 January 2005; accepted (revised) 8 June 2005

The 3,5-diarylpyrazolines and pyrazoles have been easily synthesized in excellent yields by the reaction of 2'-hydroxy-
chalcones with hydrazine hydrate. The 2'-hydroxychalcones are converted into flavanones and flavones by simple
cyclisation methods and then into pyrazolines and pyrazoles, respectively. Alternatively, one-pot synthesis of pyrazoles has
also been achieved by converting 2'-hydroxychalcones into pyrazolines and thereafter their dehydrogenation using I2-DMSO
reagent. The regiochemistry of pyrazoles obtained via pyrazolines and from flavones has been compared.

Keywords: Diarylpyrazolines, pyrazoles, chalcones, hydrazine hydrate, flavanones, flavones, pyrazolines

IPC: Int.Cl.7 C 07 D

Many pyrazole compounds have interesting pharma-
cological properties and are widely used as pharma-
ceuticals, inhibitors of protein kinases1, anesthetics,
analgesics2, antiaggregating3 agents and agro-
chemicals4,5. Similarly, pyrazolines have anti-
bacterial6, antiviral, antiinflammatory and analgesic
activity7.
The reactions of 1,3-diketones and hydrazines have
been extensively studied as means to prepare
pyrazoles8. Pyrazoles prepared by this method differ
at 3,5-substitutions1,8. Due to this variation in
regiochemistry of pyrazoles at 3 and 5 positions, there
is a significant interest in the preparation of 3, 5-
disubstituted (alkyl or aryl) pyrazoles9. The reactions
of hydrazine with β-difunctional compounds give 3,5
or 5,3-disubstituted pyrazoles. In cycloaddition
reactions, the percentage and yield of these isomers
depend on the nucleophilicity of C-1 and C-3 atoms
of difunctional compounds. A few successful methods
have been developed for the synthesis of regio-
selective pyrazoles1, 10-12. In this paper, we report one-
pot regioselective synthesis of 3, 5-diaryl pyrazoles.
The 2'-hydroxychalcones 1a-e were prepared by
condensation of 2'-hydroxyacetophenones with substi-
tuted aromatic aldehydes in the presence of 40%
NaOH. The 2'-hydroxyacetophenones were prepared
by Fries rearrangement of aryl acetates13,14. The 2'-
hydroxychalcones were treated with hydrazine
hydrate in methanol to get 3, 5-diarylpyrazolines 2a-e.
In methanol, reaction rate was slow (2 hr) and
required reflux temperature, however, in DMSO it
was fast (5 min) at room temperature itself.
The IR spectra of compounds 2a-e showed sharp
absorption bands at 3330, 3341, 3341, 3345 and 3311
cm-1, respectively due to -NH stretching, whereas it
did not exhibit band assignable for >C=O group
excluding the possibility of open chain or hydrazone
type structure. 1H NMR spectrum revealed the
presence of doublet of doublet represented by typical
ABX splitting pattern assignable for non-magnetically
equivalent methelene (H-4) and vicinal methyne
(H-5) protons (Figure 1).
Alternatively, the 2'-hydroxychalcones 1c, d when
refluxed in ethanol in the presence of ethylene
diamine (EDA) were isomerised to flavanones15, and
when treated with hydrazine hydrate in DMSO at
room temperature gave pyrazolines (Scheme I).
The pyrazolines obtained from 2'-hydroxy-
chalcones and from flavanones 3c,d were heated with
catalytic amount of I2 in DMSO at 130–40°C for 2 hr
to afford 3,5-diarylpyrazoles 5c,d. Different oxidizing
agents were used for dehydrogenation of pyrazolines7
but I2-DMSO has its own advantage over these agents
and reaction has higher yields at 130°C.
Since pyrazolines were prepared from 2'-
hydroxychalcones in DMSO and further I2-DMSO
used as oxidising agent for conversion of pyrazolines
to pyrazoles, we thought that pyrazoles could be
prepared from 2'-hydroxychalcones in one-pot fashion
(Scheme I). To prepare 3,5-diarylpyrazoles in one-
 LOKHANDE et al.: REGIOSELECTIVE ONE-POT SYNTHESIS OF 3, 5-DIARYLPYRAZOLES 2339

pot, 2'-hydroxychalcones were initially treated with
hydrazine hydrate in DMSO for 5 min at r. t. and then
catalytic amount of I2 added to reaction mixture and
then heated at 130–40°C for 2 hr to get pyrazoles.
Pyrazoles can also be synthesized from flavones,
but it has been reported15,16 to result in two
regioisomers (I and II, Figure 3) when reacted with
hydrazine (Scheme II). The regioisomer I is formed if
one of the nucleophilic nitrogen atoms of hydrazine
initially attacks at C-2 of the flavone and then another
nitrogen atom at C-4 to get pyrazole (path-I).
However, isomer II is formed by initial attack of one
of the nucleophilic nitrogen atom at C-4 (path-II), but
we could isolate single regioisomer in higher yield.
The regioisomer isolated was analogous to the
pyrazoles obtained by oxidation of pyrazolines.
OH
HA
R HB
N N HX
H for intramolecular H-bonded pyrazoles than non-
Figure 1—ABX type of protons in pyrazoline
R2
The IR spectra of pyrazoles 5a-e showed sharp
absorption bands due to -NH stretching at 3364, 3353,
3358, 3351 and 3378 cm-1, respectively. 1H NMR
spectra showed both -NH and -OH peaks in the offset
region of spectra and were D2O exchangeable. This
indicated intramolecular H-bonding between -OH and
nitrogen atom of pyrazole rings as shown in Figure 2.
Chemical shift of H-4 in pyrazoles was well
distinguished in intramolecular hydrogen bonded
pyrazoles. Similarly, UV spectra of these pyrazoles
showed typical absorption maxima. These absorption
maxima shifted towards blue region in non-bonded
pyrazoles15. The chemical shift values of H-4 in
pyrazoles 5a-e clearly indicated that phenolic -OH is
engaged with intramolecular H-bonding with nitrogen
of pyrazole ring. These values (see Experimental)
were in good agreement with reported values15, only
R1 if the intramolecular H-bonding and co-planarity of
the pyrazole and 2'-hydroxyaryl rings are taken into
account. The stability of pyrazoles is supposed to be
associated with this criterion.
The UV absorption pattern was entirely different
bonded pyrazoles15. In the present study, the pattern
R2 R2

R1 R1 R1

O OH O
iii iv
R R R

O O O
3 a-e 1 a-e 4 a-e

i or ii i or ii i or ii and iv ii

R2 R2

OH R1 R1
OH
iv
R R

N N N N
H H
2 a-e 5 a-e

1a, 2a, 3a, 4a, 5a R = 4-OCH2Ph, R1 = H, R2 = H

1b, 2b, 3b, 4b, 5b R = 4-OCH2Ph, R1 = OMe, R2 = H
1c, 2c, 3c, 4c, 5c R = 5-OCH2Ph, R1 = OMe, R2 = H
1d, 2d, 3d, 4d, 5d R = 5-OCH2Ph, R1 = OMe, R2 = OMe
1e, 2e, 3e, 4e, 5e R = 5 - Cl, R1 = OMe, R2 = H
Reagents and conditions
i = NH2NH2. H2O, MeOH, reflux, 2 hr
ii = NH2NH2 .H2O, DMSO, r. t., 5 min.
iii = EDA, ethanol, reflux, 24 hr
iv = I2-DMSO, 130- 40 OC, 2 hr
Scheme I
2340 INDIAN J. CHEM., SEC B, NOVEMBER 2005

R2
R1

O
R
NH2.NH2.H2O NH2.NH2.H2O
O

R2 R2

OH R1 R1
OH
R R

N N N N
H H
3, 5 - diarylpyrazole 5, 3 - diarylpyrazole

Path (I) Path (II)

Scheme II ⎯ egioisomer formation of pyrazoles

O pyrazoles, many of which could not be prepared from

H
R : β-diketones. Also, the I2-DMSO can be used for
N oxidative dehydrogenation of pyrazolines to pyrazoles
N H and flavanone to flavones. Since 2'-hydroxychalcones
were easily converted into 3,5-diarylpyrazolines,
flavanone, flavones and then to 3,5-diarylpyrazoles, a
one-pot synthesis of pyrazoles could be achieved.

Experimental Section
R All melting points are uncorrected. All reported
Figure 2 ─ H-Bonding in 3, 5 - disubstituted pyrazole yields are for crystallised pure compounds. UV
spectra were recorded for dilute solutions in distilled
OH methanol on a Shimadzu UV 300 model; IR spectra
O H
H R on a Perkin-Elmer FTIR; and 1H NMR spectra on a
R : N Perkin-Elmer Jeol FX 90 QC (90 MHz) in CDCl3
N
N unless mentioned otherwise (chemical shifts in δ, ppm).
N H

General procedure for the preparation of 3, 5 -

diarylpyrazolines 2a-e
Preparation of 3-(2'-hydroxy-4'-benzyloxyphenyl)-
R 5-phenylpyrazoline 2a. 2'-Hydroxy-4'-benzyloxy-
R chalcone (0.5 g, 1.5151 mmoles) was dissolved in 10
I II ml of DMSO and then hydrazine hydrate (5 mL, [80%
Figure 3 ─ Forms of pyrazoles solution]) was added dropwise with constant stirring
of UV spectra of prepared pyrazoles matches with at r.t. The yellow coloured solution turned colourless
form I and not with form II, hence the latter is out of with the formation of precipitate when crushed ice
consideration (Figure 3). (20 g) was added to it. The colourless product
From the preparative point of view, we can obtained was filtered, washed with water and dried.
conclude that, the reactions of 2'-hydroxychalcones The crude product was recrystallised from methanol,
and flavones with hydrazine hydrate can be widely yield 75%, m.p. 81°C; UV: 235, 300 nm; IR: 3330,
used in the regioselective synthesis of 3,5-diaryl- 1626, 1594 cm-1; 1H NMR: δ 3.34 (dd, 2H, C4-H,
 LOKHANDE et al.: REGIOSELECTIVE ONE-POT SYNTHESIS OF 3, 5-DIARYLPYRAZOLES
J = 9 Hz), 4.91 (t, 1H, C5 - H, J =9 Hz), 5.14 (s, 2H, -
OCH2-), 5.17 (s, 1H, -NH, D2O exchangeable), 6.37-
8.00 (m, 13H, Ar-H), 11.28 (s, 1H, -OH, D2O
exchangeable)
3-(2'-Hydroxy-4'-benzyloxyphenyl)-5-(4'-metho-
xyphenyl) pyrazoline 2b: Yield 95%, m.p. 125-29°C;
UV: 300, 340 nm; IR: 3341, 1630, 1591 cm-1;
1
H NMR: δ 3.17 (dd, 2H, C4-H, J=9, 15.42 Hz), 3.85
(s, 3H, -OCH3), 4.86 (t, 1H, C5-H, J=9 Hz), 5.14 (s,
2H, -OCH2), 5.74 (s, 1H, -NH, D2O exchangeable),
6.57–8.00 (m, 12H, Ar-H), 11.37 (s, 1H, -OH, D2O
exchangeable).
3-(2'-Hydroxy-5'-benzyloxyphenyl)-5-(4'-metho-
xyphenyl) pyrazoline 2c: Yield 70%, m.p. 120-22°C;
-1 1
UV: 280, 360 nm; IR: 3341, 1630, 1591 cm ; H
NMR: δ 3.17 (dd, 2H, C4-H, J =9, 15.42 Hz), 3.85 (s,
3H, -OCH3), 4.86 (t, 1H, C5-H, J =9 Hz), 5.14 (s, 2H,
-OCH2), 5.74 (s, 1H, -NH, D2O exchangeable), 6.57–
8.00 (m, 12H, Ar-H), 11.37 (s, 1H, -OH, D2O
exchangeable).
3-(2'-Hydroxy-5'-benzyloxyphenyl)–5-(3', 4'-dime-
thoxyphenyl) pyrazoline 2d: Yield 68%, m.p. 140–
43 °C; UV: 300, 400 nm; IR: 3345, 1630, 1591 cm-1;
1
H NMR: δ 3.15 (dd, 2H, C4-H, J =9, 16 Hz), 3.88 (s,
6H, -OCH3), 4.89 (t, 1H, C5-H, J =9 Hz), 5.14 (s, 2H,
-OCH2), 5.76 (s, 1H, -NH, D2O exchangeable), 6.58–
8.00 (m, 11H, Ar-H), 11.40 (s, 1H, -OH, D2O
exchangeable).
3-(2'-Hydroxy-5'-chlorophenyl)-5-(4'-methoxy-
phenyl) pyrazoline 2e: Yield 65%, m.p. 82–85°C;
UV: 300, 340 nm; IR: 3311, 1609, 1588 cm-1; 1H
NMR: δ 3.28 (dd, 2H, C4-H, J=10.28 Hz), 3.80 (s,
3H, -OCH3), 4.87 (t, 1H, C5-H, J=10.28 Hz), 6.00 (s,
1H, -NH, D2O exchangeable), 6.92-7.21 (m, 7H, Ar-
H), 11.02 (s, 1H, -OH, D2O exchangeable).
The pyrazolines 2a-e were also prepared by using
methanol as a solvent at reflux temperature.
General procedure for preparation 3,5-diaryl-
pyrazoles 5a-e
3-(2'-Hydroxy-4'-benzyloxyphenyl)-5-phenylpyra-
zole 5a. Compound 2a (0.5 g, 1.4619 mmoles) was
dissolved in DMSO (15 mL) in 250 mL R. B. flask
fitted with condenser and guard tube and then iodine
(8 mg) was added to it. The reaction mixture was
stirred and heated in an oil-bath at 130-40°C for 2 hr.
The contents were cooled and poured into crushed ice
(50 g). The product obtained was filtered, washed
with saturated solution of sodium thiosulphate and
water and dried. The crude product was purified by
column chromatography on silica gel (hexane-ethyl
2341
acetate, 80:20), yield 65%, m.p. 154°C; UV: 235, 300
nm; IR: 3364, 1632 cm-1; 1H NMR: δ 5.14 (s, 2H, -
OCH2), 6.68 (s, 1H, C4-H), 7.80 (m, 13H, Ar-H),
11.14 (bs, 1H, -NH, D2O exchangeable), 13.42 (bs,
1H, -OH, D2O exchangeable).
3-(2'-Hydroxy-4'-benzyloxyphenyl)-5-(4'-metho-
xyphenyl) pyrazole 5b: Yield 70%, m.p. 162-64°C;
UV: 300 nm; IR: 3353, 1634 cm-1; 1H NMR: δ 3.87
(s, 3H, -OCH3), 5.14 (s, 2H, -OCH2), 6.65 (s, 1H, C4-
H), 6.67-7.81 (m, 12H, Ar-H), 11.20 (bs, 1H, -NH,
D2O exchangeable), 12.88 (bs, 1H, -OH, D2O
exchangeable).
3-(2'-Hydroxy-5'-benzyloxyphenyl)-5-(4'-metho-
xyphenyl) pyrazole 5c: Yield 68%, m.p. 167-70 °C;
UV: 300 nm; IR: 3358, 1640 cm-1; 1H NMR: δ 3.88
(s, 3H, -OCH3), 5.14 (s, 2H, -OCH2), 6.68 (s, 1H, C4-
H), 6.88–8.00 (m, 12H, Ar-H), 11.28 (bs, 1H, -NH,
D2O exchangeable), 12.78 (bs, 1H, -OH, D2O
exchangeable).
3-(2'-Hydroxy-5'-benzyloxyphenyl)-5-(3',4'-di-
methoxyphenyl) pyrazole 5d: Yield 65%, m.p. 175-
77 °C; UV: 300 nm; IR: 3351, 1635 cm-1; 1H NMR:
δ 3.85 (s, 6H, -OCH3), 5.14 (s, 2H, -OCH2), 6.67
(s, 1H, C4-H), 6.68–8.00 (m, 11H, Ar-H), 11.30 (bs,
1H, -NH, D2O exchangeable), 12.68 (bs, 1H, -OH,
D2O exchangeable).
3-(2'-Hydroxy-5'-chlorophenyl)-5-(4'-methoxy-
phenyl) pyrazole 5e: Yield 69%, m.p. 180–83 °C;
UV: 300 nm; IR: 3378, 1618 cm-1; 1H NMR: δ 3.88
(s, 3H, -OCH3), 6.86 (s, 1H, C4-H), 6.89 - 7.80 (m,
7H, Ar - H), 11.28 (bs, 1H, -NH, D2O exchangeable),
12.80 (bs, 1H, -OH, D2O exchangeable).
General procedure for one-pot synthesis of 3, 5-
diarylpyrazole from 2′-hydroxychalcone..
Compound 1a, (330 mg, 1 mmole) was dissolved in
15 mL of DMSO in 250 mL R. B. flask attached with
condenser and guard tube. To this was added
hydrazine hydrate (5 mL, 80% solution) dropwise
with constant stirring at r.t. for 5 min. The formation
of pyrazoline was monitored by TLC and compared
with co-TLC of authentic sample. Then, molecular
iodine in catalytic amount was added to the reaction
mixture and the mixture was further heated upto 130-
40°C for 2 hr. After the completion of the reaction,
the reaction mixture was cooled and poured into
crushed ice (50 g) and extracted with ethyl acetate and
washed with sodium thiosulphate and water to remove
the iodine. Then crude product was filtered and
purified by the column chromatography on silica gel
(hexane-ethyl acetate, 80:20).
2342 INDIAN J. CHEM., SEC B, NOVEMBER 2005
References
1 Giese N A, Lokker N, Laibelman A M, Scarbrough & Robert
M, Chem Abstr, 125(9), 1996, 135, 105089p.
2 Bondavalli F, Bruno O, Ranise A, Schenone P, Donnoli D,
Cenicola M L, Matera C, Russo S & Marmo E, Farmaco,
44(7-8), 1989, 655.
3 Bruno O, Ranise A, Bondavalli F, Schenone S, D'Amico M,
Falciani M, Vacca C & Filipplli A, Farmaco, 49 (9), 1994,
533.
4 Hanefeld U, Rees C W, White A J P & Williams D J, J Chem
Soc Perkin Trans 1, 1996, 1545.
5 Liu Y, Chem Abstr, 110, 75390 a, 110, 1989, 641.
6 Barot H & Vijay M, Asian J Chem, 8 (3), 1996, 565.
7 Mishriky N, Fahmy M A, Yehia A I & Adel S G, Indian J
Chem, 35B, 1996, 935.
8 Katritzky A R & Charles W R, Comprehensive Heterocyclic
Chemistry, Vol. 5, (Pregmann Press Ltd, Oxford, England),
1984, 279.
9 Schmidt P, Eicheberger K, Wilhelm M & Druey J, Helv Chim
Acta, 42, 1959, 763.
10 Miller R D & Reiser O, J Heterocyclic Chem, 30, 1993, 755.
11 Lyga J W & Patera R M, J Heterocyclic Chem, 27, 1990, 919.
12 Hoja H, Heterocycles, 34(4), 1992, 791.
13 Paul M, Dewick & David Ward, Phytochemistry, 17, 1978,
1751.
14 Lorand F, Gottsegen A & Mihaly N, J Chem Soc Perkin
Trans 1, 1974, 305.
15 Catalan J, Del Valle J C, Claramunt R M, Maria M D S,
Bobosik V, Mocelo R & Elguero J, J Org Chem, 60, 1995,
3427.
16 Wlodzimierz B & Zofia J, Polish J Chem, 53, 1979, 229.