Regioselective synthesis of 1,3,5-trisubstituted pyrazoles

Article abstract of DOI:10.1080/00397911.2010.531492

A new and a simple approach toward synthesis of 1,3,5-trisubstituted pyrazoles from chalcone arylhydrazones via oxidative cyclization has been achieved. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone was successfully used as an oxidizing agent to give excellen

Full text of DOI:10.1080/00397911.2010.531492

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Regioselective Synthesis of 1,3,5-
Trisubstituted Pyrazoles
Vidya G. Desai a , Pooja C. Satardekar a , Sampada Polo a &
Kashinath Dhumaskar a
a Department of Chemistry, Dnyanprassarak Mandal's College of Arts,
Science, and Commerce, Goa, India
Accepted author version posted online: 24 Aug 2011. Version of
record first published: 11 Nov 2011
To cite this article: Vidya G. Desai, Pooja C. Satardekar, Sampada Polo & Kashinath Dhumaskar
(2012): Regioselective Synthesis of 1,3,5-Trisubstituted Pyrazoles, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:6, 836-842
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Synthetic Communications1, 42: 836–842, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.531492
REGIOSELECTIVE SYNTHESIS OF
1,3,5-TRISUBSTITUTED PYRAZOLES
Vidya G. Desai, Pooja C. Satardekar, Sampada Polo, and
Kashinath Dhumaskar
Department of Chemistry, Dnyanprassarak Mandal’s College of Arts,
Science, and Commerce, Goa, India
GRAPHICAL ABSTRACT
Abstract A new and a simple approach toward synthesis of 1,3,5-trisubstituted pyrazoles
from chalcone arylhydrazones via oxidative cyclization has been achieved.
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone was successfully used as an oxidizing agent to
give excellent yields of pyrazoles.
Keywords Chalcones; hydrazones; oxidative cyclization; pyrazoles; regioselective
INTRODUCTION
Heterocyclic compounds form an important constituent in several biologically
active natural products. Among them, five-membered ring compounds are known to
exhibit varied biological properties.[1] There are numerous pyrazole derivatives
known for their diverse medicinal properties such as anti-inflammatory, anticancer,
anticoagulant, antimicrobial, analgesic, antidiabetic, hypoglycemic, and antibacter-
ial activities.[2] Various literature methods are known, wherein pyrazoles have been
obtained by oxidation of 2-pyrazolines using oxidizing agents such as iodobenzene
diacetate,[3a] manganese dioxide,[3b] lead tetraacetate,[3c] zirconium nitrate,[3d]
iodine,[3e] and activated carbon.[3f]
However, few methods are known for the synthesis of 1,3,5-trisubstituted
pyrazoles from phenyl hydrazones via oxidative cyclization; among them is use of
iodobenzenediacetate.[4a] Earlier methods include using manganese dioxide,[3b] lead
tetraacetate,[3c] thianthrene cation radical,[4b] and anodic oxidation.[4c]
Received September 5, 2010.
Address correspondence to Vidya G. Desai, Department of Chemistry, Dnyanprassarak Mandal’s
College of Arts, Science and Commerce, Assagao, Mapusa, Bardez-Goa, 403507, India. E-mail:
vidchem@gmx.net
836

1,3,5-TRISUBSTITUTED PYRAZOLES
837
These methods have drawbacks such as drastic reaction conditions and longer
reaction time, or they involve formation of inseparable side products. In our endea-
vor to use newer reagents toward synthesis of heterocycles,[5] we selected a much sim-
pler reagent that would do away with any side product from the substrate and also
involve milder reaction conditions. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) is a well-known reagent for oxidation of several functional groups. It is
cheap, available, easy to handle, and readily soluble in most of the solvents at ambi-
ent temperature. Furthermore, pyrazoline derivative has been known oxidize to cor-
responding pyrazole using DDQ.[6] This prompted us to use DDQ for obtaining
1,3,5-trisubstituted pyrazoles from open-chain chalcone arylhydrazones.
RESULTS AND DISCUSSION
Chalcone arylhydrazones 3 needed as substrates were synthesized by the litera-
ture method[7]. The treatment of chalcone 1 with the corresponding N-substituted
hydrazines 2 in methanol with a catalytic amount of concentrated sulfuric acid at
50–60 ꢀC for 10 min gave 3. N-Arylhydrazones of chalcones were subjected to oxidat-
ive cyclization using 2 equivalents of DDQ in dichloromethane at room temperature
for 2 h to give pyrazoles 4 (Scheme 1, Table 1, entries 1–12) in 55–97% yields. The
reaction involves simple, mild reaction conditions and an easy workup procedure.
The chalcone N-arylhydrazones prepared by the literature method are well
characterized by infrared (IR) and NMR spectroscopy. In its IR spectrum, com-
pound 3 showed a characteristic absorption band for NH group at 3350 cmꢁ1 and
1
two bands at 1600 and 1560 cmꢁ1 due to the C C and C N stretch. Its H NMR
exhibited two doublets of one proton intensity each at around d 6.51 and 8.090
(Jtrans ¼ 16.3 Hz) due to the trans olefinic protons, a singlet of one proton at around
d 3.85 due to the NH group, and multiplets of aromatic proton at around d
7.34–9.09. This methodology was also extended to the synthesis of 3-alkyl-1,5-
diarylsubstituted pyrazole. Here, the starting N-arylhydrazones 6 from benzal-
acetones and dibenzylidene acetone were also prepared by a method similar to that
of chalcone N-arylhydrazone synthesis.7 We successfully synthesized five such pyra-
zoles 7 (Scheme 2, Table 2, entries 1–5) in 67–94% yields.
=
=
We also synthesized pyrazole 10 from N-phenyl hydrazone of chalcone 8
(Scheme 3) in a very good yield.
The 1,3,5-trisubstituted pyrazoles were confirmed by comparing them with
authentic compounds prepared by the known literature method, literature melting
Scheme 1. Synthesis of 1,3,5-triaryl-substituted pyrazoles.

838
V. G. DESAI ET AL.
Table 1. 1,3,5-Triaryl-substituted pyrazolesa
Compound 4
Entry
R1
R2
X
Y
Yield (%)b
Mp (ꢀC)c
1
2
H
H
H
4-Br
H
H
H
H
65.10
95.85
68.71
56.29
55
140–141
159–160
114–116
135–136
140–141
78–79
3
4-Cl
H
H
4-Cl
H
H
4
H
H
5
H
4-NO2
4-OCH3
4-OCH3
4-OCH3
H
H
H
6
H
H
H
84.49
93.31
69.73
89.9
88.43
97.8
86.77
71
7
4-Cl
2-Cl
H
H
H
100–101
63–64
8
H
H
9
NO2
NO2
NO2
NO2
H
NO2
NO2
NO2
NO2
H
150–152
196–198
188–190
155–157
138
10
11
12
13
14
15
H
4-Cl
4-OCH3
H
H
4-Cl
4-OCH3
4-OCH3
4-Cl
4-OCH3
4-Br
4-Br
H
NO2
H
NO2
84
75
139
146
aConditions: N-Arylhydrazones, DDQ (2 equivalents), dichloromethane, rt, stir, 2 h.
bYields after recrystallization.
cDetermined mp compared to lit. mp.[3f,4b,8–15,17–19]
Scheme 2. Synthesis of 3-alkyl-1,5-diaryl-substituted pyrazoles.
Table 2. 3-Alkyl-1,5-diaryl-substituted pyrazolesa
Compound 6
Entry
R1
R2
X
Y
Yield (%)b
Mp (ꢀC)c
1
2
3
4
5
H
4-Cl
H
CH3
CH3
Styryl
CH3
CH3
H
H
H
H
67.81
73.29
94.13
90.05
91.51
62
70
H
H
141
133
63
H
4-Cl
NO2
NO2
NO2
NO2
aConditions: N-Arylhydrazones, DDQ (2 equivalents), dichloromethane, rt, stir, 2 h.
bYields after recrystallization.
cDetermined mp compared to lit. mp.[4b,15,16]

1,3,5-TRISUBSTITUTED PYRAZOLES
839
Scheme 3. Synthesis of pyrazole 9.[20]
1
points, and IR and NMR data. H NMR of pyrazoles 4 showed the disappearance
of both olefinic protons; however, a singlet of one proton intensity corresponding to
pyrazole 4-H was observed at about d 6.85.
It was visualized that the first step in the synthesis of pyrazoles may be cycliza-
tion, which would lead to the formation of dihydropyrazoles and on dehydrogenation
give pyrazoles. This is evident by the traces of dihydropyrazoles formed in the reaction.
CONCLUSION
In conclusion, we were successful in synthesizing a variety of pyrazole deriva-
tives in good to excellent yields. The convenience and novelty of this work is reflected
in its several advantages such as ambient reaction conditions, easy workup
procedure, short reaction time, and no need for chromatographic purification. A
variety of substrates that include chalcone N-arylhydrazones containing electron-
withdrawing groups have been successfully cyclized to their corresponding pyrazoles.
EXPERIMENTAL
All melting points are uncorrected and measured by the normal Thiels tube
(paraffin) method. Column chromatography was performed on silica gel G (13%
CaSO4 as binder). IR spectra were recorded on a Perkin Elmer Fourier transform
(FT)–IR spectrophotometer (as solution with carbon tetrachloride and also using
1
KBr pellets) t max in cmꢁ1. H and 13CNMR spectra were measured on a Bruker
instrument at 300 and 75 MHz, respectively. Chemical shifts are expressed in d-scale
downfield from tetramethylsilane (TMS) as an internal standard.
Typical Procedure for the Synthesis of N-Aryl Hydrazones (3 and 6)
A hot (50–60 ꢀC) acidic solution of N-arylhydrazine 2 (2.88 mmol), prepared by
carefully adding concentrated sulfuric acid (1.44 mL) to a suspension of phenylhy-
drazine in methanol (18 mL), was added to a well-mixed hot (50–60 ꢀC) solution
of a,b-unsaturated carbonyl compound 1 or 5 (2.4 mmol) in methanol (15 mL).
The hot mixture was stirred for 10 min at the same temperature and then cooled
in an ice bath. The precipitate obtained was filtered, dried, and recrystallized from
ethanol to yield 3 or 6. All the N-arylhydrazones were prepared by the same
procedure.

840
V. G. DESAI ET AL.
General Procedure for the Synthesis of Pyrazoles from N-Aryl
Hydrazones (4 and 7)
Dichlorodicyanoquinone (1.33 mmol) was added with stirring to a solution of
N-arylhydrazones 3 or 6 (0.669 mmol) in dichloromethane (5 mL) at rt. The solution
immediately turned greenish in color. After stirring for 2 h, the reaction mixture was
monitored by thin-layer chromatography (TLC) and was then filtered and washed
with dichloromethane. The dichloromethane layer was washed with 2N sodium
hydroxide (2 ꢂ 10 mL) and then with water (1 ꢂ 5 mL). The organic layer was dried
over anhydrous sodium sulfate and concentrated to give a light yellow solid, which
was recrystallized from ethanol to give 1,3,5-triarylsubstitutedpyrazole 4 or 7.
Selected Data
5-(4’-Chlorophenyl)-1,3-diphenylpyrazole 4 (Table 1, Entry 3). Yield
1
68.71%; mp 114–116ꢀC. H NMR (300 MHz, CDCl3): d 6.83 (s, 1H), 7.20–7.29
(m, 5H), 7.31–7.42 (m, 5H) 7.92 (d, 2H), 7.45 (d, 2H).
3-(4’-Methoxyphenyl)-1,5-diphenylpyrazole 4 (Table 1, Entry 6). Yield
84.5%; mp 78–79 ꢀC. IR (KBr): 3050, 2880, 1600, 1490, 1250 cmꢁ1 1H NMR
.
(300 MHz, CDCl3): d3.88 (s, 3H), d 6.75 (s, 1H, 4-H), d7.828–8.058 (m, 5H),
7.53–7.66 (m, 5H) 6.97–7.35 (m, 4H).
3-(p-Chlorophenyl)-5-phenyl-1-(2’,4’-dinitrophenyl)pyrazole 4 (Table 1,
Entry 10). Yield 88.43%; mp 196–197 ꢀC, IR (KBr): 3100, 1620, 1550, 1500,
680 cmꢁ1 1H NMR (300 MHz, CDCl3): d 6.9 (s, 1H, 4-H), 7.1–7.4 (m, 5H),
.
7.76–7.83 (m, 4H), 7.83 (d, 1H), 8.75 (d, 1H), 9.058 (d, 1H). 13C NMR (75 MHz,
CDCl3): d 116, 117, 116, 126,127, 127.6, 128.3, 128.4, 128.7, 129.05, 129.11,
129.45, 129.46, 129.53, 129.6, 129.91, 130.0, 130.19, 130.39, 130.61, 137.469, 141.3,
155.1, 157.5.
3-(4’’-Methoxyphenyl)-5-phenyl-1-(2’,4’-dinitrophenyl)-pyrazole4(Table1,
Entry 11). Yield 88.43%; mp 196–197 ꢀC. IR (KBr): 3100, 2950, 1630, 1550, 1500,
1
1250 cmꢁ1. H NMR (300 MHz, CDCl3): d 3.87 (s, 3H), d 6.87 (s, 1H), 7.25–7.44
(m, 5H), 7.78 (d, 2H), 7.35 (d, 2H) 7.78 (d, 2H), 8.71 (d, 1H).
3-(4’’Bromophenyl)-5-(4’-methoxyphenyl)-1-phenylpyrazole 4 (Table 1,
Entry 14). Yield 84%; mp 139 ꢀC. IR (KBr): 3050, 2900, 1600, 1510, 1250,
1
700 cmꢁ1. H NMR (300 MHz, CDCl3): d 3.85 (s, 3H,), d 6.834 (s, 1H), 7.34–7.37
(m, 4H), 7.530–7.642 (m, 5H), 7.772–7.88 (m, 4H).
3-(p-Bromophenyl)-5-(p-chlorophenyl)-1-(2’,4’-dinitrophenyl)pyrazole 4
(Table 1, Entry 16). Yield 75%; mp 146 ꢀC. IR (KBr): 3100, 1620, 1550, 1500, 820,
1
650 cmꢁ1. H NMR (300 MHz, CDCl3): d 6.79 (s, 1H), 7.29–7.81 (m, 8H), 8.30 (d,
2H), 8.68 (d, 1H).
3-Methyl-5-(p-chlorophenyl)-1-(2’,4’-dinitrophenyl)pyrazole 7a (Table 2,
1
Entry 4). Yield 90%; mp 133 ꢀC. H NMR (300 MHz, CDCl3): d 2.35 (s, 3H), 6.79
(s, 1H, 4-H), 7.08–7.51 (m, 4H), 8.75 (dd, 1H, J ¼ 1.8 Hz), 9.16 (d, 2H, J ¼ 1.2 Hz).
13C NMR (75 MHz, CDCl3): d 14.1, 107.1, 110, 117, 120, 121.4, 123.9, 127.7, 128.3,

1,3,5-TRISUBSTITUTED PYRAZOLES
841
128.7, 129.1, 129.46, 129.63, 130.0, 130.2, 130.59, 132.04, 134.14, 134.9, 135.36,
144.90, 153.22.
Compound 9. Yield 93%; mp 160 ꢀC. IR (KBr): 3050, 2925, 1600, 1490 cmꢁ1
.
1H NMR (300 MHz, CDCl3): d 1.78 (quintet, 2H), 2.92 (m, 4H), 6.80 (s, 1H),
7.35–7.47 (m, 15H).
ACKNOWLEDGMENT
The authors thank the Department of Science and Technology, government of
Goa, for financial assistance.
REFERENCES
1. (a) Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed.; Addison-Wesley Longman: London,
1998; (b) Azarifar, D.; Shaebanzadeh, M. Synthesis and characterisation of new
3,5-dinaphthyl substituted 2-pyrazolines and study of their antimicrobial properties.
Molecules 2002, 7, 885–895.
2. (a) Katayama, H.; Oshiyama, T. Preparation and bioactivity of pyrazole derivatives as
potential cross-linking agents. Can. J. Chem. 1997, 75, 913–919; (b) Faid, H. M.;
Mokhtar, H. M. Pyrazole derivatives with possible hypoglycemic activity. Ind. J. Chem.
1988, 27B, 245–249.
3. (a) Singh, S. P.; Kumar, D.; Prakash, O.; Kapoor, R. P. Hypervalent iodine oxidation of
1,3,5-trisubstituted pyrazolines: A facile synthesis of 1,3,5-trisubstituted pyrazoles. Synth.
Commun. 1997, 27 (15), 2683; (b) Bhatnagar, I.; George, M. V. Oxidation with metal
oxides II: Oxidation of chalcone phenylhydrazones, pyrazolines, o-aminobenzylidine
anils, and o-hydroxybenzylidine anils with manganese dioxide. Tetrahedron 1968, 24,
1293; (c) Gladstone, W. A. F.; Norman, R. O. C. Reactions of lead tetra-acetate, part
VII: Some reactions leading to pyrazoles. J. Chem. Soc., Chem. 1966, 1536; (d) Sabitha,
G.; Kumar Reddy, G. S. K.; Reddy, Ch. S.; Fatima, N.; Yadav, J. S. Zr(NO3)4: A versa-
tile oxidizing agent for aromatization of Hantzsch 1,4-dihydropyridines and 1,3,5-trisub-
stituted pyrazolines. Synthesis 2003, 8, 1267; (e) Ponnala, S.; Sahu, D. P. Iodine-mediated
synthesis of 2-arylbenzoxazoles, 2-arylbenzimidazoles, and 1,3,5-trisubstituted pyrazoles.
Synth. Commun. 2006, 36, 2189; (f) Nakamuchi, N.; Kawashita, Y.; Hayashi, M. Acti-
vated carbon-promoted oxidative aromatization of Hantzsch 1,4-dihydropyridines and
1,3,5-trisubstituted pyrazolines using molecular oxygen. Synthesis 2004, 7, 1015.
4. (a) Aggarwal, R.; Kumar, R. Iodobenzene diacetate–mediated oxidation of N-substituted
hydrazones of chalcones: An efficient regioselective synthesis of 1,3,5-trisubstituted pyra-
zoles. Synth. Commun. 2009, 39, 2169; (b) Kovelesky, A. C.; Shine, H. J. Oxidative cycliza-
tion of arylhydrazones of chalcones and benzalacetones to pyrazoles by thianthrene cation
radical. J. Org. Chem. 1988, 53, 1973; (c) Tabakovic, I.; Lacan, M.; Damoni, S. Electro-
chemical syntheses of heterocyclic compounds III: Anodic oxidation of chalcone phenyl-
hydrazone. Electrochim. Acta 1976, 21, 621.
5. (a) Desai, V.; Tilve, S. A novel and a convenient method for the synthesis of 3,5-diarylisox-
azoles. Synth. Commun. 1999, 29, 3017–3020; (b) Kurangi, R.; Kawthankar, R.; Sawal, S.;
Desai, V.; Tilve, S. Convenient synthesis of 3, 5-diarylisoxazoles. Synth. Commun. 2007, 37,
585–587.
6. (a) Jedlovska, E.; Fisera, L.; Liptag, T. Regio- and stereoselectivity of aromatic and
heteroaromatic nitrilimines in 1,3-dipolar cycloadditions. T. Chem. Pap. 2005, 59 (5), 354.

842
V. G. DESAI ET AL.
7. Rezende, C. M.; Pizarro, C.; Millan, D. Preparation, spectroscopic, and acidity properties
of two hydrazones: An organic experiment. Quim. Nova. 2007, 30 (1), 229.
8. Harris, D. J.; Kan, G. Y. P.; Snieckus, V. The synthesis of 1, 2-diazepines from thiapyr-
ylium salts. Can. J. Chem. 1974, 52, 2798.
9. Morrocohi, S.; Ricca, A.; Zanarotti, A. New features of the reaction between nitrilimines
and arylacetylenes. Tetrahedron Lett. 1970, 3215.
10. Landge, S. M.; Schmidt, A.; Outerbridge, V.; Torok, B. Synthesis of pyrazoles by a
one-pot tandem cyclization–dehydrogenation approach on PD=C=K-10 catalyst. Synlett
2007, 10, 1600.
11. Azarifar, D.; Zulfigol, M. A.; Maleki, B. 1,3-Dibromo-5,5-dimethylhydantoin as a novel
oxidizing agent for the oxidation of 1,3,5-trisubstituted pyrazolines under both hetero-
geneous as well as solvent-free conditions. Bull. Korean Chem. Soc. 2004, 25 (1), 23.
12. Zulfigol, M. A.; Azarifar, D.; Mallakpour, S.; Baltork, I. M.; Forghaniha, A.; Haleki, B.
Abdollahi-Alibeik, M. 4-(p-Chloro)phenyl-1,2,4-triazole-3,5-dione as a novel and reusable
reagent for the oxidation of 1,3,5-trisubstituted pyrazolines under mild conditions. Tetra-
hedron Lett. 2006, 47, 833.
13. Azarifar, D.; Maleki, B.; Sahraei, M. Microwave-promoted oxidation of 1,3,5-
trisubstituted-4,5-dihydro-1H-pyrazoles by in situ generation of NOþ NO2þ respectively
from sodium nitrite and sodium nitrate in acetic acid. J. Heterocycl. Chem. 2008, 45, 563.
14. Azarifar, D.; Zulfigol, M. A.; Maleki, B. Silica-supported-1,3-dibromo-5,5-
dimethylhydantoin (DBH) as a useful reagent for microwave-assisted aromatization of
1,3,5-trisubstituted pyrazolines under solvent-free conditions. Synthesis 2004, 11, 1744.
15. Jones, L. A.; Hancock, C. K.; Seligman, R. B. The reaction of 2,4-dinitrophenylhydrazone
with some dicarbonyl compounds and a-substituted carbonyl compounds. J. Org. Chem.
1961, 26, 228.
16. Shah, J. N.; Shah, C. K. Oxidative dehydrogenation of pyrazolines with cobalt(II) and
oxygen. J. Org. Chem. 1978, 43 (6), 1266.
17. Van Steeris, J. Nitration of dianisoylmethane and p-methoxydesoxybenzoin. Recueil des
Travaux Chimiques des Pays-Bas et de la Belgique 1947, 66, 29–46.
18. Orlov, V. D.; Shkumat, A. P.; Kotlyar, V. N. Oxidation of 2-pyrazolines. Visnik
Kharkivis’kogo Universitetu 1999, 437, 99–102.
19. Deng, X.; Mani Neelakandha, S. Regioselective synthesis of 1,3,5-tri- and 1,3,4,5-
tetrasubstituted pyrazole from N-arylhydrazones and nitroolefins. J. Org. Chem. 2008,
73 (6), 2412.
20. Gella, I. M.; Amadu, R.; Orlov, V. D. 2-Pyrazolines based on diarylidene-cyclohexanes:
Synthesis and stereochemistry of partially hydrogenated N-arylindazoles. Visnik Kharki-
vis’kogo Universitetu 2001, 532, 103–108.