Synthesis and applications of bipyrazole systems

Abstract

This review focuses on the synthetic methodologies towards ten main classes of bipyrazole systems (according to the type of connection between them): 1,1'-, 1,3'-, 1,4'-, 1,5'-, 3,3'-, 3,4'-, 3,5'-, 4,4'-, 4,5'-and 5,5'-junctions. The research and industrial applications of these bipyrazoles are reported as well.

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Synthesis and applications of bipyrazole systems
Bakr F. Abdel-Wahab
a
and Kamal M. Dawood
b*
a
Applied Organic Chemistry Department, National Research Centre, Dokki, Giza, Egypt
b
Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt
E-mail: dr
-
dawood@yahoo.com
Abstract
This review focuses on the synthetic methodologies towards ten main classes of bipyrazole
systems (according to the type of connection between them): 1,1'-, 1,3'-, 1,4'-, 1,5'-, 3,3'-, 3,4'-,
3,5'-, 4,4'-, 4,5'- and 5,5'-junctions. The research and industrial applications of these
bipyrazoles are reported as well.
Keywords: Pyrazoles, bipyrazoles, synthesis, cycloaddition, heterocycles
Table of Contents
1. Introduction
2. Synthesis and Reactions of Bipyrazoles
2.1. 1,1'-Bipyrazoles
2.2. 1,3'-Bipyrazoles
2.3. 1,4'-Bipyrazoles
2.4. 1,5'-Bipyrazoles
2.5. 3,3'-Bipyrazoles
2.6. 3,4'-Bipyrazoles
2.7. 3,5'-Bipyrazoles
2.8. 4,4'-Bipyrazoles
2.9. 4,5'-Bipyrazoles
2.10. 5,5'-Bipyrazoles
3. Applications of Bipyrazoles
4. References
1. Introduction
Three main types of connections between two pyrazole moieties can be considered; N,N-,
C,N-, and C,C-linked bipyrazoles. According to numbering there are pertinent ten systems of
bipyrazole which differ in the position of the bond between the two pyrazole rings as shown
in Figure 1.

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Figure 1
The NH-forms of all of these compounds represented in Figure 1, except the 1,1'-, 1,4'-
and 4,4'-forms, are subject to annular tautomerism.
1,2
Bipyrazoles were synthesized for the
first time in 1893.
3
Since then many publications about bipyrazole derivatives have been
reported in the literature.
4
Such compounds are very interesting class of heterocycles that have
remarkable pharmacological activities. For example, they were reported to possess potential
antitumor,
5
anti-inflamatory,
6-8
antimicrobial,
9
cytotoxic,
10,11
antiallergic,
12
cardiovascular
13
and diuretic
14
activities.
Bipyrazoles were also found to be useful as insecticides,
15
herbicides,
16
fungicides,
17-19
in the photographic and paint industry,
20-22
and in the synthesis of
heat resistant polymers.
23
Furthermore, bipyrazole derivatives were used as agents for
preventing or treating various diseases induced by active oxygen,
24
and as agents for free
radical scavenging.
25
In the current review article, the bipyrazole systems are classified
according to the type of linkage between the two rings and a survey on the synthesis and
applications of all those bipyrazole systems is presented covering all publications till 2011.
2. Synthesis and Reactions of Bipyrazoles
2.1. 1,1'-Bipyrazoles
Photolysis of ethyl 5-amino-3-(phenylamino)pyrazole-4-carboxylate 1, which is a very good
antioxidant, with tert-butyl peroxide or with dibenzoyl peroxide under mild reaction
conditions resulted in radical dimerization of the pyrazole 1 and led to the formation of the
1,1'-bipyrazole derivative 2 in 40 and 20% yields, respectively (Scheme 1).
26
Scheme 1

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Treatment of 3-methoxycarbonyl-2-pyrazoline 3 with 1.1 equivalent of lead tetraacetate in
benzene at 60 °C gave the pyrazoline intermediate 4 which underwent further attack on 3 to
give the 1,1'-bipyrazole derivative 6 in 17% yield. The oxidation of 6 with N-
bromosuccinimide (NBS) in refluxing carbon tetrachloride in the presence of few drops of dry
pyridine gave the symmetrical 3,3'-dimethoxycarbonyl-1,1'-bipyrazole 7 in 55% yield
(Scheme 2).
27
Scheme 2
2.2. 1,3'-Bipyrazoles
Diazotization of 3-amino-5-methylpyrazole 8 in HCl followed by reduction with tin chloride
gave 3-hydrazino-5-methyl-1H-pyrazole 9. Cyclocondensation reaction of 9 with
acetylacetone 10 afforded 3,5,5'-trimethyl-1'H-1,3'-bipyrazole 11 in high yield. The
methylation of 11 in the presence of t-BuOK led to the formation of 1',3,5,5'-tetramethyl-1'H-
1,3'-bipyrazole 12 in high yield (Scheme 3).
28-30
Scheme 3
The 1,3'-bipyrazole derivatives 15 were prepared in good yields by cyclocondensation of
the acrylonitrile derivatives 14 with 3-pyrazolylhydrazines 13 in the presence of potassium

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carbonate in refluxing ethanol (Scheme 4).
16,31
Scheme 4
Bromination of a cold solution of the silver salt of pyrazole 16 in ether at 0 °C resulted in
the formation of 1,3'-bipyrazole derivative 17 as outlined in Scheme 5.
32
Scheme 5
Transformation of the 5-hydrazino-1,3-oxazole-4-carbonitriles 18 into 5-(pyrazol-1-yl)-
1,3-oxazole-4-carbonitriles 19, in good yields, was achieved upon its heating with
acetylacetone 10. Further treatment of 5-(pyrazol-1-yl)-1,3-oxazole-4-carbonitriles 19 with
hydrazine hydrate in refluxing ethanol resulted in the opening of 1,3-oxazole ring of 19 and
furnished the corresponding 1,3'-bipyrazoles 21 in moderate to high yields via the
intermediates 20 as depicted in Scheme 6.
33,34
Scheme 6

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Electrochlorination of the unsubstituted pyrazole 22 in aqueous NaCl solution in the
presence of CHCl
3
on Pt anode at a current of 3 A and 15 °C led to the formation of 4-
chloropyrazole 23 which underwent further dimerization under the reaction condition to give
4,4'-dichloro-1,3'-bipyrazole 25 in reasonable yield, through the intermediate 24 (Scheme
7).
35
Scheme 7
Treatment of 3-hydrazinopyrazole 9 with the benzoylpyruvate ester 26 yielded the 1,3'-
bipyrazole ester derivative 27 in 36% yield. Methylation of 26 in the presence of t-BuOK
gave the 1,3'-bipyrazole derivative 28 in 29%. Finally, reduction of 28 using LiAlH
4
in THF
afforded 1,5'-dimethyl-3-hydroxymethyl-5-phenyl-1,3'-bipyrazole 29 in 86% yield (Scheme
8).
36
Scheme 8
5-Chlorination of ethyl 3-ethoxypyrazole-4-carboxylate 30 with N-chlorosuccinimide
(NCS) under microwave irradiation at 130 °C in dichloroethane (DCE) led to the formation of
the 1,3'-bipyrazole derivative 32 in 23%. Mechanistically, occurrence of 32 was suggested via
the hydrolysis of the 4-chlorinated ethoxypyrazole moiety of the intermediate 31 upon
working-up of the reaction (Scheme 9).
37,38
Scheme 9

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2.3. 1,4'-Bipyrazoles
Reaction of 1H-pyrazole-4-carbonitrile 33 with 4-chlorophenacyl bromide 34 followed by
condensation with formaldehyde resulted in the formation of the pyrazole derivative 35.
When the latter compound was heated with hydrazine, the 1,4'-bipyrazole 36 was obtained.
Reaction of the 1,4'-bipyrazole 36 4-phenylphenylisocyanate afforded the 1,4'-bipyrazole
derivative 37 in 69% yield (Scheme 10).
39,40
Scheme 10
4-Nitro-1'H-1,4'-bipyrazole 39 was obtained via condensation reaction of 2-(4-nitro-1H-
pyrazol-1-yl)malonaldehyde 38 with hydrazine hydrate (Scheme 11).
41
Scheme 11
Alkylation of 4-bromopyrazole 40 with ethyl bromoacetate or bromoacetonitrile in
anhydrous THF, followed by formylation with dimethyl formamide-diethyl acetal (DMF-
DEA) under microwave irradiating condition gave the 2-(4-bromopyrazol-1-yl)-3-
dimethylaminoacrylic acid derivatives 41 (X = CN, CO
2
Et). Further microwave irradiation of
41 (X = CN) with hydrazines in ethanol afforded the corresponding 1,4'-bipyrazoles 42 in
good yields. Similar heating of 41 (X = CO
2
Et) and hydrazine gave the 1,4'-bipyrazole
derivative 43 in excellent yield (Scheme 12).
42
Keeping a mixture of bis(dimethylamino)methane 45 and α-(4-chloro-1-pyrazolyl)-4-
chloroacetophenone 44 in dichloromethane at 20-25 °C for 90 min gave the non-isolable
intermediate 46 which upon treatment with hydrazine hydrate gave the 1,4'-bipyrazole
derivative 47 in 58% yield (Scheme 13).
43

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Scheme 12
Scheme 13
2-(3,5-Dimethyl-1H-1-pyrazolyl)acetophenone 50 was prepared in 71% yield through the
alkylation reaction of 3,5-dimethyl-1H-pyrazole 48 with phenacyl bromide 49 under reflux of
anhydrous acetone containing potassium carbonate. Condensation of the latter compound with
1.2 equivalent of neat N,N-dimethylformamide-dimethylacetal (DMF-DMA) under reflux
gave 3-dimethylamino-2-(3,5-dimethyl-1H-1-pyrazolyl)-1-phenyl-2-propen-1-one 51 in 92%
yield. The dimethylaminoenone 51 was converted into 1,4'-bipyrazoles 52 by its reaction with
hydrazine derivatives (Scheme 14).
44
Scheme 14

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Next, the synthesis 5-(di-tert-butylphosphino)-1-(1,3,5-triphenyl-1H-pyrazol-4-yl)-1H-
pyrazole (Bippyphos) 57 and its derivatives has been reported in four steps. The key precursor
to Bippyphos 57 was the preparation of the bipyrazole derivative 56 via a one-pot
bromination of 1,3-diphenylpropane-1,3-dione 53 followed by alkylation with pyrazole 54 in
N-methyl-2-pyrrolidinone (NMP) followed by condensation of the product 55 with
phenylhydrazine. Lithiation of 56 followed by trapping with di-alkylchlorophosphine afforded
the Bippyphos derivatives 57 in good yields (Scheme 15).
45,46
O
Ph
O
Ph
PyrH Br3
or NBS
MeCN
O
Ph
O
Ph
Br
N
NH
NMP, H2O
rt
O
Ph
OH
Ph
N
N
ArNHNH2
MeOH/AcOH/rt
1. n-BuLi, THF, -78 °C
2. R2PCl
53
54 95% 55 97%
56 70-80% 57 60-84%
22
N
NN
N
Ph
Ph Ar N
NN
N
Ph
Ph Ar
P
RR
R = t-Bu, cyclohexyl, 1-adamantyl, Ph Ar = Ph, 4-MeOC6H4, 2-MeOC6H4
Scheme 15
N-Hetarylation of 1H-pyrazole 22 through its coupling with 4-iodo-1-methylpyrazole 58
using cesium carbonate as a base, in the presence of Cu
2
O as co-catalyst and salicylaldoxime
59 as ligand, in acetonitrile furnished 96% yield of the 1,4'-bipyrazole derivative 60 (Scheme
16).
47
Scheme 16
The reaction of 3,4,5-trinitro-1H-pyrazole (TNP) 61 with 1H-pyrazoles 62 in water in the
presence of 2 equiv. NaOH at 80–90 °C followed by acidification gave the corresponding
1,4´-bipyrazoles 63 in good yields, where the 1H-pyrazoles 62 selectively substitute the 4-
positioned nitro group in the TNP 61 (Scheme 17).
48

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Scheme 17
2.4. 1,5'-Bipyrazoles
In contrast to the behavior of 3,4,5-trinitro-1H-pyrazole (TNP) 61 towards 1H-pyrazoles
where the substitution took place at the 4-positioned nitro group, the reactivity of 1-methyl-
3,4,5-trinitropyrazole (MTNP) 64 behaved completely different compared to TNP 61 and the
nucleophilic substitution proceeded regiospecifically at the 5-position. Thus, reaction of
MTNP 64 with 1H-pyrazole 22 or nitropyrazoles 62 in the presence of NaOH at room
temperature afforded the corresponding 1,5´-bipyrazole derivatives 65 in high yields (Scheme
18).
49
Scheme 18
The activated 5-chloropyrazoles 66 underwent nucleophilic substitution of its chlorine
atom with pyrazole 22 (as a nucleophile) in dimethylsulfoxide (DMSO) at room temperature
led to the formation 1,5'-bipyrazole derivatives 67 in good yields.
Further reduction of the
nitro group in compounds 67 using NaBH
4
/SnCl
2
followed by treatment with
methanesulfonyl chloride and pyridine in dichloromethane afforded 4'-
(methylsulfonylamino)-1,5'-bipyrazole 68 (Scheme 19).
50,51
Scheme 19

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Reaction of pyrazole 22 with 1,4-dinitropyrazole 69 in acetonitrile at room temperature
resulted in the formation of 4'-nitro-1,5'-bipyrazole 70 in excellent yield through cine-
substitution reaction where the entering group (pyrazole 22) occupied position-2 adjacent to
the leaving group (NO
2
). Further, nitration of 70 with nitric acid in a mixture of acetic acid
and acetic anhydride at reflux led to the formation of 1',4',4-trinitro-1,5'-bipyrazole 71 in 90%
yield (Scheme 20).
52,53
Scheme 20
Reaction of pyrazole 22 with 2,6-dimethyl-1-(2-methylpyrazol-1-yl)-4-phenylpyridinium
bistetrafluoroborate 72, in water at room temperature afforded 1´-methyl-1,5´-bipyrazole 75
in 73% yield via loss of pyridinium tetraflouroborate 74 from the intermediate 73 under the
reaction conditions (Scheme 21).
54
Scheme 21
1'-tert-Butyl-1,5'-bipyrazolyl-4'-carboxylic acid-N-(adamantan-2-yl)amide 77 was
prepared through the microwave irradiation of a mixture of 1-tert-butyl-5-chloro-1H-
pyrazole-4-carboxylic acid-N-(2-adamantyl)amide 76 with pyrazole 22 using KF as a base
and DMSO solvent (Scheme 22).
55
Scheme 22

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Cyclocondensation of 5-hydrazinopyrazole derivative 78 with 1,3-dicarbonyl compounds
10 and 53 gave the corresponding 1,5'-bipyrazoles 79. The latter 1,5'-bipyrazole 79 (R = R
1
=
Me) underwent electrophilic substitution reactions (nitration and bromination) at the position-
4 of the pyrazole ring to give the corresponding 1,5'-bipyrazole derivatives 80 in high yield.
Condensation of the pyrazol-5-ylhydrazine 78 with ethyl 2-cyano-3-ethoxyacrylate 81
afforded the 1,5'-bipyrazole derivative 82 in 69% yield (Scheme 23).
56
Scheme 23
The treatment of 3,3-dichlorovinyl methyl ketone 83 with hydrazine led to the formation
of the 1,5´-bipyrazole derivative 85 in 40% yield. The reaction proceeded through initial
formation of 5-chloro-3-methylpyrazole 84 followed by its dimerization under the basic
reaction condition with loss of HCl (Scheme 24).
57
Scheme 24
The 4-bromo-3-phenylpyrazol-5-ylhydrazonyl chloride 86 was reported to react with
the active methylene compounds 87 and 88 in ethanolic sodium ethoxide solution at room
temperature to give the 1,5'-bipyrazole derivatives 89 and 90, respectively (Scheme 25).
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Scheme 25
2.5. 3,3'-Bipyrazoles
Treatment of the methyl ketones 91 with diethyl oxalate in the presence of an alkoxide base
gave the corresponding 1,3,4,6-tetraketones 92 via a double Claisen condensation. Reaction
of 92 with hydrazine hydrate in refluxing ethanol afforded the 5,5'-disubstituted-3,3'-
bipyrazoles 93. Further N,N'-arylation of 93 with fluoronitrobenzenes under microwave
irradiation and under classical heating conditions, afforded high yields of 1,1´-diaryl-3,3´-
bipyrazole derivatives 94 (Scheme 26).
11,61,62
Treatment of the bipyrazole derivatives 93 with
benzylbromide and ethyl chloroacetate in refluxing THF gave the corresponding alkylated
3,3´-bipyrazole derivatives 95 in moderate to good yields (Scheme 26).
63-69
O
R Me
(CO
2
Et)
2
, Et
2
O
MeONa or
t
BuOK
NH
2
NH
2
.H
2
O
EtOH, ∆
HN N
NH
N
R
R
Ar-F
t
BuOK, DMSO
NN
N
N
R
R
Ar
Ar
R = n-Pr; n-Bu, i-Pr; i-Bu; t-Bu
Ar = 4-NO
2
C
6
H
4
; 2-NO
2
C
6
H
4
R
1
= Ph, CO
2
Et, CH
2
OH, X = Cl, Br
91 92
93 42-95%
94 54-96%
O
R
O
O
R
O
NN
N
N
R
R
R
1
R
1
R
1
X
Scheme 26
95 20-96%
t
BuOK, THF
reflux
Scheme 26
Reaction of 1,6-aryl-2,4,6,7-hexanetetrones 96 with hydrazine and arylhydrazines in
refluxing ethanol afforded the corresponding 3,3'-bipyrazole derivatives 97 in moderate yields

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(Scheme 27).
70-72
Scheme 27
Treatment of 3-epoxypropionyl-2-pyrazolines 98 with hydrazine hydrate in refluxing
methanol gave 69-70% of 3,3'-bipyrazolines 99, which were acetylated by acetylchloride to
give 64-70% of 100. Hydrolysis of 100 gave 87% of 1-acetyl-4'-methyl-4-phenyl-4,5-
dihydro-3,3'-bipyrazole 101. Dehydrogenation of compound 100 by sulfur gave 73% of 4-
methyl-4'-phenyl-3,3'-bipyrazole 101 (Scheme 28).
73
Scheme 28
Oxidative dehydrogenation of 3,3′,4,4′,5,5′-hexahydro-3,3′-bipyrazole 103 with MnO
2
, in
benzene at room temperature, led to the formation of a mixture of 3,3'-bipyrazole 104 and 3-
cyclopropyl-1H-pyrazole 105 in 27 and 18% yields, respectively (Scheme 29).
74,75
Scheme 29

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Reaction of 2,3-bis(phenylsulfonyl)-l,3-butadiene 106 with diazomethane in
dicholomethane (DCM) at room temperature under nitrogen gave a 1:1 mixture (98%) of the
pyrazoline 107 and 3,3'-bipyrazoline 108 derivatives. Thermal extrusion of nitrogen occurred
from the 3,3'-bipyrazoline 108 producing mainly the E,E-diene 109 (Scheme 30).
76
Scheme 30
When an excess of diazomethane was allowed to react with 2-phenylsulfinyl-3-
phenylsulfonyl-1,3-butadiene 110 and for longer periods of time furnished only dihydro-
3H,l'H-3,3'-bipyrazole 112 in 73% yield. The formation of 112 was explained by reaction of
diazomethane (excess) with both π-bonds in a sequential manner giving the 2:l-adduct 111 as
a transient species. This intermediate underwent a subsequent syn elimination of PhSOH
followed by a 1,5-sigmatropic hydrogen shift (Scheme 31).
76
Scheme 31
Treatment of the bis-arylnitrilimines 114 [generated in situ from treatment of bis-
hydrazonyl halides 113 with triethylamine in dry benzene] with active methylene compounds
115 furnished the polysubstituted 3,3'-bipyrazole derivatives 116 in good to high yields.
Furthermore, the bis-arylnitrilimines 114 underwent 1,3-dipolar cycloaddition reactions with
some olefins 117 to give the corresponding 3,3'-bi(2-pyrazolines) 118 in good yield.
Oxidation of the latter compound 118 (R
2
= Ph, R
3
= COPh, Ar = Ph) with chloranil afforded
the corresponding 3,3'-bipyrazole derivative 119 in 71% yield (Scheme 32).
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Scheme 32
Regioselective synthesis of polysubstituted 3,3'-bi-1H-pyrazole derivatives 122 via 1,3-
dipolar cycloaddition reactions has also been reported. Thus, the bis-arylnitrilimines 114
reacted regioselectively with the cinnamonitriles 120 to yield the cycloadducts 5,5'-dicyano-
4,4',5,5'-tetrahydro-3,3'-bi-1H-pyrazoles 121 in 40-75% yields. Compounds 121 underwent
aromatization via thermal elimination of hydrogen cyanide under the basic reaction conditions
and afforded the corresponding 3,3'-bi-1H-pyrazole derivatives 122 in 55-75% yields
(Scheme 33).
78
Scheme 33
Furthermore, regioselective 1,3-dipolar cycloaddition of the bis-hydrazonyl halides 113

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with the benzylidene chroman-4-one and thiochroman-4-one derivatives 123 afforded the
corresponding bis-spiropyrazoline-5,3'-chroman(thiochroman)-4-one derivatives 124 in good
yields. The regio- and stereoselective cycloaddition was elucidated using X-ray analysis.
Similar reaction of the bis-hydrazonyl halides 113 with 2-benzylidene-3-coumaranone 125
furnished the 3,3'-bipyrazole derivatives 126 in moderate yields (Scheme 34).
79
Scheme 34
Bis-hydrazonyl halides 113 underwent similar cycloaddition reaction with fumaronitrile
127 in benzene under reflux in the presence of triethylamine to afford 1,1'-diphenyl-3,3'-
bipyrazole-4,4'-dicarbonitrile 129 in 59% yield through loss of two molecules of HCN from
the cycloadduct intermediates 128 (Scheme 35).
80
Scheme 35
Cyclocondensation of 1,6-diethoxyhexa-1,5-diene-3,4-dione 130 with phenylhydrazine in
m-cresol provided 1,1'-diphenyl-3,3'-bipyrazole 131 in 85% yield (Scheme 36).
81
Scheme 36

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Treatment of the cyanoacetylpyrazole derivative 132 with hydrazine hydrate, in refluxing
ethanol afforded the corresponding 3,3'-bipyrazole derivative 133 (Scheme 36).
82
Reaction of
the cyanoacetylpyrazole 132 with phenyl isothiocyanate, in the presence of potassium
hydroxide, at room temperature followed by addition of methyl iodide afforded 3-(2-cyano-3-
methylthio-3-phenylaminoacryloyl)-1,5-diphenyl-1H-pyrazole-4-carbonitrile 135. When
compound 135 was treated with hydrazine hydrate in refluxing ethanol it afforded 1,5-
diphenyl-5'-phenylamino-3,3'-bipyrazolyl-4,4'-dicarbonitrile 137 in high yield (Scheme 37).
83
Scheme 37
3-[(E)-3-(N,N-Dimethylamino)acryloyl]-1-(4-chlorophenyl)-5-phenyl-1H-pyrazole-4-
carboxylate 139 was prepared
via condensation of the pyrazole derivative 138
with
dimethylformamide-dimethylacetal (DMF-DMA). Treatment of 139 with hydrazine hydrate
in ethanol under reflux yielded 3-(1H-pyrazol-3-yl)-1-(4-chlorophenyl)-5-phenyl-1H-
pyrazole-4-carbohydrazide 140 in 80% yield (Scheme 38).
84,85
Scheme 38
Heating a mixture of 3-acetyl-4-(4-nitrophenyl)-1-aryl-1H-pyrazoles 141 and
dimethylformamide dimethylacetal gave the corresponding enaminone 142 in 80-88% yields.
Treatment of the enaminones 142 with hydrazine hydrate in ethanol under reflux afforded the

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3,3'-bipyrazoles 143 in 90% yield. The products were formed via initial addition of hydrazine
to the enaminone double bond, followed by elimination of dimethylamine and water
molecules to give 143 (Scheme 39).
86
Scheme 39
The reaction of diacetylene 144 with 2-diazopropane
145 took place in two steps to give at
first the acetylenic pyrazole 146 which underwent further cycloaddition to 2-diazopropane
145 in diethyl ether at 0°C to afford the 5,5,5',5'-tetramethyl-3,3'-bipyrazole 147 in 60% yield.
Photolysis of the latter bipyrazole 147 led to the formation of 2,7-dimethylocta-2,6-dien-4-
yne 148 via loss of two N
2
molecules (Scheme 40).
87
Scheme 40
The conversion of isothiazoles into pyrazoles using neat anhydrous hydrazine was also
reported. Thus, 5,5'-diphenyl-3,3'-biisothiazole-4,4'-dicarbonitrile 149 was easily transformed
into 5,5'-diphenyl-3,3'-bi(1H-pyrazole)-4,4'-dicarbonitrile 152 in 65% yield upon heating in
neat anhydrous hydrazine according to the mechanism outlined in Scheme 41.
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Scheme 41
2.6. 3,4'-Bipyrazoles
1,3-Dipolar cycloaddition of 4-pyrazolylformylhydrazone 153 with electron-poor
dipolarophiles namely; dimethyl fumarate 154 and ethyl 3-phenylpropiolate 155 under
microwave irradiation in solvent-free conditions within 15-45 min afforded the corresponding
3,4'-bipyrazoles 156 and 157, respectively. Similar microwave heating of the hydrazone 153
with ethyl propiolate 158 at 170 °C for 15 min gave a mixture of the 3,4'-bipyrazole
derivatives 159 and 160 (Scheme 42).
89,90
Scheme 42
Conducting the 1,3-dipolar cycloaddition of the 4-pyrazolylformylhydrazones 153 with β-
nitrostyrenes 161 under solvent-free microwave irradiation at 130
°
C for 10 min was reported
to afford a mixture of the 3,4'-bipyrazoles 162 and 163 (Scheme 43).
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Scheme 43
Similar 1,3-dipolar cycloaddition reactions of the pyrazolylhydrazone 164 with ethyl 3-
phenylpropiolate 155 under microwave irradiation for 10 min gave the 3,4'-bipyrazole 166 in
80% yield, via the formation of the nitrilimine intermediate 165 generated by elimination of
methane from 164. In contrast, it was reported that heating the same mixture under classical
heating did not proceed at all (Scheme 44).
89,92
Scheme 44
The formation of several fullereno-3,4'-bipyrayole adducts 169 from nitrilimines has been
also reported. Thus, treatment of the pyrazolylhydrazone 153 with N-bromosuccinimide
(NBS) followed by Et
3
N then addition of C
60
under microwave irradiation conditions resulted
in the formation of 169 in moderate yields (Scheme 45).
93
Scheme 45
Reaction of 1-(5-methyl-1-phenylpyrazol-4-yl)-3-(N,N-dimethylamino)-2-propen-1-one
170 with hydrazine or phenyl hydrazine afforded the corresponding 3,4'-bipyrazoles 171 in

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good yields (Scheme 46).
94
Scheme 46
The reaction of the pyrazolylenamine derivatives 172 with hydrazine or phenylhydrazine
led to the formation of 3,4'-bipyrazoles 173 (Scheme 47).
95
Scheme 47
Reaction of cyanoacetylpyrazole 174 with hydrazines gave the corresponding 3,4'-
bipyrazoles 175. Heating a mixture of the bipyrazole derivatives 175 and aromatic aldehydes
in ethanol at reflux in the presence of piperidine gave the corresponding 5-amino-4-
arylidenepyrazoles 176 in good yields (Scheme 48).
96-98
Scheme 48
Treatment of 4-acetylpyrazolone derivative 177 with aromatic aldehydes gave the
corresponding chalcones 178 which upon heating with hydrazine hydrate yielded the 3,4'-
bipyrazoles 179 (Scheme 49).
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Scheme 49
The 3,4'-bipyrazole derivative 181 was prepared in moderate yield by condensation of 3-
(2-hydroxyphenyl)-1-(1-phenyl-3-(2-thienyl)-1H-pyrazol-4-yl)prop-2-en-1-one 180 with
hydrazine hydrate in refluxing acetic acid (Scheme 50).
100
Scheme 50
Reaction of 4-oxo-3-chromenecarboxaldehyde 182 with 4-acetyl-5-methyl-1,2-dihydro-3-
pyrazolone 183 gave the corresponding enone 184. Subsequent cyclocondensation of 184
with hydrazine hydrate under microwave irradiation conditions gave the 3,4'-bipyrazole
derivative 185 (Scheme 51).
101
Scheme 51
Knoevenagel condensation of N-(benzothiazol-2-yl)-2-cyanoacetamide 187 with 1,3-

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diphenylpyrazole-4-carboxaldehyde 186 in ethanolic sodium hydroxide (10%) afforded 2-
cyano-3-(1,3-diphenyl-1H-pyrazol-4-yl)acrylamide 188. The addition of hydrazine hydrate to
the activated double bond of compound 188 in boiling ethanol afforded 5-amino-1',3'-
diphenyl-3,4'-bipyrazole-4-carboxamide 189 in a reasonable yield (Scheme 52).
102
Scheme 52
Heating a mixture of 1-(pyrazol-4-yl)butane-1,3-dione 190 and hydrazine hydrate in
ethanol furnished 1'-(2-fluorophenyl)-5,3'-dimethyl-3,4'-bipyrazolyl-5'-ol 191 which is useful
as central nervous system agents (Scheme 53).
103
Scheme 53
Treatment of the γ-pyrone derivative 192 with two equivalents of hydrazine resulted in the
formation of the 3,4'-bipyrazole derivative 196. A proposed mechanism for the formation of
196 is outlined in Scheme 54 where hydrazinloysis of ester group was firstly attempted
followed by nucleophilic attack of another hydrazine molecule resulting in ring opening then
closing via loss of water molecule to give the 3,4'-bipyrazole derivative 196 (Scheme 54).
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Scheme 54
3,4'-Bipyrazole derivative 199 was obtained from the reaction of 3-(diformylmethyl)-4-
nitropyrazole 197 with hydrazine hydrochloride in basic aqueous solution. The same
compound 199 was more conveniently obtained from the reaction of the perchlorate
trimethinium salt 198 under similar condition using a double amount of the base (Scheme
55).
105
Scheme 55
The 1,3-cycloaddition reaction of diphenyldiacetylene 200 with 2-diazopropane 145 led to
a mixture of 3,3-dimethy-5-phenyl-4-phenylethynyl-3H-pyrazole 201, 3,3-dimethyl-4-phenyl-
5-phenylethynyl-3H-pyrazole 202. Treatment of the pyrazole derivative 201 with 2-
diazopropane 145 gave the 3,4'-bipyrazole derivative 203 with 67% yield (Scheme 56).
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Scheme 56
2.7. 3,5'-Bipyrazoles
Heating 5-pyrazolylformylhydrazones 204 with β-nitrostyrenes 161 under microwave
irradiation at 130 °C, without solvent, afforded a mixture of the 3,5'-bipyrazoles 205 and 206
via 1,3-dipolar cycloaddition in overall moderate yields (Scheme 57).
89,91
Scheme 57
3,5'-Bipyrazole derivatives 207 and 208 were prepared in reasonable yields via 1,3-dipolar
cycloaddition of 5-pyrazolylformylhydrazone 204 with the electron poor dipolarophiles;
dimethyl fumarate 154 and ethyl 3-phenylpropiolate 155, respectively, under microwave
irradiation condition (Scheme 58).
89
Scheme 58
A regioselective 1,3-dipolar cycloaddition of the activated alkenes 117 with 4-
pyrazolylhydrazonoyl bromides 209 furnished the corresponding unsaturated 3,5'-bipyrazole

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derivatives 210 in good yields. Similar cycloaddition of acetylenedicarboxylate ester 211 gave
the 3,5'-bipyrazole 212 (Scheme 59).
108
Scheme 59
Reaction of 3-(pyrazol-3-yl)-3-oxo-propanenitrile derivative 132 with
dimethylformamide-dimethylacetal (DMF-DMA) in refluxing xylene gave the enaminonitrile
derivatives 213 in 92% yield. Treatment of the latter compounds 213 with hydrazine
derivatives afforded the 3,5'-bipyrazole derivatives 214 in good yields (Scheme 60).
82
Scheme 60
3-Bromoacetyl-1,5-diphenyl-1H-pyrazole-4-carbonitrile 215 was reported to react with
sodium benzenesulfinate in refluxing ethanol and afforded 1,5-diphenyl-3-(2-
(phenylsulfonyl)acetyl)-1H-pyrazole-4-carbonitrile 216. Reaction of the ketosulfone 216 with
hydrazonoyl chlorides 217 in ethanolic sodium ethoxide solution at room temperature
afforded 5'-acetyl-1-aryl-2',5-diphenyl-4'-(phenylsulfonyl)-3,3'-bipyrazole-4-carbonitriles 219
in good yields (Scheme 61).
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Scheme 61
The unsubstituted 3,5'-bipyrazole 221 was prepared by Effenberger, in 75% yield, from
1,6-diethoxy-1,5-hexadiene-3,4-dione 130 and hydrazine hydrate in THF at room
temperature, in the presence of p-toluenesulfonic acid (Scheme 62).
110
Scheme 62
3-Formyl-1-phenyl-5-(2-thiazolylimino)pyrazole 222 was condensed with arylketones 223
to give the α,β-unsaturated ketones 224 which underwent cyclocondensation with hydrazines
afforded the 3,5'-bipyrazoline derivatives 225 (Scheme 63).
111
Scheme 63
1,3-Dipolar cycloaddition of 3-styrylpyrazoles 226 with the hydrazonyl chloride 227, in
benzene at reflux, in in the presence of triethylamine, gave the corresponding 3,5'-bipyrazole
derivatives 228 in high yields (Scheme 64).
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Scheme 64
The reaction of 3-cyanoacetylpyrazole 132 with hydrazonoyl chlorides 229 in ethanol
and sodium ethoxide at room temperature afforded the 3,5'-bipyrazole derivatives 230 in
acceptable yields (Scheme 65).
83
Scheme 65
Reaction of the 3-(1-phenyl-5-methylpyrazol-4-yl)-3-chloropropenal 231 with
arylhydrazines led to the formation of 3,4'-bipyrazole derivatives 232 (Scheme 66).
113
.
Scheme 66
2.8. 4,4'-Bipyrazoles
Bruno et al. reported the diastereoselective reductive dimerization 4-tolylmethylene-3-
phenylpyrazol-5-one 233, via single electron transfer generated in situ using 2-
arylbenzimidazoline 234 as catalyst, to afford the corresponding 4,4'-bipyrazoline derivative
235 (Scheme 67).
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Scheme 67
4,4'-Bipyrazolin-3,3'-ones 241 were prepared by direct nucleophilic 1,4-addition of 2-
pyrazolin-5-ones 237 to the conjugated azoalkenes 236 in the presence of the strong base
anion exchanger resin Duolite
®
A10
2
. This reaction proceeded via the intermediate CH-
hydrazone 238 and then NH-hydrazone form 239 in tautomeric equilibrium with the relevant
NH-hydrazine form 240 (Scheme 68).
115
Scheme 68
The addition of hydrazine to functionalized furans led also to the formation of 4,4'-
bipyrazoles. Thus, 4-acetyl-2-amino-5-methylfurans 241 were converted into 7-amino-4,5-
dimethylfuro[3,4-d]pyridazines 242, which were then transformed into the 4,4'-bipyrazole
derivatives 243 upon treatment of 242 with hydrazine (Scheme 69). Conversion of the
furo[3,4-d]pyridazine 242 into 4,4'-bipyrazole 243 was undertaken via ring opening followed
by ring closure according to the mechanism outlined in Scheme 70.
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Scheme 69
Scheme 70
Cyclocondensation of 1,4-diphenyl-2,3-diformylbutadiene 244 with variety of
hydrazines in refluxing ethanol gave the corresponding 4,4´-bipyrazoline derivatives 245 in
moderate yields (Scheme 71).
117
Scheme 71
Dimerization of acetylacetone 10 was conducted using iodine and NaOH to give 3,4-
diacetylhexan-2,5-dione 246 which upon reaction with hydrazine hydrate afforded 3,3',5,5'-
tetramethyl-4,4'-bipyrazole 247 in good yield (Scheme 72).
118,119
Alkylation of 4,4'-bipyrazole
247 with benzyl chlorides using tetrabuylammonium bromide, as phase transfer catalyst, in
refluxing toluene gave the corresponding 1,1´-dialkylated 4,4'-bipyrazoles 248.
10
5,5´-Bi(2-
bromoethylpyrazole) 249 was prepared in 11% yield by reaction of 4,4'-bipyrazole 247 with
an excess of 1,2-dibromoethane using liquid-liquid phase transfer catalysis (Scheme 72).
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Scheme 72
Lycka et. al reported the synthesis of 5'-hydroxy-5,5'-dimethyl-2-phenyl-1'-aryl-1',5'-
dihydro-4,4'-bipyrazolylidene-3-one 252 from the coupling reaction between 4-(α-
acetylethylidene)pyrazole 250 and aryldiazonium fluoroborates 251 (Scheme 73).
121
Scheme 73
The reaction of succinonitrile 254 with two equivalents of the hydrazonoyl chloride
229, in the presence of sodium ethoxide at room temperature, resulted in the formation of the
4,4'-bipyrazole derivative 255 in 68% yield. The reaction took place via 1,3-dipolar
cycloaddition of the nitrilimine intermediate 253 on the nitrile function of 354 (Scheme
74).
122
Scheme 74

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The 5,5'-dihydroxy-4,4'-bipyrazole derivatives 258 were obtained as a dimerization
product during the bromination of the pyrazolone 256 with N-bromosuccinimide (NBS) or
bromine in chloroform (Scheme 75).
123
Scheme 75
Dimerization of the pyrazolinone derivative 259 resulted in the formation of the 5,5'-
dihydroxy-4,4'-bipyrazole derivatives 260 in 50-61% yields when 259 was treated with 30%
hydrogen peroxide in the presence of selenium oxide in methanol at 0°C under a nitrogen
atmosphere (Scheme 76).
25
Scheme 76
Heating a mixture of 4-bromopyrazolone 261 with ethyl acetoacetate gave the pyrazole
ester 262 which upon reaction with phenylhydrazine gave the 4,4'-bipyrazole-5,5'-dione 263
(X = O). Compound 263 (X = O) was converted into 263 (X = S) by the action of P
2
S
5
.
Reaction of Vilsmeier reagent (DMF/POCl
3
) with 4,4'-bipyrazole 263 (X = S, O) at 5-10 °C
afforded 5-chloro-4,4'-bipyrazole derivatives 264. However, when the reaction was carried
out on hot at 70-75 °C, the tricyclic fused compound 1,6-diphenylthieno[2,3-c:5,4-
c']dipyrazole 265 was obtained. (Scheme 77).
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Scheme 77
2.9. 4,5'-Bipyrazoles
Suzuki cross-coupling reaction of 5-pyrazolylboronic ester 266 with 4-iodo-1-[2-
(trimethylsilyl)ethoxy]methyl pyrazole 267 in the presence of Pd(PPh
3
)
4
and NaHCO
3
in
refluxing dimethoxyethane (DME)/water gave the 1,1'-di(SEM)-4,5'-bipyrazole derivative
268 in 48% yield; [2-(trimethylsilyl)ethoxy]methyl = SEM]. Deprotection of 268 using n-
Bu
4
NF and ethylenediamine in refluxing THF resulted in removing only one SEM group of
the 4,5'-bipyrazole 268 to give the mono-protected 4,5'-bipyrazole 269 in 50% yield (Scheme
78).
127
Scheme 78
Dimethyl 1-methyl-1'-(3-methylbutyl)-4,5'-bipyrazole-3,4-dicarboxylate 272 was
prepared in 33% via the Suzuki cross-coupling of the pyrazolyl triflate derivative 270 with 4-
pyrazolylboronic acid 271 catalyzed by 5 mol% of Pd(PPh
3
)
4
in anhydrous DME using
Na
2
CO
3
as a base (Scheme 79).
128

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Scheme 79
The reaction of N,N-diethylbuta-1,3-dien-1-amine 275 with two equivalents of
diarylnitrilimines 274 [derived from the hydrazonyl chloride 273 under the effect of Et
3
N] in
benzene at 80°C gave the corresponding 4,5'-bipyrazole derivatives 278 in 20-53% yields.
The reaction took place via the intermediates 276 and 277 as depicted in Scheme 80.
129
Scheme 80
Reaction of 1,2-dimethylpyrrole 279 with two equivalents of the hydrazonoyl chloride
217 yielded two products: the bis-cycloadducts 280 and 281 in 40 and 30% yields,
respectively. Ring transformation of the cycloadducts 280 and 281 into the 4,5'-bipyrazole
282 and 4,4'-bipyrazole 283 derivatives, respectively in high yields, was achieved in refluxing
ethanol in the presence of hydrochloric acid (Scheme 81).
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Scheme 81
Heating of nitropyrazolecarbonyl chloride 284 with N,3-dimethyl-1-phenylpyrazol-5-
amine 285 gave the nitropyrazolylamide derivative 286, in which the nitro function was
reduced to the corresponding amine and then converted into the diazonium salt 287 as
outlined in Scheme 82. Treatment of 287 with CuSO
4
and NaCl in the presence of ascorbic
acid afforded the tricyclic chlorinated spiroheterocycle 288. Reaction of 288 with KOH in
EtOH at room temperature gave 75% yield of the 4,5'-bipyrazole derivative 289 (Scheme
82).
131
Scheme 82
Reaction of 3-acetyl-6-methyl-3H-pyran-2,4-dione 290 or its tautomer 291 with aryl-
and hetaryl-hydrazines gave the corresponding hydrazones 292 in moderate to good yields.
Heating the latter hydrazones 292 in acetic acid underwent smooth skeletal rearrangement to

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yield the corresponding 4-acetoacetylpyrazole derivatives 293 (Scheme 83).
132-134
Thereafter,
treatment of 4-acetoacetylpyrazole derivatives 293 with aryl- and hetaryl-hydrazines in
refluxing ethanol in the presence of HCl furnished a variety of 4,5'-bipyrazoles 294. The 4,5'-
bipyrazoles 294 were available in both the NH- and OH-tautomers 294 and 295, respectively
(Scheme 83).
135-141
Scheme 83
3-Acetyl-2-pyranone 291 was transformed into 4-(acetoacetyl)-5-hydroxy-3-
methylpyrazoles 296 up on its treatment with hydrazine or phenylhydrazine in refluxing
ethanol as shown in Scheme 83. In addition, treatment of the latter pyrazoles 296 with
hydrazine derivatives resulted in the formation of the corresponding 4,5'-bipyrazoles 297
(Scheme 84).
142
Scheme 84
Treatment of 3,5-diacetyl-4-pyrone 298 with hydrazine and phenylhydrazine at room
temperature followed by acidification gave the 4-acetoacetylpyrazole derivatives 300. Further
reaction of the pyrazoles 300 with hydrazines afforded the 4,5'-bipyrazole derivatives 301 in
reasonable yields (Scheme 85).
143

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Scheme 85
The base catalyzed condensation of pyrazole-4-carboxaldehydes 302 with 2-
hydroxyacetophenones 303 gave the corresponding propenones 304 which upon treatment
with hydrazine or phenylhydrazine yielded the 4,5'-bipyrazole derivatives 305 (Scheme
86).
144-146
Scheme 86
Reaction of pyrazole-4-carboxaldehyde 302 with acetophenones 223 in NaOH and
ethanol at 50 °C afforded the 4-pyrazolylpropenones 306 in high yields. Heating the latter
propenones 306 with hydrazines yielded the corresponding 4,5'-bipyrazole derivatives 307
(Scheme 87).
147-149

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Scheme 87
Aldol condensation reaction of acetophenones 223 with the polysubstituted pyrazole-4-
carboxaldehyde 308 afforded the corresponding chalcone derivatives 309. Treatment of the
chalcones 309 with hydrazine in glacial acetic acid under reflux conditions gave the 4,5'-
bipyrazole derivatives 310 in good yields (Scheme 88).
150-151
Scheme 88
4-Formylpyrazolone 311 reacted with acetophenones 223 to give the corresponding
chalcones 312 which were readily cyclized upon treatment with hydrazine hydrate in ethanol
at reflux condition to give the corresponding 4,5'-bipyrazole derivatives 313 in good yields.
Acylation of 313 with acetic anhydride at reflux in the presence of pyridine gave the N-
acylated 4,5'-bipyrazole derivatives 314 (Scheme 89).
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Scheme 89
Microwave irradiation of a mixture of 1-isonicotinoylpyrazole-4-carboxaldehyde 314
and acetophenones 223 in the presence of NaOH in ethanol gave the chalcone derivatives 315.
Reaction of 315 with isonicotinic acid hydrazide 316 under microwave irradiation condition
furnished the 1,1'-diisonicotinoyl-4,5'-bipyrazole derivatives 317 in high yields (Scheme
90).
153
Scheme 90
The propenone derivative 319, which was synthesized from 3-acetyl-4-
hydroxycoumarin 318 and 3-formylchromone 182, was converted into the 4,5'-bipyrazole
derivatives 323 by treatment with hydrazine and phenylhydrazine. The mechanism postulated
in Scheme 91 shows that the chromone moiety in 319 underwent ring-opening by the action
of hydrazine followed by cyclization to form the pyrazole moiety of 322. Further molecule of
hydrazine reacted with the α,β-unsaturated ketone 322 to form the 4,5'-bipyrazole derivatives
323 (Scheme 91).
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Scheme 91
Synthesis of several 1-acetyl-4,5'-bipyrazole derivatives 327 was reported in 63-75%
yields by treatment of the 3-(3-aryl-3-oxopropenyl)chromen-4-ones 324 with hydrazine
hydrate in hot acetic acid. Oxidation of the 1-acetyl-4,5'-bipyrazole derivatives 327 with 2,3-
dichloro-5,6-dicyano-p-benzoquinone (DDQ) in dioxane at reflux under nitrogen gave the
1H,1'H-4,5'-bipyrazole derivatives 328 in 51-60% yields. Mechanistically, formation of 327
may be done by reaction between 324 and hydrazine in two different ways, either via 1-
acetyl-3-aryl-5-(3-chromonyl)-2-pyrazoline 326 or α,β-unsaturated ketone 325 intermediates.
Both intermediates could then react with hydrazine to provide the 4,5'-bipyrazole derivatives
328 (Scheme 92).
155,156
Scheme 92

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2.10. 5,5'-Bipyrazoles
Lithiation of the pyrazolylacetylenes 329 followed by quenching with acetic or benzoic
anhydrides led to formation of the pyrazolylacetylenic ketones 330. Heating of the acetylenic
ketones 330 with phenyl hydrazine hydrochloride and potassium carbonate in methanol led to
formation of 5,5'-bipyrazoles 331 in moderate yields (Scheme 93).
157
Scheme 93
Treatment of the bis-(benzoylacetylene) 332 with methyl hydrazine in DCM gave the
symmetric 5,5'-bipyrazole 333 in a good yield (Scheme 94).
157
Scheme 94
5,5'-Bipyrazole derivatives 335 were obtained in good yields by treating (1,5-diaryl-2-
hydroxy-3-oxopyrrolidin-2-yl)acetates 334 with hydrazine hydrate in ethanol at reflux with
loss of aniline derivative and water. The 5,5'-bipyrazole derivatives 335 were alternatively
synthesized by hydrazinolysis of the 5-aryl-2-alkoxycarbonylmethylene-2,3-dihydro-3-
furanones 336 (Scheme 95).
158,159
Scheme 95
Lithiation of 1-benzyloxypyrazole 337 followed by transmetallation with zinc chloride
in THF gave 1-benzyloxypyrazol-5-ylzinc(II) chloride 338 which underwent Negishi cross-

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coupling when treated with 5-iodo-1-benzyloxypyrazole 339 to give 1,1'-(dibenzyloxy)-5,5'-
bipyrazole 340. Treating 5,5'-bipyrazole 340 with a large excess of iodine monochloride using
potassium carbonate as base resulted in a rapid introduction of the iodine and gave 4,4'-
diiodo-1,1'-(dibenzyloxy)-5,5'-bipyrazole 341 in excellent yield. The Negishi conditions were
applied for the introduction of phenyl groups at C-4 and C-4' in 5,5'-bipyrazole 341, however
the iodine of 341 did not react. Instead, the reaction occurred by a double iodine–magnesium
exchange to the dimagnesium species, followed by magnesium–zinc exchange, and then
cross-coupling with iodobenzene, resulted in the formation of 1,1'-(dibenzyloxy)-4,4'-
diphenyl-5,5'-bipyrazole 343 in 70% yield but the disadvantage of this method was that a
huge excess of phenylmagnesium chloride had to be applied to get the dimagnesium
intermediate 342. Alternatively, Suzuki reaction of 4,4'-diiodo-1,1'-(dibenzyloxy)-5,5'-
bipyrazole 341 with phenylboronic acid afforded 1,1'-(dibenzyloxy)-4,4'-diphenyl-5,5'-
bipyrazole 343 more efficiently in 80% yield. Heating of 343 in concentrated sulfuric acid led
to debenzylation and afforded the corresponding 1,1'-(dihydroxy)-4,4'-diphenyl-5,5'-
bipyrazole 344 in low yield (Scheme 96).
160,161
N
N
OBn
ICl, K2CO3
CHCl3, rt
341 91%
NN
OBn
I
1) n-BuLi, -78°C, THF
2) ZnCl2, THF N
N
OBn
ZnCl
337 338
339
Pd(PPh3)4
DMF/THF, 60°C
340 88%
N
N
OBn
NN
OBn
N
N
OBn
NN
OBn
II
PhMgCl
THF, rt
N
N
BnO
NN
OBn
Mg
Mg
Cl
Cl
1) ZnCl2, 1M, THF
2) PhI, Pd(PPh3)4,
DMF/THF 70°C
342
343 70%
N
N
OBn
NN
OBn
Ph Ph
PhB(OH)2, K2CO3
PdCl2(PPh3)2,
DME, 70°C
343 80%
N
N
OBn
NN
OBn
Ph Ph
N
N
OH
NN
OH
Ph Ph
H2SO4
70°C
344 22%
Scheme 96
Treatment of 3,5-dichloropyrazoles 345 with Ni(cod)
2
[cod = 1,5-cyclooctadiene] in the
presence of 2,2'-bipyridine in DMF, had been reported to afford bis-(pyrazolyl)nickel(II)
complexes 346 in good yields, via oxidative addition where the C(5)–Cl bond of the two C–Cl

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bonds reacted with Ni(0)L
m
. Treatment of the bis(pyrazolyl)nickel(II) complexes 346 with
nitric acid resulted in reductive elimination to give the 3,3'-dichloro-5,5'-bipyrazoles 347
(Scheme 97).
162,163
Scheme 97
1,1'-Difluoroamino-3,3',4,4'-tetranitro-5,5'-bipyrazole 350 have been synthesized in
reasonable yield by reacting 3,3',4,4'-tetranitro-1H,1'H-5,5'-bipyrazole 348 with O-
fluorosulfonyl-N,N-difluorohydroxylamine 349 under phase-transfer catalysis using PEG-400
in the presence of NaHCO
3
.
164
However, treatment of 350 with NaF/NaOH in methanol
followed by addition of F
2
/N
2
at -70 °C resulted in the formation of 1,1'-difluoro-3,3',4,4'-
tetranitro-5,5'-bipyrazole 351 (Scheme 98).
165
Scheme 98
3. Applications of Bipyrazoles
Bipyrazole derivatives were used as new class of supramolecular complexes, organometallic
cage-like structures and self-assembling metallomacrocycles with bipyrazole ligands that are
promising as catalysts, molecular mimics, molecular magnetic devices and sensors.
166-168
Poly(5,5'-bipyrazole-3,3'-diyl) derivatives 352 were synthesized from 3,3'-dichloro-

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5,5'-bipyrazoles 347 through dehalogenative polycondensation using a mixture of Ni(cod)
2
and 2,2´-bipyridine in DMF at 60 °C (Scheme 99). The obtained polymers were characterized
by their high thermal stability and electrochemical activity.
162
Scheme 99
Polycondensation of 5,5'-dimethyl-3-chloromethyl-1,3'-bipyrazole 353 was achieved in
refluxing benzene in the presence of 50% NaOH solution and led to the formation of the
polypyrazolic macrocycle 354 in 75% yield (Scheme 100).
30
Scheme 100
Palladium(II) and platinum(II) complexes of 5,5'-dimethyl-3,3'-bipyrazole 355 were
reported to have potential anti-tumor properties.
169
HN
NNH
N
Me
Me
M
M = Pd, Pt
Cl Cl
NH
N
HN
N
Me
Me
355
1',3,5,5'-Tetramethyl-1,3'-bipyrazole 12 and 5,5'-disubstituted-3,3'-bipyrazoles 93 were
used as inhibitors for the corrosion of steel in 1M HCl where the inhibition efficiency

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increased with increase in inhibitor concentration. The inhibiting effect of the bipyrazoles 12
and 93 was attributed to their adsorption at the metal–solution interface, owing to the
presence of many active centers (several nitrogen atoms and many π-electrons of the pyrazole
rings) for adsorption which revealed that inhibitive actions of bipyrazole compounds were
mainly due to adsorption on steel surface.
170-172
N
N
N
N
Me
Me
Me
R
HN N
NH
N
R
R
R = Et, Ph, 4-ClC
6
H
4
93
12
R
= Me, CH
2
OH, CO
2
Et
The bipyrazole derivatives (bippyphos) 57 were applied as efficient ligands in the
palladium-catalyzed C-O and C-N cross-coupling reactions of aryl halides with primary
alcohols and with urea derivatives, respectively.
46,173-176
N
NN
N
Ph
Ph Ph
P
RR
57 R = t-Bu, 1-adamantyl
5,5'-Dihydroxy-4,4'-bipyrazoles 356 were reported as useful medicines for treatment of
cerebral ischemia, heart diseases, gastrointestinal diseases, cancer, aging and inflammation.
These medicines are useful for effectively capturing active oxygen and free radicals which
cause adult diseases where singlet oxygen generated in a photo-excited hematoporphyrin
system was reacted with 5,5'-dihydroxy-4,4'-bipyrazoles 356 to give ESR signal indicating
production of stable free radical.
25,177,178
N
N
N
N
R
1
R
1
R
R
OH
OH
R = H, Me, Et, Pr, Bu, Ph
R
1
= H, Me, Et, Pr, Bu, CH
2
OH, (CH
2
)
2
OH, (CH
2
)
3
OH, Ph, benzyl, naphthyl
356
Heating of 5,5'-bi(2-bromoethylpyrazole) 249 with methyl iminodiacetate 357 followed
by treatment with aqueous NaOH furnished 90% yield of the tetra-sodium salt of 4,4'-
bipyrazole derivative 358 (Scheme 101). The tetra-sodium salt of 4,4'-bipyrazole derivative
358 was used in Gadolonium(III) complex as Paramagnetic Contrast Agent for clinical
Magnetic Resonance Imaging (MRI).
120

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Scheme 101
The solvatochromic behavior of 3,5'-bipyrazole derivatives 358 was reported in various
solvents of different polarity. Spectroscopic studies revealed that the solvatochromic behavior
depended on both the polarity of the medium and the hydrogen-bonding properties of the
solvents. The photophysical study of 3,5'-bipyrazole derivatives 358 in different solvents
helped in assessing their potential application in different environments.
179
N
N
N
N
C
6
H
4
Br-4
Ph
Ph
CN
Me
Ph
358
3,3',5,5'-Tetramethyl-4,4'-bipyrazole 247 is an interesting class of bipyrazoles due to its
capability to form porous coordination polymers 359 with potential uses as solid sorbents, ion
exchangers and heterogeneous catalysts.
119,180-189
N
H
N
H
NN
Me
Me
359
Me Me
H
N
N
N
H
N
Me
Me
Me
Me
M
H
2
O
H
2
O
2
n
2nX
M = Cu, Co, Cd, Ni, Pd, Ag, W
Furthermore, 3,3',5,5'-tetramethyl-4,4'-bipyrazole 247 was well-studied as a hydrogen-
bonding synthon and neutral bidentate ligand for the synthesis of a flexible porous
coordination polymer with two-coordinate Ag centers 360 (Scheme 102).
190-194

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Scheme 102
Treatment of the bidentate 3,3'-bipyrazole ligands 93 and 104 with the monohydrido
ruthenium(II) complex 361 gave the corresponding carbonyl(hydrido)bis-
(triphenylphosphane)ruthenium(II) complexes 362 in 65-78% yields. The ruthenium(II)
complexes 362 showed catalytic activity and transfer of hydrogen in catalyzed hydrogenation
reactions (Scheme 103).
69,195
Scheme 103
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Authors' Biographies
Kamal M. Dawood was born in 1965. He received his PhD in 1995 in the applications of

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hydrazonoyl halides in heterocyclic chemistry. In 1997 and 1999 he was awarded the
UNESCO and JSPS Fellowships, respectively, at Tokyo Institute of Technology (TIT) in the
field of ‘Electrochemical Partial Fluorination of Heterocyclic Compounds’ with Professor T.
Fuchigami. He was awarded the Alexander von Humboldt Fellowship (AvH) at Hanover
University in 2004-2005 with Prof. A. Kirschning in the field of polymer supported palladium
catalyzed reactions and in 2007 and 2008 with Prof. P. Metz at TU-Dresden, Germany, in the
field of total synthesis of natural products. In 2002 he was promoted to Associate Professor
and in May 2007 he was appointed as Professor of Organic chemistry, Faculty of Science,
Cairo University. In 2002 he received the Cairo University Award in Chemistry and in 2007
he received the State-Award in Chemistry. He is a member of the international Editorial
Board of ISRN Organic Chemistry, part of the International Scholarly Research Network
(ISRN), open access journals. He published more than 80 scientific papers and reviews in
distinguished international journals. There are about 820 citations of his work from 1993 until
2011 (h-index 17).
Bakr F. Abdel-Wahab was born in 1978 in Mansoura, Egypt. He is a researcher of organic
chemistry at National Research Centre, Giza, Egypt. He has got his B.Sc. in 1999 from
Chemistry Department, Faculty of Science, Mansoura University, Egypt. He received his
M.Sc. in 2003 from Mansoura University under the supervision of Professor Fathy A. Amer.
He has awarded his Ph.D. degree in 2007 from Ain-Shams University, Cairo under the
supervision of Professor Maher A. El-Hashash (D.Sc). He worked as an assistant professor at
Department of Chemistry, Faculty of Science and Arts, King Abdul-Aziz University, Khulais
Branch, Saudi Arabia. His current research interests cover the development and mechanistic
aspects of organic reactions and their applications in medicinal chemistry.