advances in the chemistry of...

Turk J Chem

(2013) 37: 1 – 35

c© TUBITAK

doi:10.3906/kim-1204-50

Turkish Journal of Chemistry

http :// journa l s . tub i tak .gov . t r/chem/

Review Article

Advances in the chemistry of pyrazolopyrazoles

Rizk Elsyad KHIDRE,1,2 Hanan Ahmed MOHAMED,3,4 Bakr Fathy ABDEL-WAHAB3,4,∗1Chemical Industries Division, National Research Center, Dokki, 12622 Giza, Egypt2Chemistry Department, Faculty of Science, Jazan University, Jazan, Saudi Arabia

3Applied Organic Chemistry Department, National Research Center, Dokki 12622 Giza, Egypt4Preparatory Year, Shaqra University, Al Dawadmi, Saudi Arabia

Received: 18.04.2012 • Accepted: 30.11.2012 • Published Online: 24.01.2013 • Printed: 25.02.2013

Abstract: Published data on the methods of preparation of pyrazolopyrazoles are summarized and described systemat-

ically. The title compounds are subdivided according to the position of fusion between the 2 pyrazole rings.

Key words: Pyrazoles, pyrazolo[1,2-a ]pyrazoles, pyrazolo[3,4-c ]pyrazoles, pyrazolo[4,3-c ] pyrazoles

1. IntroductionRecently, much attention has been paid to the synthesis of fused pyrazolopyrazole compounds since they havevarious applications. These include, for example, Lilly’s bicyclic pyrazolidinone LY 186826, exhibiting antibiotic

activity greater than that of several penicillins and cephalosporins,1,2 and herbicides3 and potent drugs for

treatment of cognitive dysfunctions such as Alzheimer disease.4

NN

FO

O

Ar

Herbicides

NN

O

Ar

O

anti-Alzheimer

NN

OHO2C

O

Me

HN O

N

MeO S

NNH2

LY 186826

Additionally, pyrazolo[1,5-b ]pyrazoles is used as hair dye5,6 and 2,3-diamino-6,7-dihydro-1H ,5H -pyra-

zolo[1,2-a ]pyrazole-1-one or its salts are used as a hair dye with red nuances and/or intense copper tone.7 The

3-oxo-3H -pyrazolo[1,2-a ]pyrazol-4-ium-1-olates are nitrification inhibitors for use with fertilizers.8

In addition, pyrazolo[3,4-c ]pyrazoles are useful for the treatment of esophageal and gastrointestinal

mucosa injury9 and brain injury,10 and also as immunostimulatory,11 antianginal,12 and antitumor13 agents.A review covering the literature data on the synthesis of compounds with 2 or more pyrazole rings linked to

each other published before 1995 appeared in 1995.14 In view of the above facts and in connection to our

previous review articles about biologically active heterocyclic systems,15−29 we decided to prepare this reviewto present to readers a survey of the literature of pyrazolopyrazoles. Some of the commercial applications ofpyrazolopyrazole derivatives are also mentioned.∗Correspondence: [email protected]

1

KHIDRE et al./Turk J Chem

NNHN

R1

RR2

R3

R = H or a coupling releasing group;R1, R2, R3 = H or a substituent

Hair dye

N

N

O

H2N

H2NN

N

O

R3

R2 R1

O

R4

R1, R3 = H or a C1-4 alkyl;R2 = H, halo or C1-4-alkyl;R1CCR2 = 5- or 6-membered cycloalkyl;R4 = carboxyalkyl or (un)substituted Ph

Nitrification inhibitors for use with fertilizers

2. Pyrazolo[1,2-a ]pyrazoles

There are a number of practically important routes to the synthesis of pyrazolo[1,2-a ]pyrazoles, e.g., (i) 1,3-

dipolar cycloaddition of various acetylenes to azomethinimines, (ii) cycloaddition of azines to dipolarophiles,

and (iii) reaction of pyrazoles with ketene, 1,3-dicarbonyl, or dinitrile compounds.

2.1. 1,3-Dipolar cycloaddition

Dimethylpyrazolidinone 1 was condensed with aromatic aldehydes to give [(Z)-arylmethylene]dimethylpyrazo-lidinone azomethine imines 2. 1,3-Dipolar cycloaddition of 2 with methyl propiolate gave a mixture of the

regioisomeric pyrazolo[1,2-a ]pyrazoles 3 and 4,30 whereas 1,3-dipolar cycloaddition of the azomethine imines

to dimethyl acetylenedicarboxylate (DMAD) afforded the corresponding pyrazolo[1,2-a ]pyrazoles 5.31,32

Ar = 2-O2NC6H4, 4-O2NC6H4, 2-MeOC6H4, 3,4,5-(MeO)3C6H2,2,4-Cl2C6H3, 2,6-Cl2C6H3, 2,4,6-Me3C6H2, 2,4,6-(MeO)3C6H2, 2,6-(MeO)2C6H3

CO2Me

HN

HN O

MeMe

ArCHO

NN O

MeMe

Ar

H

NNOMe

Me

Ar

MeO2C

NNOMe

Me

Ar

CO2Me

+

CO2MeMeO2C

NNO

Me

Me

Ar

MeO2CCO2Me

1

2

3 4

5

Cycloaddition of the ylide 6 with diallyl acetylenedicarboxylate gave the bicyclic pyrazolidinone 7.33

2


N

N

O

t-BOCHNCO2AllylAllylO2C N

N

O

t-BOCHNCO2Allyl

CO2Allyl

6 7

rel -(2R ,3R)-N -Benzoylamino-6,7-bis(methoxycarbonyl)-2,3-dihydro-1-oxo-1H ,5H -pyrazolo [1,2-a ]

pyrazoles 10 were achieved by cycloaddition of DMAD to (1Z)-rel -(4R ,5R)-1-aryl-methylidene-4-benzoylamino-

5-phenyl-3-pyrazolidinone-1-azomethine imines 8.34,35 Additionally, 3-pyrazolidinone azomethine imines 8 un-derwent 1,3-dipolar cycloaddition with olefinic dipolarophiles 9 and afforded stereoisomeric tetrahydro-1H ,5H -

pyrazolo[1,2-a ]pyrazoles 11.36

NN O

Ar

PhNHCOPh

CO2MeMeO2C NN O

Ph

MeO2C CO2Me

Ar

NHCOPh

10: Ar = Ph, 4-O2NC6H4, 3-O2NC6H4, 4-MeC6H4, 4-MeOC6H4, 2,4-Cl2C6H3

11: Ar = Ph, 4-NO2C6H4, 4-MeOC6H4, 3,4,5-(MeO)3C6H2, mesityl,2,6-Cl2C6H3; R1, R2 = CO2Me, H

CH

CH

R2R1

NN OAr

Ph NHCOPh

R2R1

10

11

89

Svete et al., in 1997, reported the stereoselectivity reaction of (1Z)-rel -(4R ,5R)-1-benzylidene-4-benzo-

ylamino-5-phenyl-3-pyrazolidinon-1-azomethinimine (8, Ar = Ph) with different dipolarophiles such as dimethyl

maleate and 3-hydroxybut-2-enoates 12 to afford pyrazolo[1,2-a ]pyrazoles 13 and 14, respectively. Compound14 underwent dehydration by heating in acidic medium to afford 15, and the latter compounds were prepared

directly by heating of 8 with 12 in ethanol containing a catalytic amount of acid.35

Pyrazolidin-1-ium-2-ides 17 were synthesized, in good yield, by refluxing pyrazolidin-3-ones 16 witharomatic aldehydes for 1 h in absolute ethanol containing a catalytic amount of trifluoroacetic acid. 1,3-Dipolarcycloaddition of azomethines 17 with DMAD, dimethyl maleate, or methyl acetoacetate afforded pyrazolo[1,2-

a ]pyrazoles 18–20, respectively.37−39

3


NN O

Ph

PhNHCOPh

H

CO2MeMeO2C

NNO

Ph

PhNHCOPh

H

CO2MeMeO2C

H H

64%

OH

CH3RO2C

MeOH, Et3N, 20 °CNN

O

Ph

PhNHCOPh

H

OH

MeO2C H CH3

EtOH, H+, reflux

NNO

Ph

PhNHCOPh

H

MeO2CCH3

OH

CH3RO2C

ROH, H+, reflux

R= Me, Et

R= Me 40%R= Et 63%

∼ 62%

8

12

13

14

15

12

NHHN

OPh

NR2

ArCHO,

CF3CO2H, EtOH,reflux, 1 h

NN

OPh

NR2

Ar

CO2MeMeO2C

toluene or anisole

NN

OPh

NR2

Ar CO2Me

CO2Me

CO2Me

CO2Me

NN

OPh

NR2

Ar CO2Me

CO2Me

MeO2C

O

MeCF3CO2H

toluene

NN

OPh

NR2

Ar Me

CO2Me

R2 = N-morphinyl, N(allyl)2; Ar = Ph, 4-MeOC6H4

16 17

181920

Copper(I)-exchanged zeolites were used as heterogeneous ligand-free catalysts for [3+2] cycloaddition of

azomethine ylides 21 to terminal alkynes 22 to afford pyrazolopyrazolone derivatives 23.40

4


R1, R2 = H, Me; R3 = n-C5H11, cyclohexyl, Ph, 4-ClC6H4, 4-Et2NC6H4;R4 = COCHMe2, CO2Et, 4-F3CC6H4

HC C R4+N

NO

R1R2

R3

NN

R4

R3

O

R2

R1

21 22 23

Cu-zeolites

A copper-catalyzed regioselective 1,3-dipolar cycloaddition of azomethine imines 24 with terminal alkynes25 in the presence of a chiral phosphaferrocene-oxazoline ligand gave dihydropyrazolo[1,2-a ]pyrazolones 27 with

very good enantiomeric excess (up to 95% ee).41 2-Nitro- and 2-amino-5-oxoperhydropyrazolo[1,2-a ]pyrazoles

28 were prepared by the condensation of 24 with nitroalkenes 26.42,43

NN

O

R1H

R2

5% CuI/ 5.5% ligand

0.5 equiv Cy2NMeCH2Cl2

N

NO

R2

R1

R1 = n-pentyl, cyclohexyl, 1-cyclohexenyl, Ph, 3-BrC6H4R2 = n-pentyl, Ph, 4-F3CC6H4, MeCO, EtO2C, 2-pyridyl

R1 = Ph, 4-ClC6H4; R= H,NO2; R2 =H, NO2, R3 = H, NO2

CH

CH

NO2R3 NNO

R R3

R2

R124

25

26

27

28

The enantioselective 1,3-dipolar cycloaddition of azomethine imines 30 to 2-acryloyl-3-pyrazolidinone 29was catalyzed by Cu(OTf)2 /bis(oxazoline) to give cycloadducts 31 with high diastereoselectivities (up to >96:4

exo/endo) and enantioselectivities (up to 98% ee).44

NN

O

Ph

O

+ NN

O

R

RCu(OTf)2

10 mol% ligand

NN

O

Ph

O

NN

O

R

R

H

>90%

96:0.4 (exo:endo)up to 98% ee

R = H, Me

29 3031

5


Jungheim in 1989 reported the conversion of pyrazolidinones 32a–c to bicyclic compounds 35a–c via1,3-dipolar cycloaddition. Thus, ylides 33 were generated in situ by treating 32a–c with aqueous formaldehydefollowed by heating to reflux in 1,2-dichloroethane. Diallyl acetylenedicarboxylate readily underwent cycload-

dition with 33 giving rise to 34. Removal of the allyl esters via the method of McCombie45 completed the

preparation of C-3 carboxy-substituted bicyclic pyrazolidinones 35a–c.46

NH

NH

O

Me

R1R

H

H2CO (37% aq.)

ClCH2CH2Cl, refluxN

N

O

Me

R1R

H

CH2 CO2AllylAllylO2C

ClCH2CH2Cl, reflux18%–20%

NN

O

Me

R1R

H

CO2Allyl

CO2Allyl

Pd(OAc)2, Ph3P

sod. 2-ethylhexanoate, acetone

NN

O

MeH

CO2H

CO2H

35a

NN

O

MeH

CO2Na

CO2Na

OH

35b

3233

NN

O

MeH

CO2Na

CO2Na

OH

35c

34

a: R = R1 = Hb: R = OH, R1 = Hc: R = H, R1 = OH

Jungheim also reported in 1989 that the (E)-olefin geometry is required for high regioselectivity. Thus,ylides 33a–c underwent 1,3-dipolar cycloaddition with vinyl sulfone 36 and subsequent base-catalyzed elimi-nation of benzenesulfinic acid to give 37a–c. Pd(0)-mediated allyl ester deprotection gave rise to acids 38a–c.

Nitrile 40 was prepared via cycloaddition of (E)-vinyl sulfoxide 39 followed by in situ thermal elimination of

benzene sulfenic. Compound 40 was converted to sodium (S)-2-cyano-6-((R)-1-hydroxyethyl)-7-oxo-3,5,6,7-

tetrahydropyrazolo[1,2-a ]pyrazole-1-carboxylate 41 using diacetoxypalladium.46

In 2009, Syroeshkina et al. reported the synthesis of 1,3-diaryl-2-nitrotetrahydro-1H ,5H -pyrazolo[1,2-

a ]pyrazoles 46 by the action of 1-nitro-2-(3-nitrophenyl)ethylene 44a on 6-aryl-1,5-diazabicyclo[3.1.0]hexanes42 in ionic liquid with the Et2 O.BF3 catalyst. The same reaction with unsubstituted β -nitrostyrene producedonly 1,3-diaryl-2-nitrotetrahydro-1H ,5H -pyrazolo[1,2-a ]pyrazole derivatives 48. Thus, there were reactions

of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes 42a-d with dipolarophiles in ionic liquids. β -Nitrostyrenes 44a,b

were used as dipolarophiles and [bmim][BF4 ] and [bmim][PF6 ] as ionic liquids. Et2 O ·BF3 in a catalyticamount was added to the reaction mixture to break the diaziridine ring in initial compounds 42a–d to reactiveazomethine iminic intermediates 43a–d. It could be expected that the addition of β -nitrostyrenes 44a,b todipolar intermediates 45 should run via the Michael addition pathway through intermediates 45, generating1,3-diaryl-2-nitrotetrahydro-1H ,5H -pyrazolo[1,2-a ]pyrazoles 46a–d, which are potential inhibitors of neuronal

NO synthase.47 The reaction was carried out at room temperature or with moderate heating. Compounds 48were formed as a result of the interaction of β -nitrostyrene 44a with dipolar intermediates 47b–d, contraryto the Michael addition mechanism, generating second intermediates 45’, which were then cyclized to bicycles

48.48

6


33

CO2allyl

O2S

O

Phi) (ClCH2)2, refluxii) N-methylmorpholine

NN

CO2allyl

CO2MeO

H

R R1

37a-c

Pd(OAc)2, Ph3Psod. 2-ethylhexanoate,acetone

NN

CO2H

CO2MeO

H

R R1

38a-c

CO2allyl

CNOS

Ph33b

N

N

CO2allyl

CNO

H

OH

(ClCH2)2, reflux

Pd(OAc)2, Ph3Psod. 2-ethylhexanoate,acetone

NN

CO2Na

CNO

H

OH

40

41

36

39

NN

Ar1

i NNAr1

42 43

ii, 44a

45`

NNAr1 NO2

Ar2

NN

Ar1

NO2

Ar2H

H

47

48

NN

Ar1 H

Ar2

ii, 44a,b

NNAr1

NO2

Ar2

NN

Ar1NO2

Ar2

HH

H

45

46

X-

X = BF4; BF6

Ar1 Ar2

a 4-PriOC6H43-NO2C6H4

b 4-MeC6H4 Arc 4-MeOC6H4d 4-EtOC6H4

i, 0.5 mmol of 1, 0.4–0.6 g [bmim][BF4 ]or [bmim][PF6 ] and 2 drops of Et2O·BF3ii, 0.5 mmol of β -nitrostyrene 44

7


Molchanov et al., in 2003, reported the reaction of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes 42 with fumaric

acid derivatives 49 in a stereoselective fashion to afford perhydropyrazolo[1,2-a ]pyrazoles 50.49

N N

Ar

+R

Rtoluene

50%–75% N

N

R

Ar

R

Ar = Ph; R = CN, CO2PhAr = 4-MeOC6H4, 4-ClC6H4; R = CN

42 49 50

2.2. Cycloaddition of azines to dipolarophiles

Pyrazolopyrazoles 53–55 were obtained by a “crisscross” cycloaddition reaction of 1,2-bis(perfluoropropan-2-

ylidene)hydrazine 51 with 2 equivalents of olefins 52; the principal products were 53 obtained in yields of

approximately 65%.50

NN

CO2R

CF3

F3C

CF3CF3

CO2R

53

+ NN

CO2R

CF3

F3C

CF3CF3

CO2R

54

+ NN

CF3

F3C

CF3CF3

CO2R

RO2C

55

N NCF3

CF3

F3C

F3C+ CO2R

R = Me, Et, Bu

51 52

N

N

R

Me

F3CCF3

CF3

CF3

N

N

R

Me

F3CCF3

F3CCF3

R1

R2N

N

R

Me

F3CCF3

F3CCF3

R3

57

6061

N NCF3

CF3

F3C

F3C+ RMe

C C R1R2

R = OEt; R1 = R2 = H, CO2Me; R1 = H, R2 = CO2MeR = NEt2, R1 = H, R2 = CO2Me; R1 = CO2Me, R2 = H

H2C CH

R3

R = OEt; R3 = H, CO2Me

51 56

5859

8


Similarly, the crisscross cycloaddition of 51 with 1-ethoxyprop-1-yne 56 gave 3-ethoxy-4-methyl-2-(perfluoropropan-2-ylidene)-5,5-bis(trifluoromethyl)-2,5-dihydropyrazol-2-ium-1-ide 57, stable only in solution.Subsequently, the latter compound was reacted with alkynes 58 and alkenes 59 to give 60 and 61, respectively,

in good yields.51−53

1,2-Di(propan-2-ylidene)hydrazine 62 reacted with 2,2-diphenylethenone to give pyrazolopyrazole 63.54

NMe

MeN

Me

MeC O

Ph

Ph+

N

N

O

Ph

Ph

MeMe

O

Ph

Ph

MeMe

6263

Cycloaddition of azines 64 with maleic acid gave tetrahydro-1H ,5H -pyrazolo[1,2-a ]pyrazole-2,3,6,7-

tetracarboxylic acid 65.55

N

N CO2H

CO2HHO2C

HO2CCO2H

CO2H

R1

R1

+N N CH

CH

R1 R1

64 65

Aldazines or ketazines 66 were reacted with 2 equivalents of DMAD in [2+3] cycloaddition reactions to

give pyrazolopyrazole 67.56

N

N

R1

R2R2

R1

+ 2 mol

CO2Me

CO2MeNN

CO2Me

MeO2C

CO2Me

CO2Me

R2

R1

R1

R2

R1 = alkyl or aryl; R2 = H, Me, alkyl

66 67

Pyrazolo[1,2-a ]pyrazole derivatives 69 were synthesized via 2:1 equivalent cycloaddition of sulfolene 68

with aldazines 64.57

S

O

O

R = Ph, 4-MeOC6H4, 4-ClC6H4, 4-FC6H4, 4-O2NC6H4, 2-furyl, 2-thienyl

N N CH

CH

RR +NN

SS

R

R

O

O O

O64 68 69

9


Adib et al., in 2005, reported the synthesis of functionalized 7-oxo-1H ,7H -pyrazolo[1,2-a ]pyrazoles 73.Thus, isocyanides 70 and dialkyl acetylenedicarboxylates 71 in the presence of 2,4-dihydro-3H -pyrazol-3-ones72 undergo a smooth 1:1:1 addition reaction in acetone at ambient temperature to produce highly functionalized

7-oxo-1H ,7H -pyrazolo[1,2-a ]pyrazole derivatives 73 in 69%–81% yields.58

N CR + CO2R1R1O2C + N NH

R2

O acetone

rt, 24 h

N

N

O

RHN

R1O2C

R1O2C

R2

R = cyclohexyl, Bu-t, R1 = Me, Et; R2 = Me, Ph

70 71 72 73

Bipyrazolidine antibiotics 78 were obtained from pyrazolidin-3-ones 74 by a 2-step reaction sequenceinvolving formation of an azomethine-imine ylide 76, which subsequently reacted in situ with acetylene derivative

77.59

NH

NH

O

HN

Acyl

+ OR2

R1N

N

O

HNAcyl

R1

R2

EWGGWE

N

N

O

HNAcyl

R1 R2

EWG

EWG

R1, R2 = alkyl

74 75 76

77

78

2.3. Reaction of pyrazoles with ketene, 1,3-dicarbonyl, or dinitrile compounds

Reactions of pyrazoles, with aryl(chlorocarbonyl)ketenes or alkylmalonyl dichlorides, were reported. Thus, pyra-zoles 79 were treated with propa-1,2-diene-1,3-dione or 3-oxo-2-phenylacryloyl chloride to give cross-conjugatedpyrazolium hydroxides 81, respectively. Similarly, (80, R = Me) and 2-ethylmalonyl dichloride (80, R1 = Et),

2-allylmalonyl dichloride (80, R1 = allyl) gave 81.60,61

NHN

R

R

R = H, Me, R1 = H, Ph; R = Me, R1= Et, allyl

C CC OO

C OPh

OCl

or

NN

R

R

O

O

R1O

Cl

O

R1Cl

or+

79

80

81

10


Substituted anhydro-1-hydroxy-3-oxopyrazolo[1,2-a ]pyrazolium hydroxides 86 were prepared by treating

1,3-dicarbonyl compounds 83 or 85 with derivatives of pyrazoles 82 or 84.62

N

NH

R1

R2

R3

C

O

R4Cl

O

route a

- HCl

N

N

O

O

R4

R1

R2

R3

+

O

OR3

R1

R2HN

N

OH

OH

R4 +

- 2H2O

route b

R1= H, Me, Ph, R2=H, benzyl, R3 = H, Me, Ph, R4 = aryl

82 83

84 85

86

The addition of (chlorocarbonyl)phenylketene 83 to pyrazol-3-one derivatives 72 led to 3-hydroxypyrazolo

[1,2-a ]pyrazolediones 87.63

NNH

O

R

+ C OPh

O

Cl

dry THF

80%–87%N N

R O

Ph

O OH

N N

R O

Ph

O O

7283

87 87`

7-Amino-3-hydroxy-5-imino-2,6-diarylpyrazolo[1,2-a ]pyrazol-1(5H)-ones 89 were prepared in yields of

30%–39% by cyclization of pyrazoles 84 with dinitriles 88.64

CN

CNR + N

HN

OH

OH

R1

DMF, 155 °C, 5 min

30%–39%N

N

O

OH

R1

NH

H2N

R

R = Ph, p-anisyl; R1 = Ph, p-anisyl, p-ClC6H4

8488 89

Thermal cyclocondensation of pyrazoles 90 with substituted diethyl malonates 91 yielded 1-oxo-1H -

pyrazolo[1,2-a ]pyrazol-4-ium-3-olates 92.65 Olates 93 were obtained by treating pyrazole 90 with diacyl dichlo-

ride 80.66

11


N

NH

R1

R1

R2

CO2EtEtO2C

ref lux

-2EtOH18%–62%

NN

R1

R1

O

O

R2

NN

R1

R1

O

O

R2

R1 = H, Me, Ph; R2 = PhCH2, Ph, EtO2C, Me

NN

R1

R1

O

OR2

R2CH(COCl)2

R = H, Me; R1 = Et, Ph, 4-ClC6H4, PhCH2

90 80

91

92 92`

93

The reaction of 5-hydroxypyrazoles 94 with β -ketoesters 95 gave mainly pyrazolo[1,2-a ]pyrazole-1,5

(1H ,5H)-diones 96.67

NNH

R

OH

NN

R

OO

R1R2

R1COCHR2CO2Et+

R = Me, Ph; R1 = Me, CH2Ph, Ph; R2 = CO2Et; R1 = Me, R2 = Ac

94 95 96

With the reaction of 3-methylpyrazolin-5-one (94, R = Me) with ethyl acetoacetate and phosphorus

tribromide in benzene, both syn-97 and anti -97‘ are formed.68

NHN

O

Me

MeCOCH2CO2Et

PBr3, C6H6

NN

O

Me

O

Me

NN

Me

O

O

Me

+

94 97 97`

2.4. Cycloaddition of l-allylpyrazoles

1-Allylpyrazole 98 was brominated and the resulting product was thermally quaternized to yield 99. Treatment

of 99 with aqueous sodium hydroxide afforded 100.69

12


N Ni) Br2

ii) Δ

N N BrOH-

N

N

98 99 100

l-Allylpyrazole (98, R = H) was dissolved in 48% hydrobromic acid and treated with bromine. The

dibromo compound that formed underwent cyclization in boiling acetone to give (101, R = X = H) in an 85%overall yield. When a similar bromination was carried out using chloroform as the solvent, the major productisolated after cyclization was the dibromobromide (101, R = H, X = Br). 1-Cinnamylpyrazole (98, R = Ph)

was reacted with bromine in chloroform to yield the salt (101, R = Ph, X = H) directly. Conversion of the

latter salt to the corresponding pyrazolo[l,2-a ]pyrazoles (102, R = Ph, X = H) by dehydrobromination was

possible with lithium hydride in deuteriodimethyl sulfoxide.70

N

N

R N

N

RBr-

XBr

N

N

R

X

R= H, Ph R =X = HR = H, X = BrR = Ph, X = H

R =X = HR = H, X = BrR = Ph, X = H

HBr/Br2 LiH

98101

102

2.5. From pyrazoles

Pyrazole reacted with phenacyl bromides 103 in 1,2-dimethoxyethane to give a salt, which on treatment withaqueous ammonia gave 1-phenacylpyrazoles 104 in 48% yield. Alkylation of compound 104 by a second mole ofphenacyl bromides 103 in dimethylformamide produced 1,2-diphenacylpyrazolium bromides 105 in 86% yield.Salts 105 were treated with 10% aqueous sodium bicarbonate and gave a 98% yield of 1-aroyl-2-aryl-1H -

pyrazolo[1,2-a ]pyrazol-8-ium-1-ide 106.71,72

N

N

O

Ar

N

N

O

Ar

O

Ar

N

N Ar

OAr

Ar= Ph, 4-ClC6H4, 4-BrC6H4, 3-NO2C6H4

O

Ar

BrNH

N+

O

ArBr

DMF

10% NaHCO3

103

501401 106

103

i) (CH2OMe)2ii) NH3

Treatment of 3,5-dimethyl-1-phenylacetylpyrazole (104, R = Ph) in benzene with NaH followed by

thiophosgene at 0 ◦C gave 5,7-dimethyl-2-phenyl-1-thioxo-1H -pyrazolo[1,2-a ]pyrazol-8-ium-3-olate 107.73

13


N

N

Me

Me O

Ph

+ SCl

Cl

NaH/C6H6 N

N

Me

Me O

Ph

S104 107

Treatment of pyrazole derivatives 100 with an equimolar amount of 2-(chloromethyl)oxirane 108 in

toluene afforded pyrazolopyrazoles 109.74

Cl ONHN

R1

R

+PhMe

N

R1

R

R, R1 = H, Me

100 108109

OH

3-(2-(Methylthio)pyrimidin-4-yl)-2-(o-tolyloxy)-6,7-dihydropyrazolo[1,2-a ]pyrazol-1(5H)-one 111 wasprepared via heterocyclization of ketoester 110 with pyrazolidine dihydrochloride, used for the prevention

of extracellular release of inflammatory cytokines.75−77

CO2Me

OO

N

N

SMe

Me NHHN+ .2HCl N

O

N

N

SMe

Me

O N

110111

The synthesis of bicyclic pyrazolidinone 118 was described using a Curtius rearrangement. Vinyl phos-phonate 113 was obtained by treatment of 112 with acetic anhydride and tetramethyl diamino methane asa formaldehyde equivalent. The crude vinyl phosphonate was used immediately in the Michael addition with114. The Michael addition was run in dichloromethane overnight followed by addition of t-butyl oxalyl chlorideand 2 equivalents of Hunig’s base in the same pot to provide 115 in 58% yield from 114 after chromatography.The allyl ester was deprotected using palladium catalysis to give 115, which was purified by chromatographyand subsequent trituration in ether/hexane to give 83% amorphous foam. Following Spry’s one-pot procedure,115 was converted to the acyl azide, rearranged to the isocyanate, and trapped as carbamate 116 with benzylalcohol in 56% yield. Hydrogenation to enamine 117 was accomplished in 83% yield using 5% palladium oncarbon in ethyl acetate at 40 psi on a Parr shaker. Acid-catalyzed hydrolysis of 117 was accomplished to give

target compound 118 in 68% yield without substantial loss of the t-Boc and t-butyl ester protecting groups.78

14


a) (Ac)2O, (Me)2NCH2N(Me)2; b) 114, CH2Cl2; c) Hunig's base, ClC(O)CO2t-Bu, CH2Cl2;

d) Pd(OAc)2/Ph3P, Et3SiH, MeCN; e) 1) (PhO)2P(O)N3, Hunig's base, CH2Cl2/Benzene, 2) PhCH2OH;f) 5% Pd on C/[H2]; g) THF/aqueous HCl, pH = 2.3

P

O

O

OEtO

EtO

a

112

P

O

O

OEtO

EtO

113

NH

NHHN

O

BtOC

b-dN

NCO2H

CO2-tBuO

HNBtOC

e fN

NNHCO2-Bz

CO2-tBuO

HN

BtOC

gN

NNH2

CO2-tBuO

HNBtOC N

NO

CO2-tBuO

HN

BtOC

118117116

115

114

(S)-Methyl 2-(tert -butoxycarbonylamino)-3-hydroxypropanoate 119 was tosylated and the product cy-

clocondensed with hydrazine to give 48% 4-(R ,S)-(tert -butoxycarbonylamino)-3-oxo-1-pyrazoline 120. Treat-

ment of 120 with 37% aq. HCHO gave the 1-methylenepyrazolidinium ylide, which underwent cycloadditionwith diallyl butynedioate to give 32.8% diallyl 7-(R ,S)-(tert -butoxycarbonylamino)-8-oxo-1,5-diazabicyclo[3.3.0]oct-2-ene-2,3-dicarboxylate 121. This was deprotected and the free amino group acylated with 2-thienylacetylchloride to give 62% 7(R ,S)-(R)-diallyl-7-oxo-6-(thiophen-2-ylmethylamino)-3,5,6,7-tetrahydropyrazolo[1,2-

a ]pyrazole-1,2-dicarboxylate 122.79−81

OO

HNO

O CMe3HO N

N

O HN

O

OCMe3

NN

O

O

O

O

OHNO

OMe3C

1. TsCl

2. NH2NH2

1.HCHO

2. diallyl butynedioate

1. deprotection

2. 2-thienylacetyl chloride NN

O

O

O

O

OHN

S

119 120

121 122

Cyclizing 3-hydrazinylpropan-1-ol in MeOH with acetylacetone gave 71% pyrazole 123, which was tosy-lated at 0 ◦C with 4-tolylsulfonyl chloride in chloroform containing pyridine to give 5,7-dimethyl-2,3-dihydro-

1H -pyrazolo[1,2-a ]pyrazol-4-ium toluenesulfonate 124.82

15


NN

Me

Me

OH

NN

Me

Me4-MeC6H4SO3

-4-MeC6H4SO2Cl

CHCl3/pyridine

HN

H2NOH

MeOH

Me Me

O O

+

123 124

Chloropyrazolinone 126 was prepared by chlorination of pyrazolinone 125 by using chlorine in 1,2-dichloroethane, and was then hydrated with potassium carbonate in dichloromethane to afford both thefluorescent and no-fluorescent isomers 2,3,5,6-tetramethylpyrazolo[1,2-a ]pyrazole-1,7-dione 127 and 2,3,6,7-

tetramethylpyrazolo[1,2-a ]pyrazole-1,5-dione 128, respectively. The fluorescent isomer has the carbonyl groups

in the proximal arrangement (syn, 127) and the no-fluorescent isomer has carbonyl groups in the distal

arrangement (anti, 128).83

NNH

O

Me

Me

Cl2

(ClCH2)2NNH

O

Me

Me

ClK2CO3 or i-Pr2NEt

CH2Cl2

N

N

O O

Me

Me Me

Me

syn

+ N

N

O

O

Me Me

Me

Me

ant i125 126 127 128

2,6-Dibromo-3,7-dimethyl-1H ,5H -pyrazolo[1,2-a ]pyrazole-1,5-dione 130 was prepared by addition of 1equivalent of sodium methoxide to pyrazolinone 129. The molecular structure of 130 was determined by X-ray

crystal structure.84

NNH

Me

O

BrBr NaOMe

NN

O

Me

BrMe

Br

O129 130

2-(p-Chlorophenylazo)tetrahydropyrazolo[1,2-a ]pyrazole-1,3,7-trione 132 was prepared by the action of

phosphorus oxychloride on 131.85

NHN

O

O

NNAr

CO2Et

POCl3N

N

O

O

NN

ArO

Ar = 4-ClC6H4

131 132

Chalcone 133 was treated with 3-hydrazinopropanol in refluxing benzene to give 3,5-bis(p-chlorophenyl)-

2-pyrazoline 134. Treatment of 134 with thionyl chloride in chloroform gave 5,7-bis-(p-chlorophenyl)-2,3,6,7-

tetrahydro-1H -pyrazolo [1,2- a ]pyrazol-4-ium chloride 135. However, if the reaction of 134 with thionyl

16


chloride was processed with aqueous sodium hydroxide, 135 and 5,7-bis-(p-chlorophenyl)-2,3-dihydro-1H -

pyrazolo[1,2-a ]pyrazol-4-ium chloride 136 were obtained. Compound 136 could also be obtained by treating

135 with aqueous sodium hydroxide in the presence of air.86

O

ArAr+

HN

H2NOH C6H6

ref luxN N

Ar Ar

HOSOCl2

N NAr

Ar

Cl

SOCl2

NaOH, O2

N NAr

Ar

ClNaOH

O2

52%

36%

Ar = 4-ClC6H4

133134

135

136

135 +

Generation of the carbamate dianion with sodium hydride and subsequent alkylation with dibromo-propane provided pyrazolidine 138 in high yield (96%). At this stage, the BOC-protecting group was removedand monoprotected hydrazide 139 was acylated with commercially available 3-chloropropionyl chloride, givingkey intermediate 140. Catalytic hydrogenation to remove the Cbz-protecting group on 140 generated a transientintermediate that smoothly underwent an intermolecular exo-tet cyclization to tetrahydro-pyrazolopyrazolone

141.87

NHbzC

NHBOCNaH

1,3-dibromopropane96%

NN

O Ot-Bu

O

OBn TFA

89%

HN

N O

OBn

DIEA86%

O

Cl ClN

NO

OBnO

Cl

Pd/C, H2

93%

NN

O

137 138 139

140 141

Reaction of 2-phenylmalonic acid dihydrazide 142 with 2,4-pentandione in absolute ethanol at room

temperature afforded pyrazolo[1,2-a ]pyrazol-4-ium-3-olate 146.88

17


O

Me

O

Me

+

H2NNH

O

Ph

O

NH

NH2

- H2ON

Me

O

Me

NH

OPh

O

HN NH2- NH2NH2

N

Me

O

Me

NH

OPh

O

NN

Me

Me

O

Ph

HO2C

NN

Me

Me

OPh

O

143 144

145 146

142

1,7-Dimethyl-3,5-di(oxo)-1H ,5H -pyrazolo[1,2-a ]pyrazole-2,6-dicarboxylic acid diethyl ester 148 (fluo-

rescent substance) and 1,5-dimethyl-3,7-di(oxo)-1H ,5H -pyrazolo[1,2-a ]pyrazole-2,6-dicarboxylic acid diethyl

ester 149 (phosphorescent substance) were prepared by action of palladium acetate on pyrazolinone 147.89

NHNH

O

Me

EtO2C

Pb(OAc)4/CH2Cl2 N

N

O

Me

EtO2C

O

CO2Et

Me

N

N

O

Me

EtO2C

Me

CO2Et

O

+

12% 12%147 941841

2.6. Miscellaneous methods

Pyrazolopyrazole 152 were prepared by treatment of 3-(4-methoxyphenyl)acrylohydrazide 150 with dithietane

151.90

NN

S

O

H2N

EtO2C

OMeS

S

CN

CO2Et

EtO2C

NC

OMe

O

HNNH2

+

150 151 152

1,5-Diaminopyrazolo[1,2-a ]pyrazole-3,7-dione 154, useful as a coupling component for azo dyes, was

prepared by cyclization of N ,N ’-bis(cyanoacetyl)hydrazine 153 in a solvent in the presence of an acid or base

at 20 ◦C to the boiling point of the solvent.91

18


HN

NH

O

CN O

CNN

N

O

O

H2N

NH2

153 154

Acrylonitrile was treated with hydrazine hydrate in the ratio of 2:1 to give 3-hydrazinylpropanenitrile(8.8%) 155 and 3,3’-(hydrazine-1,1-diyl)dipropanenitrile 156 (82%). Treatment of 156 with sulfuric acid in

the ratio of 1:4 gave 1,7-diiminoperhydropyrazolo[1,2-a ]pyrazole-2H2SO4 157 (65%).92

CNNH2NH2 . 2H2O

2:1CN

HN

H2N + CNN

H2N

CN

H2SO41:4

N

N

HNNH

. 2H2SO4

155 156

157

2,6-Dialkyl-l,3,5,7-tetraketopyrazo[1,2-a ]pyrazoles 159 have been prepared by condensing esters of alkyl-

malonic acids 158 with hydrazine in the presence of sodium ethoxide.93

R1

R2

CO2Et

CO2Et

NH2NH2 . H2O

NaOEt

R1

R2

O

O

NN

O

OR1

R2

R1 = R2 = Et, Pr, Bu, isoamyl; R1 = Et, R2 = isoamyl, 4-hexyl, Ph

158 159

The reaction of dibenzoylhydrazide 160 with Wittig reagents 161 gave rise to 3,7-diphenylpyrazolo[1,2-

a ]pyrazole-1,5-diones 163.94

HN

NH

O

O

PhPh + Ph3P CO2R

R = Me, i-Pr

Ph

O

OR

HN N

HPh

O

RO-2ROH

55%

NN

O

Ph

O

Ph

160 161162 163

19


3. Pyrazolo[1,5-b]pyrazoles

Pyrazolo[1,5-b ]pyrazole 165 was obtained by heating of 1-amino-3-methyl-5-(2-oxoiminopropyl)pyrazole 164 in

acidic medium.95

N NNH2

MeNOH

MeHCl

N N NH

Me Me

561461

Benzopyrazolopyrazole 168 was prepared in 30% yield from the reaction of 2-aminoindazolium salt 166

with acetyl acetone followed by treatment with lead acetate.96

NN NH2

Me

O

Me

O

Me

Et3N NN NH

Me

AcMe

Pb(OAc)4

NN N

Me

AcMe

166 167 168

4. Pyrazolo[3,4-c]pyrazoles

4.1. Reaction of 4-arylidenepyrazol-5-ones with hydrazines and hydrazides

Compound 72 on condensation with substituted benzaldehydes in the presence of sodium acetate as a basefurnished 5-methyl-4-substituted benzylidene-2,4-dihydro-3H -pyrazol-3-ones 169. Treatment of 169 with ph-thalimidoxyethyl bromide 170 in acetone using K2 CO3 as a base afforded 1-N -ethoxyphthalimido-3-methyl-4-(4-substituted benzylidene) pyrazol-5-one 171. The 6-N -ethoxyphthalimido-4-methyl-3-(4-substituted phenyl)-

2-thiocarbamoyl-3,3a-dihydro pyrazolo[3,4-c ]pyrazoles 172, in yields of 53%–65%, were obtained by the treat-ment of 171 with thiosemicarbazide in NaOH. Compounds 171 were converted to 6-N -ethoxyphthalimido-2-isonicotinoyl-4-methyl-3-(4-substitutedphenyl)-3,3a-dihydro pyrazolo[3,4-c ]pyrazoles 174 in yields of 60%–67%

by the cyclization with isonicotinohydrazide 173 in the presence of sodium acetate and acetic acid.97

20


N NH

O

Me ArCHO

AcONa/AcOH NNH

O

Me Ar

N O

Br

O

O

Acetone / K2CO3

NN

O

Me

Ar

NO

O

O

S

H2N NH

NH2

NaOH

N

OHN

NH2

NN

N

Me

Ar

NO

O

ON

SH2N

NN

N

Me

Ar

NO

O

O

N

O

AcONa/AcOH

N

Ar = 4-ClC6H4, 4-OCH3C6H4, 4-N(CH3)2C6H4, C6H5

72 169

170

171

172

173

174

2-Isonicotinoyl-5-methyl-2,4-dihydro-3H -pyrazol-3-one 175, upon condensation with various aldehydes,afforded the corresponding arylidene derivatives 176. 1-Isonicotinoyl-3-methyl-4-(4-substituted phenyl)-3a ,4-

dihydropyrazolo[3,4-c ]pyrazoles 177 were obtained via heterocyclization of arylidene derivatives 176 with

hydrazine hydrate.98

N N

OMe

ArCHO

AcONa/AcOH

NN O

Me Ar

Ar = 4-ClC6H4, 4-OMeC6H4, 4-N(Me)2C6H4, Ph

O

N

O

N

NH2NH2.H2O NN

N

MeAr

O

N

NH

EtOH/AcOH62%–68%

175 771671

The reaction of ethyl iodide with 4-benzylidene-3-methyl-1-phenyl-1H -pyrazol-5(4H)-one 178 gave qua-ternary salt 179, which on reaction with hydrazine in acetic acid followed by oxidation with selenium oxide

afforded tetrahydropyrazolo[3,4-c ]pyrazol-2-ium derivative 181.99

21


NN O

Ph

MeNH2NH2 . H2OPh

NN O

Ph

Me Ph

EtI

EtI

sealed tube100 °C N

N N

Ph

MePh

EtAcOHN Ac

SeO2

NN N

Ph

OHCPh

Et

N Ac

178 179 180

181

4-Arylidene-methyl-5-oxo-4,5-dihydropyrazoles 183 were prepared via the reaction of 3-methyl-5-oxo-4,5-dihydropyrazole 182 with aromatic aldehydes. Subsequently, compounds 183 were condensed with hydrazine

to give 5-[(3’-ethyl-5’-acetyl-4’-substituted pyrazolo[3,4-c ]pyrazoles 184.100−105

NN

Me

R

OArCHO

NN

Me

R

O

Ar

R1NHNH2

AcOH NN

Me

R

N

Ar

NAc

R =N

SO2

OH

Ar = Ph, 4-MeC6H4, 4-OMeC6H4, 4-NO2C6H4, 4-ClC6H4, thienylR1 = H, Ph

182 183 184

R = H; R1 = 2,4-(NO2)2C6H3

R = 2-ClC6H4; Ar = 2-MeOC6H4, 3-NO2C6H4, 3-OH-4-MeOC6H3; R1 = Ph

1,3-Diphenyl-2-pyrazolin-5-one 185 was condensed with p-methoxybenzaldehyde to give pyrazolinones

186. Then condensed with hydrazine, it gave pyrazolopyrazole 187.103,106

NN O

Ar

Ph

RCHO

NN O

Ar

Ph

RR1NHNH2

NN N

Ar

Ph

R

N

185 186 187

Ar = Ph, 4-pyridyl; R = C6H4OMe-p; R1 = H, Ph, 2,4-(O2N)2C6H3

R1

Cyclization of 3-[4-(benzo[1,3]dioxolylmethylene)-5-oxo-3-pyrazolyl]-4-hydroxy-1-methylquinolin-2(1H)-

one 188 with hydrazine hydrate gave pyrazolopyrazole 189.107

22


N

OH

O

CH3

HN

N O

OO

NH2NH2.H2O

dioxane66% N

OH

OCH3

NN

NH

OO

NH

188 189

3-Amino-1-phenyl-2-pyrazolin-5-one 190 condensed with aromatic aldehyde in the presence of AcOHto give the corresponding dibenzylidene derivative 191. The reactions of 191 with phenyl hydrazine gave

pyrazolopyrazoles 192.108

NN

H2N

O

Ph

RCHO

NN

N

O

Ph

R

R

PhNHNH2N

N

N

Ph

R R

NN

Ph

R = o-HOC6H4, p-MeOC6H4, p-Me2NC6H4, p-HOC6H4, ferrocenyl

190 191 192

Reaction of 5-chloro-1H -pyrazole-4-carbaldehydes 193 with hydrazines under microwave irradiation in

the presence of p-TsOH gave pyrazolo[3,4-c ]pyrazoles 194.109

NN

CHO

Cl

Ph

Me

+ RNHNH2p-TsOH/MW, ∼2 min

∼95%N

NN

Ph

MeN

R

R = H, Ph193 194

Pyrazolo[3,4-c ]pyrazoles 196 were prepared by reactions of 1,3-disubstituted-5-chloro-1H -pyrazole-4-

carbaldehydes 195 with hydrazine hydrate or phenylhydrazine in methanol.110−115

NN

CHO

Cl

Ph

R1

RNHNH2

MeOHN

NN

Ph

R1

N

R

R = H, Ph, naphthyridine substituent; R1 = Ph, Me, Pr

195 196

4.2. From 5-(oxo)thio-4-acylpyrazol

Hydrazonopyrazolone and thione derivatives 198 were prepared from 4-acetyl 197 by their condensation inboiling ethanol with hydrazine hydrate or phenyl hydrazine. Vilsmeier reaction on 198 at room temperature

23


(exothermic) simultaneously led to the deformylation of the 3-methyl group and ring closure to afford the

corresponding fused pyrazolo[3,4-c ]pyrazole aminoacroleins 199.116

NN

Ph

Me

X

OMe

RNHNH2 / EtOH, reflux

70%–76% NN

Ph

Me

X

NMe

HN R DMF-POCl3

68%–76% NN N

N

PhR

MeCHOMe2N

X = O, S; R = H, Ph197

198 199

New bis[6-phenyl-4-methyl-3-substituted-pyrazolo[4,5-d ]pyrazol-1-yl] thioketones 201 were obtained in

good yield by the reaction of thiocarbohydrazide with 1-phenyl-3-methyl-4-acetyl/benzoyl-pyrazol-5-one 200,

followed by cyclization of the intermediate. These compounds exhibit excellent antimicrobial activity.117

NN

NN

Ph

MeR

SN

N R

N NMe

Ph

NN

O

Ph

Me

R

O

S

NH

NH

NH2H2N+

R = Me, Ph199 200

4.3. From 5-amino-4-cyanopyrazoles

The formation of pyrazolo[3,4-c ]pyrazole 204 was accomplished by ring transformation of 1-benzyl-4-(5-methyl-

1,2,4-oxadiazol-3-yl)-1H -pyrazol-5-amine 203 under thermal conditions.118

NN

Bn

NH2

CNNH2OH/EtOH

83% NN

Bn

NH2

NH2N OH

MeCO2Et

EtOH/reflux56%

NN

Bn

NH2

NN O

Me

NaH/DMF

40% NN

Bn

NHN

HN O

Me201 202 203

204

Pyrazolopyrazole 205 was prepared from aminocyanopyrazole 201 by reaction with hydrazine.119,120

24


NN NH2

CNNH2NH2.H2O

NN

NHN

NH2

201 205R R


Pyrazolo[3,4-c ]pyrazoles 207 in 45% yield were prepared by the cyclization of 206 with hydrazine in etha-

nol.121,122

NHN

C

X

EtO2CSMe

O

OMe

N2H4.H2O / EtOH, reflux

45%

NH

NC

X

NH

O

OMeO

HN

X = NH, O206 207

The cyclocondensation of 4,5-dihydro-3-phenyl-5-[(2-propenyl)thio]-1H -1,2,4-triazole 208 with ethyl 2-

chloro-2-(2-p-tolylhydrazono)acetate 209 gave ethyl 4-phenyl-1-p-tolyl-1,6-dihydropyrazolo[3,4-c ]pyrazole-3-

carboxylate 210.123

HN N

NHS

Ph

EtO2C

NHN

Me

Cl

NN

NNH

EtO2CPh

Me

+

208210

Compound 211 was prepared via reaction of 3-methyl-1-phenyl-2-pyrazolin-5-one 182 with phenyl isoth-

iocyanate. Compound 211 was converted to pyrazolopyrazole 212 through reaction with hydrazine.124

NN O

Ph

Me

PhNCS

NN O

Ph

Me SNHPh

NH2NH2.H2O

NN N

Ph

Me

N

H

HN Ph

182 211 212

The behavior of several amino and hydroxy pyrazoles toward hydrazonyl halides is reported. Thus,

pyrazoles 213 were reacted with hydrazonyl chloride 214 to give pyrazolopyrazole 215.125

25


R = H2N, OH

NHN

Ph

R

+Ph

N

Cl

NH

Ph

NN

N

NH

PhPh

Ph

213 214 215

A convenient synthesis of pyrazolo[3,4-c ]pyrazoles 217 using some novel α -cyanoketene dithioacetals 216

was reported by reaction with hydrazines.126

CN

MeS

SMe O

HN

N ArRNHNH2

N

HNN

N

N NAr

R

R

H2N

R = H, Ph; Ar = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4

216 217

Aryl isothiocyanates 218 were reacted with the sodium salt of ethyl cyanoacetate to yield adducts 219.Compounds 219 were reacted with hydrazine to give different products depending on the reaction conditions.

O

Ar NCS +

NCCO2Et

EtONa/EtOH

50%

NCCO2Et

SNH

OAr

NCCO2Et

HSNH

OAr

219 219`N2H4.H2OEtOH80%

NC

SNH

OAr

O

HN NH2

RNHNH2EtOH75%

NN

NN

NH2

R

NHAr

OR

Ar = Ph, 1-naphthyl, R = Ph

RNHNH2EtOH

70%–72%

NN

NN

NH2NH

Ar

O

RR

Ar = Ph

218

220

221

222

26


Thus, they were reacted with hydrazine hydrate in the cold to give hydrazide derivative 220. On the otherhand, 219 or 220 reacted with excess phenylhydrazine in boiling ethanol to give pyrazolo[4,3-c ]pyrazoles 221

or 222, respectively.127,128

5. Pyrazolo[4,3-c ]pyrazoles

5.1. Dipolar cycloaddition

1,3-Dipolar cycloaddition reaction of p-tolyl P -(trimethysilyl)-ethynylsulfone 223 with 2-diazopropane 224 in16-crown-6 followed by potassium fluoride gave cycloadduct 225. The desilylated 3H -pyrazoles 226 obtained

were then allowed to react with either diazomethane or 2-diazopropane 224 to give 227.129

SO2ArMe2Si +Me

MeN2

N

N

MeMe

SiMe2

SO2Ar

F-/H+

NN

MeMeSO2Ar

R

RN2 N

N

MeMe

SO2Ar

N

NR

R

R = H, Me

223 224 225

226 227

Pyrazolopyrazoles 229 were obtained in 60%–85% yield by a double 1,3-dipolar cycloaddition of 2-

diazopropane 224 with alkynes 228.130

Me2CN2 +R1R

NN N

NR

R1

MeMe

Me Me

R = CO2Me, R1 = Ac, CN, Me; R = Ac, R1 = CN

224 922822

Dimethyl acetylenedicarboxylate is added dropwise at –20 ◦C to a solution of 2-diazopropane 224 in anether–xylene mixture to give a mixture containing dimethyl 3,3-dimethyl-3H -pyrazole-4,5-dicarboxylate 230

and 85% dimethyl 3,3,6,6-tetramethyl-3,3a,6,6a-tetrahydropyrazolo[4,3-c ]pyrazole-3a,6a-dicarboxylate 231.131

MeMe

N+N-

CO2MeMeO2C +ether–xylene

NN

MeO2C CO2Me

Me

Me +

N N

NNMeO2C

CO2Me

Me

Me

Me

Me

85%224 230231

27


The intramolecular cyclization of 4-diazo-3,5-dimethylpyrazole 232 catalyzed by HOAc gave 1H ,4H -3-

methylpyrazolo[4,3-c ]pyrazole 233.132

N

N

Me

Me

N+ N-N

NH

N

HN

Me

AcOH

232 233

5.2. From diazonium salts

Coupling reaction of pyrazolinediazonium chloride 234 with active methylene components 235 gave 55%–70%236, which on treatment with HCl-EtOH or HCl-AcOH gave 1,6a-dimethyl-2-phenyl-1,2-dihydropyrazolo[4,3-

c ]pyrazol-3(6aH)-one 237 and 1,1’-(3a,4-dimethyl-6-oxo-5-phenyl-2,3,3a,4,5,6-hexahydropyrazolo[4,3-c ]pyrazole-

3,3-diyl)dialkenone 238.133

NN

O

Me

Ph

N

Me

N

+ R2 R1

R1 = cyano, R2 = CONHPh, COC6H4NO2-3;R1 = Ac, R2 = CONHC6H4Cl-4, CONHPh, Ac, CO2Et; R1 = COPh, R2 = CO2Et

NN

O

Me

Ph

HN

Me

N

R1R2

HCl-EtOH

HCl-AcOH

NN

NN

Me

O

Ph

MeR2

+ NN

NHN

Me

O

Ph

MeCOR4

COR3

237: R2 = CONHPh, COC6H4NO2-3, CONHC6H4Cl-4

238: R3 = Ph, R4 = OEt; R3 = Me, R4 = NHPh

234 235 236

237 238

Cl

Reaction of diazotized 234 with α -chloro-β -diketones 239 in ethanol at room temperature for 2 h gave

corresponding pyrazolopyrazolones 240 in 74% and 53% yield, respectively.134

NN

O

Me

Ph

N

Me

N

+

R= Me, Et

Cl

O

CH3

O

R

NN

NN

OR

O

Ph

MeMe

234239 240

Cl

28


1,5-Dimethyl-3R-pyrazolyl-4-diazonium salts 234 were converted into corresponding 6-(1,5-dimethyl-3R -

pyrazol-4-yl)azo-1-methyl-3R -4H -pyrazolo[4,3-c ]pyrazoles 241 via intramolecular cyclization of intermediate

242.135

NN

Me

N

Me

R N

Cl

NaHCO3

NN

Me

N

CH2

R N

Cl

N NN

NMe Me

R N NMe

HNC

R

NN

NN

N

MeMe

R

Et3N/EtOH

R = H, C C Ph

234 241 242


5-Aryl-4-(arylazo)-1H -pyrazole-3-carboxylic acids 244 were prepared by reaction of 4-aryl-3-(arylhydrazono)-2,4-dioxobutanoic acids 243 with hydrazine hydrate. Cyclization of 244 with thionyl chloride gave pyrazolopy-

razolones 245, which showed moderate activity against Escherichia coli and Staphylococcus aureus.136

O

CO2H

O Ar1

NN

Ar NH2NH2.H2ON

HO2C

HNAr1

N

NAr

Ar = Ph, 4-MeOC6H4; Ar1 = 4-ClC6H4, 4-MeC6H4, 4-MeOC6H4

N N

Ar1

NNAr

O

SOCl2

243 244 245

Treatment of pyrazole 246 with disodium dithionite followed by diazotization with sodium nitrite and

treatment with sodium bicarbonate gave 3,6-diphenyl-l-methyl-4H -pyrazolo[4,3-c ]pyrazole 247.137

N NH

NN

PhPh

Me

1. Na2S2O3

2. HNO23. NaHCO3

NN

CH2Ph

Me

NNPh

Ph

742642

Arylhydrazonobromoacetoacetates 248 were reacted with arylhydrazines to give corresponding ethyl bro-modioxobutanoate diarylhydrazones 249, which on treatment with acid underwent cyclization to give corre-sponding hydropyrazolones 250. Hydrazones 250 on treatment with a base underwent direct cyclization to give

2-substituted aryltetrahydropyrazolopyrazolones 251.138

29


CO2Et

Br

O

NHN R1

RNHNH2

CO2EtBr

N

NHN R1

NH

R

H+N

N O

N NHR1Br

R

NN

ON

N R1R

R = Ph or deriv., R1 = 4-BrC6H4, 4-O2NC6H4, 2,4,6-Br3C6H2

248249 250

251

Nitration of 1-aryl-3-carbethoxy-4-hydroxy-1H -pyrazoles 252 with concentrated nitric acid under dif-ferent conditions gave corresponding 5-nitro derivatives 253, which on treatment with phosphorus oxychlorideafforded 1-aryl-3-carbethoxy-4-chloro-5-nitropyrazoles 254. Treatment of 254 with hydrazine afforded acidhydrazide 255, which on treatment with phosphorus oxychloride underwent chlorination–cyclization to form(256, R1 = Cl). Alternatively, 253 on treatment with hydrazine in the presence of potassium fluoride in

DMF afforded 5-aryl-1,5-dihydro-6-nitropyrazolo[4,3-c ]pyrazol-3-ols (256, R1 = OH), which on chlorination

with POCl3 furnished (256, R1 = Cl).139

NN

OHEtO2C

Ar

HNO3

NN

OHEtO2C

Ar

NO2

POCl3

NN

ClEtO2C

Ar

NO2

NH2NH2.H2O

NN

Cl

Ar

NO2

OHN

H2NPOCl3

NHN

NN NO2

Ar

X

NH2NH2.H2O

KF/DMF252 253 254

255 256

Ar = 4-O2NC6H4, 2,4,6-Br3C6H2; X = Cl; OH

The pyrolysis of antipyrine 4-diazonium fluoroborate 257 gave antipyrylazopyrazolopyrazolone 258,

which was formed by intermolecular and intramolecular coupling of the diazo compound at elevated temperature.140

O

NNMe

Me

Ph

N+N

BF4

pyrolysis NN

HN

N

O

Ph

MeNN

N

N

MeMe

OPh

257 258

1-Methyl-2-phenyl-1,2-dihydropyrazolo[4,3-c]pyrazol-3(4H)-one 260 was prepared by deamination and

cyclization of either 1-(1-phenyl-2,3-dimethyl-5-pyrazolon-4-yl)-3,3-dimethyltriazen 259.141

30


NN

O

Me

Ph

Me

NN N

Me

MeN

N N

NH

O

Me

Phxylene

85%

259 260

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