4.5- Dihydropyrazole

5-Dihydropyrazole has often been referred to as A -pyrazoline or 2-pyrazoline. 

The standard synthesis of 4,5-dihydropyrazole is the cyclocondensation of hydrazine, or alkyl- or arylhydrazines with a,y0-unsaturated carbonyl compounds, e.g.  

The 0x0 compounds derived from 4,5-dihydropyrazole are more important, they are often referred to as pyrazolones. They display tautomerism in the ring as well as in the side chain (ring-chain tautomer-ism) [136]  

2-dihydro-3H-pyrazol-3-one 2,4-dihydro-3H-pyrazol-3-one 5-hydroxypyrazol( NH-form CH-form OH-form 

The equilibrium position depends on the type of substituent and on the solvent used. In the gas phase and in apolar solvents, the 2,4-dihydro-3//-pyrazol-3-one dominates. Substituent tautomerism in heterocycles is observed in oxo compounds as well as in the corresponding thiones and imines. 

The standard synthesis for 4,5-dihydropyrazoles 1 is the cydocondensation of a,P-unsaturated carbonyl compounds with hydrazine or monosubstituted hydrazines  

The equilibrium position for the three tautomers (C-H tautomer 5, N-H tautomer 6, and 0-H tautomer 7) is dependent on the pyrazolone substituents and the solvent used. Tautomerism with substituent participation is observed in oxo heterocycles as well as for the corresponding thiones and imines. 

For instance, the pyrazolone 10 undergoes Knoeve nagel condensation (with aldehydes 9) and azo coupHng (with diazonium ions 11) at C-4, N-alkylation (e.g., with CH3I or (CH30)2S02 12) and O-alkylation (e g., with diazomethane - 13)  

The pyrazolone dye 16 may serve as an example of the use of pyrazolones as couplers in color photography, which react with the developer (e.g., N,N-diethyl-p-phenylenediamine) in an oxidative coupling process during the chromogenic development. 

Pyrazolone derivatives were widely used in the last century, but nowadays their medicinal application has been strongly reduced due to their considerable side-effects. 

---

Extensive reviews have been pubUshed, covering the Hterature to about 1967 (1 3). Pyrazoles and the benzopyrazoles have been well reviewed in References 4 and 5. More up-to-date reviews, though much narrower in scope, have been pubUshed on pyrazole oxides (6), dihydropyrazoles as insecticides (7), the anticancer dmgs anthrapyrazoles (8,9), and pyrazole sulfonylureas as herbicides (10). 

Dihydroazoles can exist in at least three forms (cf. Section 4.01.1.3), which in the absence of substituents are tautomeric with each other. The forms in which there is no hydrogen on at least one ring nitrogen normally predominate because imines are generally more stable than vinylamines in aliphatic chemistry. Thus for dihydropyrazoles the stability order is A" (hydrazone) (288) > A (azo) (289) >A (enehydrazine) (290). 

There are four possible pyrazol-3-(Mie structures I-IV. The nomenclature most frequently used in the literature has been taken from Chemical Abstracts, wlwre for example, structure I is named 2,3-dihydropyrazol-3(lW)-(Mie and structure II is named 4,5-dihydropyrazol-5(l//)-one. Compounds I and II have also been named as pyrazolinones. Compounds with structure IV have been referred to as 2,3-diaza-2,4-cyclopentadienones. To avoid this needless confusion, the nomenclature used throughout this review is in accord with the recommendations set forth by lUPAC. 

Hydrazones that are formed by heating the y3-keto ester and the hydrazine in an alcohol usually require more vigorous conditions in order to cyclize to pyrazol-3-ones. Thus, hydrazone 52, obtained by heating oxobutanoate 51 and phenylhy-drazine in ethanol, required heating under reflux in benzene ccMitaining phosphorus pentoxide in order to cyclize into l,2-dihydropyrazol-3-one 53 (66JOU1103) (Scheme 16). 

On the other hand, hydrazone 54 cyclized by heating in an ethanolic solution of aqueous sodium hydroxide to give 1,2-dihydropyrazol-3-one 55 in 92% yield (88JHC543) (Scheme 17). 

The reaction of disubstituted diacetylenes with hydrazine hydrate was reported by Darbinyan et al. (70AKZ640). In the first stage the addition of hydrazine to the terminal carbon atom of the diacetylene system is analogous to that of primary amines to diacetylene (69ZC108 69ZC110). With monosubstituted diacetylenes (R = H), hydrazine adds to the terminal triple bond. This leads to the formation of vinylacetylenic hydrazine 22 which cyclizes to dihydropyrazole 23 subjected to further isomerization to the pyrazole 25. It is possible that hydrazine 22 undergoes hydration to the ketone 24 which can easily be cyclized to the pyrazole 25... 

The cycloaddition reaction of diazomethane 4 and an olefin, e.g. methyl acrylate 5, leads to a dihydropyrazole derivative 6 ... 

The 1,3-dipolar reagent diazomethane reacts with oxepin and substituted derivatives to afford 1 1 or 2 1 adducts 13 or 14 across the C-C double bonds of the isomeric benzene oxides.238 239 In the 1 1 addition product 13, the two heterocycles adopt a cis orientation.238 The nitrogen can be extruded by irradiation of the dihydropyrazole. 

Methyl-5-oxo-l-phenyl-4,5-dihydropyrazol-4-ylidene)-2,3-dihydro-l//-azepine (3), formed in 62% yield by the condensation of 2-amino- or 2-butoxy-37/-azepine with 3-methyl-l-phenylpyrazol-5(4//)-one, with Meerwein s reagent yields the tetrafluoroborate salt 4 which, on treatment with sodium dihydrogen phosphate, liberates the free base 5.64... 

The (diazoacetyl)dihydropyrazole 4a is converted into the 1 //-l, 2-diazepin-6(7//)-one 5a in hot acetic acid 73 a somewhat similar reaction affords the diphenyl analog 5b.74... 

A solution of dihydropyrazole 4b (10 g, 34.5 mmol) in MeOH (200 mL) and THF (50 mL) was cooled to 0 C and treated with methanolic KOH (3 mL, 3 mmol). After 4 h, coned HC1 was added to pH 7 and the mixture was stirred until evolution of N2 ceased (1 h). The solvents were removed under reduced pressure to leave a syrup, which was heated with Et20 (200 mL). The Et20 extract left a solid, which was again extracted with hot Et20. The combined Et,0 extracts were evaporated to leave 5b yield 7.1 g (79%) mp 195 — 198 C (EtOH) orange crystals. 

Dihydropyrazoles were prepared by reaction of a monosubstituted hydrazine with benzimidazole amino acrylates 120. The reaction was carried... 

The same reaction, carried out with conventional heating at the same temperature, took more that 6 h to give comparable yields of the products. Dihydropyrazoles were also obtained by microwave-assisted reaction of poly-substituted vinyl ketones 122 with hydrazines, followed by reaction of the unstable pyrazole 123 with electrophiles (Scheme 43) [80]. 

Irradiation of 3,4-diarylsydnones 329 possessing an allyl or alkenyloxy substituent provided fused dihydropyrazoles 331 presumably via decarboxylation of sydnones 329 to nitrilimine 330 and the latter s INIC reaction (Eq. 38) [94]. 

Photoelimination of nitrogen from the tetrazole 429 results in the formation of the dihydropyrazole 430, presumably via intramolecular addition of the photochemically generated nitrile imine 431.358 Other examples of this type of behavior have been reported.359... 

An alternative strategy for generating 4,5-dihydropyrazoles is to perform 1,3-dipo-lar cydoaddition reactions of nitrile imines and alkenes. Langa and coworkers have... 

Pyrazole was hydrogenated over palladium on barium sulfate in acetic acid to 4,5-dihydropyrazole (A -pyrazoline), and 1-phenylpyrazole at 70-80° to 1-phenylpyrazolidine [478]. In benzopyrazole (indazole) and its homologs and derivatives the six-membered ring is hydrogenated preferentially to give... 

Arylhydrazones of /3-aryl-a,/3-unsaturated ketones are converted into pyrazoles by 3 mol equivalents of T CIO4 (Scheme 2). The ring closure occurs via radical cation 45 and is not simply oxidation of a preclosed dihydropyrazole, as evidenced by dimerization (- 46) of such a possible intermediate upon treatment with the radical cation (Scheme 3) (88JOC1973). 

Krasavin et al. described the synthesis of dihydropyrazol pyrazine diones via Ugi-4CR, employing ferf-butyl isocyanide as a convertible reagent [102], The authors reported that, under microwave irradiation, the ferf-butyl isocyanide behaves similar to Armstrong s isocyanide, furnishing the DKPs in good yields. It is noteworthy that the low priced isonitrile applied may be helpful for developing large-scale syntheses in the future (Scheme 6). 

The final products derived from 1 1 addition of sydnones to alkenes are usually pyrazoles or dihydropyrazoles. The pyrazoles are formed by oxidation of intermediate dihydropyrazoles. An unusual example of aromatization by elimination of an alkane (toluene) in prefence to hydrogen is illustrated in Scheme 7 <89TL4625>. 

The belief that ring transformations of 1,2,4-oxadiazoles require an vinyl substituent in the 3-position had to be abandoned when it was found that compounds like (47) with saturated side chains undergo smooth ring transformation to 4,5-dihydropyrazoles (Scheme 16) <79JCR(S)64, 79JCR(M)801>. 

The standard route to sydnones is the cyclodehydration of iV-nitroso-P-amino acids. 2-Chloro-4,5-dihydro-13-dimethylimidazolium chloride 97 has been shown to be an excellent reagent for this conversion, as, for example, in the synthesis of 3-phenylsydnone 98 <99JOC6989>. Functional group manipulations of fused sydnones have led to the isolation of several new compounds including 99 and 100 <99H(51)1433>. 4-Acetylsydnones react with hydrazine at room temperature to give 2,4-dihydropyrazol-3-ones 101 <99H(51)95>. ... 

---