Monosubstituted hydrazines, reaction

An alternative method involves reaction of an a-acylaminoketone (12) with a primary amine and subsequent ring closure of the resultant Schiff s base (13) with phosphoryl chloride. This enables the introduction of a 1-substituent as in (14) to be carried out efficiently, and if the amine were replaced with a monosubstituted hydrazine, the imidazole derivative (IS) resulted (78LA1916). 

Scheme 4 shows in a general manner cyclocondensations considered to involve reaction mechanisms in which nucleophilic heteroatoms condense with electrophilic carbonyl groups in a 1,3-relationship to each other. The standard method of preparation of pyrazoles involves such condensations (see Chapter 4.04). With hydrazine itself the question of regiospecificity in the condensation does not occur. However, with a monosubstituted hydrazine such as methylhydrazine and 4,4-dimethoxybutan-2-one (105) two products were obtained the 1,3-dimethylpyrazole (106) and the 1,5-dimethylpyrazole (107). Although Scheme 4 represents this type of reaction as a relatively straightforward process, it is considerably more complex and an appreciable effort has been expended on its study (77BSF1163). Details of these reactions and the possible variations of the procedure may be found in Chapter 4.04. 

The imonium salt (199), obtained from ynamines and phosgeneimonium chloVide, underwent ready reaction with monosubstituted hydrazines to give the 3,5-bis(dimethyl-amino)pyrazole (200) (68T4217, 69T3453). Similarly, the adduct (201), resulting from the addition of phosgene to ynamines, likewise reacted with sym-disubstituted hydrazines to give pyrazoles (202). With hydroxylamine derivatives the isoxazolinone (203) was obtained. 

A recent paper by Singh et al. summarized the mechanism of the pyrazole formation via the Knorr reaction between diketones and monosubstituted hydrazines. The diketone is in equilibrium with its enolate forms 28a and 28b and NMR studies have shown the carbonyl group to react faster than its enolate forms.Computational studies were done to show that the product distribution ratio depended on the rates of dehydration of the 3,5-dihydroxy pyrazolidine intermediates of the two isomeric pathways for an unsymmetrical diketone 28. The affect of the hydrazine substituent R on the dehydration of the dihydroxy intermediates 19 and 22 was studied using semi-empirical calculations. ... 

The reaction of 4-diethylaminobut-3-en-2-one with monosubstituted hydrazines (95°C, H+, MeOH, HjO, 10 h) leads to pyrazoles 261 and 263 (yield 54%) at a ratio depending on the acidity of the medium. In an acidic medium the isomers 263 are predominantly obtained (76ZOR2063). Aminobutenones with hydrazine give only 5-methylpyrazoles (263) (69ZOR223). Enhydrazones 260 and 262 appear to be the synthesis intermediates. 

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

Monosubstituted hydrazines treated with nitrous acid give azides in a reaction exactly analogous to the formation of aliphatic diazo compounds mentioned in 12-47. Among other reagents used for this conversion have been N204 ° and nitrosyl tetrafluoroborate (NOBp4). ... 

Syntheses of fluoro-substituted pyrazoles continue to be of interest. Both 3- and 5-fluoropyrazoles (44 and 45, respectively) can be prepared from 43 <96JOC2763>. Treatment of 43 with hydrazine followed by N-alkylation provides 44, whereas reactions with monosubstituted hydrazines afford 45. The 4-(trifluoromcthyl)pyrazoles 47 are obtained from J-trifluoromethyl vinamidinium salt 46 <96TL1829>. The 5-trifluoromethyl-3-carboethoxypyrazoles 49 are obtained from the 1,3-dipolar cycloadditions of trifluoromethyl alkenes 48 with ethyl diazoacetate <96T4383>. 

The groups of Giacomelli and Taddei have developed a rapid solution-phase protocol for the synthesis of 1,4,5-trisubstituted pyrazole libraries (Scheme 6.194) [356]. The transformations involved the cyclization of a monosubstituted hydrazine with an enamino-/8-ketoester derived from a /8-ketoester and N,N-dimethylformamide dimethyl acetal (DMFDMA). The sites for molecular diversity in this approach are the substituents on the hydrazine (R3) and on the starting j3-keto ester (R1, R2). Subjecting a solution of the /8-keto ester in DMFDMA as solvent to 5 min of microwave irradiation (domestic oven) led to full and clean conversion to the corresponding enamine. After evaporation of the excess DMFDMA, ethanol was added to the crude reaction mixture followed by 1 equivalent of the hydrazine hydrochloride and 1.5 equivalents of triethylamine base. Further microwave irradiation for 8 min provided - after purification by filtration through a short silica gel column - the desired pyrazoles in >90% purity. 

In an extension of earlier work with 1,2-disubstituted hydrazines the hexahydro-1,4,5-oxadiazepines (529) have been prepared by the reaction of various monosubstituted hydrazines with (528) (75MI51803). 

Reaction of the 2-acetoxy-3(2//)-furanones (526) with monosubstituted hydrazines gives good yields of the pyridazinium-5-olates (527) together with varying amounts of isomeric products. Alkyl derivatives (527 R = alkyl) have also been prepared by base-catalyzed alkylation (Mel, Me2SO4, PhCH2Cl) of 3-methyl-6-phenyl-5-ethoxycarbonyl-4( 1 //)-pyridazinone. Reduction of the diphenyl compound 527 (R = Ar = Ph) by zinc and hydrochloric acid gives 3-ethoxycarbonyl-5-hydroxy-5-methyl-l,2-diphenyl-2-pyrrolin-4-one (528 R = Ar = Ph) (Scheme 21... 

Hexahydro-l,4,5-oxadiazepines (511) are prepared by the reaction of monosubstituted hydrazines with 0(CH2CH2C1)2 (75MI51803). 

The mechanism of these reactions has been studied by several authors. The first product of the reaction between aldehydes and hydrazine or monosubstituted hydrazines is the hydrazone (378), which can be isolated in a few cases. The dimerization of the hydrazones proceeds at room temperature and is catalyzed by acids. As mentioned above, protonation affords the intermediate (379) which dimerizes to yield (377 R1 = H). 

In cases where formaldehyde is used as the aldehyde component and hydrazine or monosubstituted hydrazines are the second component, further reactions can occur such as hydroxymethylation of the hexahydrotetrazine, or the formation of condensed systems. 

The reactions of monosubstituted hydrazines with higher valent halo or oxo complexes yields organodiazenido complexes (equations 132 and 133). 

Mahy JP, Gaspard S, Delaforge M et al (1994) Reactions of prostaglandin-H synthase with monosubstituted hydrazines and diazenes - formation of iron(II)-diazene and iron(III)-sigma-alkyl or iron(III)-sigma-aryl complexes. Eur J Biochem 226 445 157... 

In a one-pot reaction, a,a-disubstituted a-halo carbonyl compounds 1 (R, potassium thiocyanate, acetic acid, and monosubstituted hydrazines 3 are transformed into dihydro-lfT-imidazo[l,5- 7][l,2,4]triazole-2,5 (3H,6H)dithiones 8 (Scheme 1) (93TH, 01TH). With R =H, the reaction takes a different course (cf. Section 2.3). 

Monosubstituted hydrazines and hydrazides are converted into azides by a variety of nitrosating agents. The mildest reagent appears to be dinitrogen tetroxide, which can be used below 0 C in acetonitrile to convert benzoylhydrazine, p-toluenesulfonylhydrazine and 4-nitrobenzoylhydrazine, among others, into the corresponding azides in high yield. Another mild method involves the use of iron(lll) nitrate supported on clay. These reactions probably proceed by way of transient N-nitroso compounds (Scheme 19). 

The reaction between a monosubstituted maleic anhydride and a monosubstituted hydrazine can give two possible pyridazinone isomers, 28 or 29. The reaction between citraconic anhydride and... 

Reduction of hydrazines. Monosubstituted hydrazines are converted into hydrocarbons by reaction with the reagent under phase-transfer conditions (equation I). Yields are poor to moderate (6-40%) for aryihydrazines, but often fairiy high for heterocyclic substrates (7-95%). 

Treatment of 0 -benzotriazolyl-Q ,/3-unsaturated ketones with monosubstituted hydrazines followed by alkylation at the 4-position of the pyrazoline ring afforded unsymmetrical l,3,5-triaryl-4-alkylpyrazolines and -pyrazoles <2001JOC6787>. One-pot reactions of a,/3-unsaturated ketones 615 with hydrazinediium dithiocyanate gave... 

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