Hydrazine diketones

From Hydrazines and P-Bifunctional Compounds. One of the oldest examples in this class is the reaction of a p-diketone with a substituted hydrazine to give a pyrazole (eq. 1). 

In these types of 1,3-dipolar cycloaddition only one of two possible isomers is obtained and the pyrazole functions have different orientations by the two methods. Another classical synthesis of pyrazoles (Section 4.04.3.2.l(ii)), the reaction between hydrazines and )3-diketones, has been used with success to prepare high molecular weight polypyrazoles (Scheme 65) (81MI40400). A-Arylation (Section 4.04.2.1.3(ix)) of 4,4 -dipyrazolyl with 1,4-diiodobenzene also yields polymeric pyrazoles (69RRC1263). 

A solution of bismuth trioxide in hot glacial acetic acid provides a specific method for the oxidation of acyloins. " The reaction rate is dependent on the steric accessibility of the ketol system. A 2,3-ketol requires less than one hour for completion but an 11,12-ketol is not yet fully oxidized in thirty hours." The reaction is highly selective as a-keto acids, hydrazines and phenols are not oxidized. In a direct comparison with cupric acetate, this procedure is somewhat superior for the preparation of a 2,3-diketone from a 2-keto-3-hydroxy steroid. ... 

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. ... 

A solventless synthesis of pyrazoles, a green chemistry approach, has been described where an equimolar amount of the diketone and the hydrazine are mixed in a mortar with a drop of sulfuric acid and ground up. After an appropriate length of time ( 1 h) the product is purified to provide clean products. Even acyl pyrazoles 42 were obtained under the solvent-less reaction conditions in good yields. 

Sanofi-Synthelabo researchers discovered pyrazole 53 and analogs to have potent Cannabinoid receptor-1 (CB-1) antagonist/inverse agonist activity and have progressed 53 into development for treatment of obesity and alcohol dependence. The synthesis of 53 was accomplished by heating the diketone sodium salt 51 with the aryl hydrazine hydrochloride in acetic acid to provide the intermediate 52, which was further derivatized... 

Application of the Knorr pyrazole synthesis has also been demonstrated on solid support. ° To prepare trisubstituted pyrazoles, the diketone was linked to the solid support to make 57 using a linker with an amide bond. Alkylation of the diketone followed by condensation of the hydrazine with the resulting diketone gave the desired pyrazoles as mixtures of isomers. Subsequent cleavage of the amide bond linker then provided the pyrazole amides 59. ... 

The diketone 1 reacts with hydrazine to give the 5/7-2,3-benzodiazepine 2.127... 

The potential of such reaction sequences for the generation of molecular diversity was also demonstrated by the synthesis of a library of heterocycles. Epoxide ring-opening with hydrazine and subsequent condensation with (3-diketones or other bifunctional electrophiles gave rise to a variety of functionalized heterocyclic structures in high purity [34]. A selection based on the substrate derived from cyclohexene oxide is shown in Scheme 12.12. 

Unactivated aziridines, such as 24, are not as reactive as their N-sulfonyl analogues. Nevertheless, in aqueous conditions they react with different nucleophiles, as Scheme 12.23 illustrates. Treatment with buffered azide at 50 °C gave 25 in 90% yield. Hydrazine proved potent even at room temperature and 26 was fonned in 95 % yield, while phenyltetrazole required heating at reflux in water. The resulting amines participated in dipolar cycloadditions with alkynes and condensations with P-diketones. 

A similar strategy has been used to prepare pyrimidines, as well as pyra-zoles and isoxazoles by reacting the enamine intermediate with a variety of bidentate nucleophiles [78]. Microwave irradiation of a cyclic 1,3-diketone 49 and acetal 45 in water generated the corresponding enaminoketone 50 in situ which reacted with amidines, substituted hydrazines or hydroxylamine in only 2 min in a one-pot process to give 4-acylpyrimidines, pyrazoles or isoxazoles, respectively (Scheme 20). 

Different approaches towards pyrazoles have been described using microwave-accelerated cyclizations. A classical approach to pyrazoles is the cyclization of a j6-diketone with hydrazines. A series of 5-trichloromethyl-pyrazoles 58 and pyrazolium chlorides 59 were synthesized by reaction of a 4-methoxy-trihalo-3-alken-one 57 with differently substituted hydrazines (Scheme 19). The use of microwave and conventional heating for making pyrazoles gave... 

Reaction between hydrazines and P-diketones or P-keto esters... 

The reaction of 5,6-diphenyl-3-cyano-l,2,4-triazine with hydrazine gives the amidrazone which, with 1,2-diketones, yields 3,3 -bistriazinyls 74 <95MI03 96CA(124)86945>. 

Substituted 1,2,4-triazines were conveniently prepared in one pot by the condensation of amides and 1,2-diketones followed by cyclization with hydrazine hydrate <06MI67>. 

A somewhat related approach was followed by Molteni and coworkers, who have described the three-component, one-pot synthesis of fused pyrazoles by reacting cyclic 1,3-diketones with DMFDMA and a suitable bidentate nucleophile, such as a hydrazine derivative (Scheme 6.195) [357]. Again, the reaction proceeds by initial formation of an enamino ketone as the key intermediate from the 1,3-diketone and DMFDMA precursors, followed by a tandem addition-elimination/cydodehydration step. The details of this reaction, carried out in superheated water as solvent, have been described in Section 4.3.3.1. 

A different example of this general type involves the ds-dihydrazone complex (64). This complex is prepared by condensation of the corresponding dialdehyde with hydrazine in the presence of nickel or copper ion (Curtis, Einstein Willis, 1984). The two uncoordinated -NH2 groups react with a ketone or a diketone such that cyclization occurs in each case [2.8], In these systems, the pendant -NH2 groups are expected to be reactive since their non-coordination results in the respective nitrogen lone pairs being readily available for nucleophilic reaction. 

Szczepaikiewicz et al. [85] reported the synthesis of pyrazoles (e.g., 167) from the diketone 168 with hydrazine hydrate, shown in Scheme 43. Nigram et al. executed a similar synthetic sequence [86]. 

Pyrazoles were obtained from corresponding 2-hydroxy(or aIkoxy-)imino-1,3-diketones or related ketoesters and hydrazine . Thus, reaction of oximes 112 with hydrazine in ethanol afforded aminopyrazoles 113 in 48-95% yields (equation 48) . Interaction of... 

The resin-bound 1,3-oxazinium salt 116, obtained by oxidation of 4//-l,3-oxazines 115 with 2,3-dicyano-5,6-dichloro-p-benzoquinone (DDQ), behaved as /3-diketone equivalents and formed pyrazoles 117 through a functionalizing release process on treatment with hydrazines (Scheme 18). When the hydrazines were substituted (R = Me, Ph), the oxazinium salts reacted selectively to afford one regioisomer 117 <2004JC0846>. 

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