1.4- Dicarbonyl compounds, reaction with hydrazines

The standard syntheses for pyrazoles (17) and isoxazoles (19) involve the reactions of (3-dicarbonyl compounds (18) with hydrazines and hydroxylamine, respectively. These reactions take place under mild conditions and are of very wide applicability the substituents Y can be H, R, Ar, CN, C02Et, etc. 

The 1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-577-2,3-benzodiazepine 63, a known anxiolytic agent, is prepared by the reaction of a monoketal derivative of a 1,5-dicarbonyl compound 62 with hydrazine or its hydrate or its salt <2003W02003050092A2> (Equation 7). 

Pyrazoles and isoxazoles from 1,3-diketones. The standard syntheses for pyrazoles 41 and isoxazoles 43 involve the reactions of -dicarbonyl compounds 42 with hydrazines and hydroxylamine, respectively (Scheme 31). These reactions take place under mild conditions and are of very wide applicability the substituents R can be H, alkyl, aryl, GN, G02Et, etc. For example, 4-alkoxypyrazoles 45 can be prepared from diketones 44 and hydrazine (Scheme 32) <2002SL1170>, while diketooximes 46 react with excess hydrazine in ethanol to give 4-amino-3,5-disubstituted pyrazoles 47 in generally good yields (Scheme 33) <2004TL2137>. 

The reaction between 1,3-dicarbonyl compounds 1 and hydrazines is the most general method for preparing l//-pyrazoles 2 (Scheme 2).2-4,5 If a 2,2-disubstituted 1,3-diketone is employed (1 R3, R4 H), reaction with hydrazine hydrate gives instead a 4//-pyrazole 3, as was first reported by Knorr.Sa Generally, the reactants are heated under reflux in a solvent such as methanol, ethanol, benzene, or carbon tetrachloride yields range from 50% to quantitative. 

Dicarbonyl compounds with a double bond in the 2,3-position condense with hydrazine to give pyridazines (e.g. 91 — 92). If one of the carbonyl groups in the starting material is part of a carboxyl group or a potential carboxyl group, then reactions with hydrazines or hydroxylamine lead to pyridazinones or 1,2-oxazinones (e.g. 93 — 94 Z = NH, NPh, O). Similarly a cyano group leads to an amino or imino product. 

Pyridazine syntheses from unsaturated 1,4-diketones have been applied in several new ways. ° The reaction with hydrazines is usually performed in the presence of mineral acid otherwise JV-aminopyrroles may be formed. Some saturated 1,4-diketones are claimed to react with hydrazines to give pyridazines. Instead of 1,4-dicarbonyl compounds,... 

The synthesis of pyrazolcs starting from a hydrazine and a 1,3-dicarbonyl compound is a well established reaction in organic synthesis. If a mono-suhstituted hydrazine is reacted with an unsymmctrically substituted 1,3-dicarbonyl compound, two different pyrazole products which arc regioisomers could he formed (sec figure 10.3-2). 

Because of the potential for the formation of two product isomers from the reactions of hydrazines with unsymmetrical dicarbonyl compounds and the resulting difficulty in separations, many efforts have been reported in the literature to enhance the selectivity of... 

Reaction of substituted hydrazine analogue with protected 3-dicarbonyl compound 67 leads to a ring-forming two-site reaction and formation of the pyrazoline diuretic agent, muzolimine (68). ... 

Pyridazines 160 were obtained by microwave-assisted reaction of 1,4-dicarbonyl compounds and hydrazine in AcOH and in the presence of DDQ as oxidant in order to obtain the aromatic compound in a one pot reaction [ 105]. The yields reported were relatively low although the method can be applied to the preparation of arrays of trisubstituted pyridazines with high molecular diversity (Scheme 57). 

Reaction of hydrazine or substituted hydrazine with 1,3-dicarbonyl compounds to provide the pyrazole or pyrazolone ring system. Cf. Paal-Knorr pyrrole synthesis (page 333). 

A more classical method of introducing the ting nitrogens of pyridazines is the reaction of hydrazine with a 1,4-dicarbonyl compound. This was illustrated by Hafez and co-workers in which the reactions of 120 with hydrazine produced pyridazine derivatives 122 <99JCR(S)360>. It was noted that depending on the substituents on pyrazoles 120, this reaction may not proceed at aU (120 121). 

The reaction of o-aminophenylhydrazine with ar-dicarbonyl compounds to give 1,2,5-benzotriazepines has been known for a long time but its attraction is lessened by the difficulty of synthesizing the hydrazine (55G1098). 

The condensation reaction gives very high yields, but the preparation of the reactants (106) is often complicated. For the preparation of pseudoazulene systems 5 and 6 formed by exchange of two C—C bonds of the seven-membered ring in azulene (Scheme 1), five-membered dicarbonyl compounds of type 107 are used. Their reaction with alkyl or aryl hydrazines gives heterocyclic bases (108), which can be transformed to the pseudoazulene system (49) by alkylation and deprotonation (see Section III,A,l).136... 

In the reaction of hydrazine with 2-(l-alkoxyalkylidene)-l,3-dicarbonyl compounds, the 13 C NMR spectral evidence indicates that the only point of initial hydrazine attack is the carbon atom in die ethylene bond and the only observed intermediate is the corresponding enehydrazine. MNDO calculations of the electronic characteristics showed that the reaction obeys orbital control.75... 

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