Maleic hydrazide derivative

Pyridazines with a hydroxy group at an a- or y-position to a ring nitrogen atom, i.e. 3-and 4-hydroxypyridazines (4) and (5), exist predominantly in the oxo form. This conclusion is based on spectroscopic evidence from UV spectra of unsubstituted compounds and their A-methyl and O-methyl derivatives in alkaline, neutral and acidic solutions. In some instances, as for example for 6-oxo-l,6-dihydropyridazine-3-carboxamide, there is also evidence from X-ray analysis <54AX199, 63AX318). Maleic hydrazide and substituted maleic hydrazides exist in the monohydroxymonooxo form (6). 

The methylation of N-methyl derivatives of maleic hydrazide gives in general O-alkylated products. The opposite results are obtained with benzyl halides as alkylating agents. In this case the O-benzyl derivative (71) is formed, which is then further benzylated to the lV,0-dibenzyl derivative (72). When ethyl chloroacetate is used, the direction of alkylation is dependent on pH. At pH above 8, O-alkylation occurs at pH below 8, N-alkylation takes place exclusively in neutral and acidic solutions only IV-alkylated products are formed. 

The most useful syntheses of pyridazines and their alkyl and other derivatives begins with the reaction between maleic anhydride and hydrazine to give maleic hydrazide. This is further transformed into 3,6-dichloropyridazine which is amenable to nucleophilic substitution of one or both halogen atoms alternatively, the halogen(s) can be replaced by hydrogen as shown in Scheme 110. In this manner a great number of pyridazine derivatives are prepared. 

Table 7 Spectral Data for Maleic Hydrazide and Derivatives (DMSO) ...

In some respects, the actions of (2-chloroethyl)trimethylammonium chloride derivatives and MH in altering the growth of plants appear similar. There is no apparent similarity in the chemical structure of maleic hydrazide,... 

The saturated analogs, e.g., succinic anhydride or succinic esters, behave differently and only in few cases were pyridazines obtained. The reaction between succinic anhydride and various amounts of hydrazine hydrate has been studied under different reaction conditions, but always uncyclized products were formed. One of these is a polymeric hydrazide which, when treated with benzenesulfonyl chloride, yielded the monobenzenesulfonyl derivative of cyclic succinhydrazide (30, R = PhS02) along with a compound formulated as bicyclic disuccinhydrazide (152, Section IV,H, 4), but later shown to be 153. Authentic cyclic succinhydrazide (30, R = H) was obtained upon reducing maleic hydrazide with aluminum amalgam. Previous claims that 30 (R = H) may be obtained from succinic acid or A-aminosuccinimide proved to be incorrect. 

As expected, maleic hydrazide is alkylated to give various mono- or dialkylated products and many investigations have been devoted to this problem. Methylation with diazomethane was investigated formerly in connection with the structure of maleic hydrazide. The mono-O-methyl derivative was formed first and further methylation afforded the A,0-dimethyl compound (85). ... 

Methylation of maleic hydrazide with dimethyl sulfate can give, depending on reaction conditions, three different methylated products. In the presence of aqueous jbase the 2-methyl derivative (83) is obtained, whereas heating with dimethyl sulfate at... 

Acylations of pyridazinones, maleic hydrazide, and related compounds are known. Either 0-acylation or A-acylation is reported. Using the Schotten-Baumann procedure maleic hydrazide is O-acylated with benzoyl chloride and chlorocarbonates and similarly 0-sulphonyl and phosphoryl derivatives have been prepared. ... 

The iV-acylated derivatives of maleic hydrazide, prepared from open-chain compounds, have been found to differ from acylated products obtained from maleic hydrazide acylations. Acylation of 4- or 5-substituted maleic hydrazides should permit the existence of two 0-acylated isomers. So far, only one isomer of unknown structure has been isolated from benzoylation of the 4-methyl analog. Maleic hydrazide and its 2-substituted analogs are 0-acylated with acetic anhydride, acyl halides, and 0,0-dialkylphosphorochlor-... 

A few instances of A-acylation are also known. 6-Chloro-3(2.H)-pyridazinone reacts preferentially on the nitrogen with chloro-carbonates and the structure of the products has been assigned on the basis of IR data. A-Acylations of maleic hydrazide are claimed to proceed with unsaturated acid chlorides in nitrobenzene at 160° or with chloromethylsulfonyl chloride. The acetylated 4-methyl analog of maleic hydrazide has been also assigned as the A-acyl derivative on the basis of spectroscopic evidence. Finally, N-acylated maleic hydrazides result from the rearrangement of the corresponding acylated A-aminomaleimides. ... 

The Michael-type addition of maleic hydrazide to activated olefins has been investigated. Maleic hydrazide when treated with methyl acrylate, acrylonitrile, methyl vinyl ketone, and other activated olefins forms monoaddition products - for which the structure as A-substituted derivatives has been determined. The exclusive formation of monoaddition products is in contrast to the saturated cyclic succinhydrazide which can form mono- and diaddition products. Additions of the foregoing type are valid also for pyrid-azinones. Low yields of addition products have been obtained when adding dihydropyran or its thio analog and dihydrofuran to pyrid-azinones or pyridazinethiones. ... 

Hydroxymethylation and Mannich reaction have been performed with pyridazinones and maleic hydrazide, because they are acidic enough for these types of additions. Although it has been claimed that pyridazinones form only A-hydroxymethyl derivatives in the Mannich reaction it was reported that the corresponding Mannich bases are formed easily. The substituted aminomethyl residue is attached always on the ring nitrogen. Mannich bases were likewise obtained from maleic hydrazide and its analogs, but not from its 2-phenyl... 

The reactivity and chemistry of tetrahydro-3,6-pyridazinediones has not been much investigated. The parent compound (cyclic succinhydrazide) has been obtained by aluminum amalgam reduction of maleic hydrazide. Attempts to prepare it by alternative methods were unsuccessful (Section III,D). It forms a A,A-dimethyl or diacetyl and a A-monoethyl derivative with benzenesulfonyl... 

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