Pyridazine reaction with maleic anhydride

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. 

When cycloadducts 174, obtained in the reaction of pyridazine and phthalazine with maleic anhydride, were subjected to solvolysis with hot... 

Furo[3,4-J]pyridazines have also been used in Diels-Alder reactions (331a with maleic anhydride, acrylic acid, 1,4-naphthoquinone, dibenzoyl-ethylene, 1,4-benzoquinone, benzo[c]furandione ° 331c with maleic anhydride) 331a has been shown to be more reactive than 331c. 1,3-Diphenylfuro[3,4-b]quinoxaline (335) has been obtained from phthalide 334 (Eq. 17) as a green crystalline, quite stable solid (mp 244-246°C). In DMSO (deep blue solution), 335 reacts instantaneously with such dienophiles... 

Pyridines add to quinones in Michael-type reactions to give phenolbetaines (64). Many other Michael acceptors behave similarly, e.g. acrylate esters and acrylamides in the presence of acid yield quaternary ions py+CH2CH2COY. Pyridazine at room temperature with maleic anhydride gives the 2 1 adduct (65). 

Dipolar cycloadditions lead to six-membered rings. Rearrangements may be encountered. Thiazole or 2-methylthiazole (129 R = H and Me) with DMAD forms an initial 1,4-dipolar species (130). Reaction of (130) with a second DMAD gives a 1 2 adduct, presumably (131). Ring opening to (132), followed by cyclization in the alternative mode, resulted in (133) (78AHC(23)263) (see also CHEC 4.19). For the similar reactions of pyridine with DMAD and pyridazine with maleic anhydride see Section 3.2.1.3.7. 

The primary adducts, cyclohexadiene derivatives, formed by [4+2] cycloaddition of thiophene dioxides with dienophiles, may further undergo [4+2] cycloaddition with the dienophiles. Thus, the adducts 84 of 3,4-di-ferf-butylthiophene dioxide 83 with maleic anhydride and AT-phenylmaleimide further react with these dienophiles to give excellent yields of bis-adducts, which are composed of the endo-endo and endo-exo isomers, 85a and 85b (Scheme 49) [160]. A similar reaction was also observed with 3,4-dichlorothiophene 1,1-dioxide with N-butyl- and A-p-nitrophenylmaleimides (Scheme 50) [133]. The reaction of highly congested thiophene dioxides 87 with 4-phenyl-1,2,4-triazoline-3,5-dione provides a unique pyridazine synthesis since the bis-adducts 88 are converted into the corresponding pyridazines 89 in one pot and in good yields by treatment with KOH in methanol (Scheme 51) [174]. 

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. 

Maleic anhydride and hydrazine give the hydroxy-pyridazinone ( maleic hydrazide ) directly, " the additional unsaturation in the 1,4-dicarbonyl component meaning that an oxidative step is not reqnired conversion of 3-hydroxypyridazin-6-one into 3,6-dichloropyridazine makes this useful intermediate very easily available. Mucohalo acids (18.1.1.4), synthons for 4-carboxy-aldehydes, are an oxidation level down and produce l-aryl-pyridazin-3-ones on reaction with arylhydrazines. ... 

Applying the synthetic principle (1) (see p 395), pyridazine itself can be prepared from maleic anhydride. Its reaction with hydrazine yields maleic hydrazide 18 which is converted with POCI3/PCI5 into 3,6-dichloropyridazine 19 due to an azinone-hydroxyazine tautomerism (see p 310) 19 gives rise to pyridazine by reductive dehalogenation with H2/Pd-C ... 

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