Pyrido pyridazines, formation

True electrophilic substitution is very difficult in pyridopyridazines. For example, the [3,4-d] parent (286) is inert to hot 65% oleum (68AJC1291), and although formation of a 3-bromo derivative (308) was reported in the [2,3-d] series, it seems to have arisen by an addition-elimination reaction via the dibromide (309) (69AJC1745). Attempted chlorination led to ring opening. A similar effect was observed in the [3,4-d] system, where an 8-bromo derivative was obtained (77BSF665), and in iV-oxides of the pyrido[2,3-c]pyridazine and fused pyridazino[3,4-c]isoquinoline series (72JHC351). The formation of (311) from (310)... 

Similarly, reaction of hydrazine hydrate with pyridinedicarboxylates 281 in boiling alcohol, followed by cyclization of the resulting dihydrazides 282, gave the pyrido[3,4-r/ pyridazine-l,4-diones 283, where deacetylation has occurred during the formation of 282 (Equation 21) <1997T8225>. 

Lithium ester enolate-imine condensation has been used for the preparation of / -lactam rings via addition at the imine moiety <1996H(43)1057>. But treatment of imino derivatives of the pyridazine 293 with the lithium enolate of ethyl a,a-dimethylacetate 294 in THE led to the formation of the pyrido[3,4-r/ pyridazine 295 and its oxidized form 296. Compound 295 was obtained by nucleophilic attack of the carbanion species at C-5 of the pyridazine ring followed by cyclization (Equation 24) <1996JHC1731>. 

The construction of a thieno[3,2-Z>]pyridine by pathway M involves the successive formation of the N(l)-C(2) and C(3)-C(4) bonds of the pyridine fragment. Various 3-aminothiophene-2-carboxylic acid derivatives are most often used as the starting reagents with 2C-components, which introduce carbon atoms C(2) and C(3) into the pyridine ring. For example, the reaction of amino ester 155 with dimethyl acetylenedicarboxylate (156) involves intramolecular cyclocondensation followed by hydrazinolysis to give derivatives of the new heterocyclic system thieno[2, 3 5,6] pyrido[2,3-<7]pyridazine (157) (1991JHC205, 1990SPH203). 

The behavior of pyrido[3,2-e]pyridazine towards hard or soft bases has been studied.106,109,110 As a general rule soft bases undergo addition to position 4 of the ring system, whereas with hard bases the formation of anion radicals has been observed.146... 

As with pyridine-2,3-dicarbonitriles, the reaction of pyridine-3,4-dicarbonitriles with hydrazine hydrate in acetic acid/dioxane at 95 °C results in cyclization to give the corresponding pyrido[3,4-t/]pyridazine-l,4-diamine in the first step, followed by an amino-hydrazino exchange in positions 1 and 4 to give pyrido[3,4-t/]pyridazine-1,4-dihydrazines (see Section 7.2.1.5,1.5.5.) 63 127 e.g. formation of8.127... 

Powerful oxidants, such as lead(IV) acetate84,101 134 or tert-butyl hypochlorite,85 convert cyclic hydrazides into diazaquinones, but the use of milder and more specific peracid oxidizing agents, such as peracetic acid, allows the preparation of the 6-oxides of 1,4-dialkoxypyrido-[3,4-ci ]pyridazines139 or pyrido[3,4-i/]pyridazine-l,4(2//,3//)-dione, e.g. formation of l.45... 

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