Pyridazine-3-carboxamide ring

Like other azines with a hydroxyl group a or y to a ring nitrogen atom, 3- and 4-hydroxypyridazines exist predominantly in the oxo form in the solid state and in aqueous solution. This has been established for 3(2/f)-pyridazinone and related compounds from correlations of ultraviolet spectra of unsubstituted compounds and their 0- and iV-methyl derivatives in neutral, acid, and alkaline solution, on the basis of infrared spectra (for a summary of this aspect of tauto-merism see Volume 1, Chapter VII, Section II, K) and from the determined crystal structure of 6-oxo-l,6-dihydro-3-pyridazine-carboxamide. Here, the bond lengths and positions of hydrogen atoms clearly indicate its structure as the oxo form. Similar conclusions were reached also for 4(lJ )-pyridazinones (75) and the predominant cationic structure is represented by... 

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). 

Both isomers of 5-benzoylpyridazine-4-carboxamide were isolated in the solid state (85LA167). The open-chain isomer obtained in the homolytic benzoylation of pyridazine-4-carboxamide is unstable and readily undergoes ring closure during recrystallization or chromatographic purification. 

The usually very powerfully ortto-directing groups such as secondary carboxamide surprisingly do not always lead to ortholithiation on pyrazine and pyridazine rings lithi-ation of 253 and 254, for example, takes place principally (at least kinetically) at the meta and para positions (Scheme 125) . ... 

The majority of pyrimido[4,5-c]pyridazines have been prepared from pyrimidine precursors. The chloropyrimidines (176) give the desired heterocyclic ring (177) on reaction with hydrazine (72BSF1483). Hydrazine also reacts with ethyl a-diazo-/3-oxo-5-(4-chloro-2-methylthiopyrimidine)propionate (178) to give the pyrimido[4,5-c]pyridazine-3-carboxamide (78). A mechanism for this interesting reaction has been proposed as shown, on the basis of the detection of hydrogen azide in the reaction mixture. There is no precedent for the reaction of the a-carbon of a-diazo-/3-oxopropionates with nucleophiles under basic conditions (76CPB2637). 

Pyridazine-3,4-dicarboxamide (187) undergoes the Hofmann reaction followed by ring closure to give pyrimido[4,5-c]pyridazine-5,7-dione (188) as the major product. In an analogous type of ring closure, 3-amino-6-methylpyridazine-4-carboxamide reacts with ethyl orthoformate to give 3-methylpyrimido[4,5-c]pyridazin-5-one (68JHC523). 

Pyrimido[5,4-c]pyridazines have been prepared by three major routes, namely (1) the Hofmann reaction on pyridazine-4,5-dicarboxamides (2) condensation of 4-aminopyridazine-3-carboxamide or 4-amino-3-cyanopyridazine with various reagents and (3) reaction of 6-methyl-5-phenylazopyrimidines with f-butoxybis(dimethylamino)methane. The first of these routes is not of practical synthetic value since the desired ring system is obtained as the minor product along with the isomeric pyrimido[4,5-c]pyridazines. 

The course of the cyclization of amino (or acylamino) ketones to pyrido[2,3-phenyl group is replaced by 2-fluorophenyl. Under mildly alkaline conditions, the amino and fluoro functions react to form a sandwiched 4-pyridinone ring. This compound is methylated (Mel-NaH-DMF) at N-2. A side-chain amino group which may be regarded as a vinylogous carboxamide displaces a bz-fluorine atom on heating with sodium hydride. 

The cyclization reaction of 39 under basic conditions furnished a 1 1 mixture of diazepines 40 and 43. The unexpected formation of 43 has been rationalized by a Smiles rearrangement involving a nucleophilic attack of the deprotonated 3 -nitrogen at position 4 of the second pyridazine ring resulting in the displacement of a carboxamide anion followed by cyclization to afford 43. ... 

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