Bicyclic Heterocyclic Systems Derived from 1, 3, 4-Trisubstituted Pyridines

The preparation of 1,3,4-trisubstituted pyridines and their conversion into bicyclic systems are reviewed. The work described in this thesis concerns the preparation of 1,3,4-trisubstituted pyridines, by both existing and novel routes, and the conversion of these precursors into bicyclic systems. Nucleophilic displacement of the nitro group in 4-nitronicotinic acid 1-oxide by amines and alcohols gives a series of 3,4-disubstituted pyridine 1-oxides; with methyl hydrazine as the nucleophile, ring closure occurs to give 3-hydroxy-2-methylpyrazolo [4, 3-c] pyridine 5-oxide. Several new 1,3,4-trisubstituted-1,2,5,6-tetrahydropyridines are prepared by reduction of the appropriate pyridinium iodides with sodium borohydride. The reduction of 3,4-dimethoxycarbonyl-1-methyl pyridinium iodide by sodium borohydride gives the expected tetrahydro derivative and 3,4-dimethoxycarbonyl-1-methylpyrid-6-one; the pyridone was also prepared by oxidation of the quaternary salt using potassium ferricyanide. The reaction of 3,4-diethoxycarbonyl-1-methyl pyridinium iodide and 1-ethyl-3,4-dimethoxycarbonyl pyridinium iodide with sodium borohydride gave the corresponding pyrid-6-ones. An investigation into the unexpected course of this reaction is described, and a possible mechanism is proposed. Two main routes are employed for the synthesis of pyrido[4, 3-d] pyrimidine 6-oxides. Condensation of 4-aminonicotinic acid 1-oxide with formamide and urea gives the corresponding pyridopyrimidinones. Treatment of 4-aminonicotinic acid 1-oxide with aroyl halides gives the appropriate 2-arylpyrido[4, 3-d] [1, 3]oxazin-4-one 6-oxides; the reaction of the pyrido-oxazine 6-oxides with ammonia generally gives the diamides, whereas reaction with hydrazine under similar conditions gives the 3-aminopyrido [4, 3-d] pyrimidin-4(3H)-one 6-oxides. The mechanisms of these reactions are discussed. The reaction of substituted pyridine o-diesters with hydrazine gives the corresponding pyrido[3,4-d] pyridazinones, and the ring closure of 4-N-(3-tolyl) aminonicotinic acid 1-oxide and 4-N-(3-methoxyphenyl) nicotinic acid 1-oxide using sulphuric acid gives the appropriate benzonaphthyridines. The infrared spectra of the substituted pyridines and of the bicyclic systems, and some of the n.m.r. spectra, are recorded. The mass spectra of the substituted pyridines and of the bicyclic systems are recorded, and possible fragmentation pathways for several of these compounds are suggested.

Name dc:type.qualificationname

Ph.D.

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

Aston University

Year dc:date.issued

1973

Author dc:creator

• Bradley, Arthur