Geoffrey Edward Gymer

Novel heterocyclic systems. Part 3. The first dipyrido-oxathiin, and new routes to a dipyridodioxin and a dipyridodithiin

Abstract The first example of a dipyrido-oxathiin has been prepared, and a dipyridodithiin and a dipyridodioxin have been obtained by improved methods. Their spectroscopic properties are compared.

Designing rapid onset selective serotonin re-uptake inhibitors. 2: structure-activity relationships of substituted (aryl)benzylamines.

A series of substituted benzylamines 2-48 were prepared as part of a strategy to identify structurally differentiated and synthetically more accessible selective serotonin reuptake inhibitors, relative to clinical candidate 1. In particular, 44 and 48; demonstrated low nanomolar potency and good selectivity, in a structurally simplified template and, in vivo, very low Vdu, significantly lower than l, and a more rapid T(max), consistent with our clinical objectives.

Designing rapid onset selective serotonin re-uptake inhibitors. Part 3: Site-directed metabolism as a strategy to avoid active circulating metabolites: Structure–activity relationships of (thioalkyl)phenoxy benzylamines

A series of thio-alkyl containing diphenylethers were designed and evaluated, as a strategy to competitively direct metabolism away from unwanted amine N-demethylation and deliver a pharmacologically inactive S-oxide metabolite. Overall, sulfonamide 20 was found to possess the best balance of target pharmacology, pharmacokinetics and metabolism profile.

Reactive intermediates. Part XXIV. 1H-Azirine intermediates in the pyrolysis of 1H-1,2,3-triazoles

Nitrogen has been extruded from several 1,2,3-triazoles by flash vacuum pyrolysis and the fate of the resulting iminocarbenes has been determined. 1-Alkyl-4,5-diphenyl-1,2,3-triazoles (1) gave nitriles (Scheme 1) and isoquinolines and hydroxyisoquinolines (Scheme 2), the former by Wolff rearrangement and the latter by 1,4-hydrogen transfer in the iminocarbene. 1,4-Dimethyl-5-phenyl-1,2,3-triazole (3) and 1,5-dimethyl-4-phenyl-1,2,3-triazole (4) both gave 3-methylisoquinoline; a mechanism involving a common, 1H-azirine intermediate is proposed (Scheme 4). From both 4- and 5-phenyl-1-(1-phenylvinyl)-1,2,3-triazole [(5a) and (6a)] mixtures of 2,4- and 2,5-diphenylpyrrole were isolated; similarly the corresponding 1-phenyltriazoles gave mixtures of 2- and 3-phenylindole (Scheme 5). 4,5-Diphenyl-v-triazole also gave 2-phenylindole. The formation of these products is rationalised in terms of 1H-azirine intermediates in the pyrolyses.

Benzonitrile N-(phthalimido)imide, a functionalised 1,3-dipole. Preparation of 4,5,8-triphenylpyridazino[4,5-d]triazine and generation of 3,6-diphenyl-4,5-didehydropyridazine

5-Phenyl-2-phthalimidotetrazole (1) has been prepared and shown to react readily with cyclohexene, dimethyl acetylenedicarboxylate, and dibenzoylacetylene, to give the cycloadducts of the functionalised 1,3-dipole, benzonitrile N-(phthalimido)imide (2). The adduct formed with dibenzoylacetylene, 4,5-dibenzoyl-3-phenyl-1-phthalimidopyrazole (5), has been converted into 4,5,8-triphenylpyridazino[4,5-d]triazine (8). This triazine undergoes thermal fragmentation to give diphenylbutadiyne, 3,6-diphenyl-4,5-didehydropyridazine being proposed as an intermediate. An alternative route to 3,6-diphenyl-4,5-didehydropyridazine is described which involves the preparation and oxidation of 1-amino-4,7-diphenyltriazolo[4,5-d]pyridazine (11).

Reactive intermediates. Part XXII. Formation of 2H-azirines by oxidation of N-aminophthalimide in the presence of alkynes

2H-Azirines (2) are isolated in low to moderate yields after oxidation of N-aminophthalimide by lead tetra-acetate in the presence of the alkynes propyne, but-2-yne, pent-1-yne, and hex-3-yne. A mechanism for the reaction is proposed which involves the transient formation and rearrangement of 1H-azhines (1). Some unsuccessful attempts to generate 1H-azirines by alternative routes are described. Reports that the products of the reactions of 1,2,3-triazole-4,5-dicarboxylic acid with acetic anhydride and of p-benzoquinone with p-nitrophenyl azide are 1H-azirines are shown to be incorrect.

Fragmentation of 3,6-diphenyl-4,5-dehydropyridazine to diphenylbutadiyne

When 3,6-diphenyl-4,5-dehydropyridazine (1) is generated in the vapour phase, by pyrolysis of the pyridazotriazine (2) or by pyrolysis of its furan adduct (5), it reacts by extrusion of nitrogen to give diphenyl-butadiyne rather than by dimerisation.

Reactive intermediates. Part XXIII. Pyrolysis of 1-phthalimido-1,2,3-triazoles: formation and thermal reactions of 2H-azirines

Pyrolysis in the vapour phase of 4,5-disubstituted 1-phthalimido-1,2,3-triazoles (1) gives 2H-azirines (2) as the primary isolable products. The azirines undergo further thermal reactions under the conditions of the pyrolysis: with a methyl or an ethyl 2-substituent they are cleaved to nitriles and phthalimido-carbenes, but with a phenyl 2-substituent they rearrange to indoles. 4-Methyl-5-phenyl-1 -phthalimido-1,2,3-triazole (1c) and 5-methyl-4-phenyl-1-phthalimido-1,2,3-triazole (1d) give identical mixtures of azirines and their pyrolysis products, indicating that the products are formed through a common intermediate, considered to be the antiaromatic 2-methyl-3-phenyl-1-phthalimido-1H-azirine.