New routes to synthesis of heterocycles based on ortho-substituted aryl benzyl ethers

Abstract

The metallation behaviour of o-substituted phenyl benzyl ethers has been examined. Although conditions for selective [1,2]-Wittig rearrangement of 2-(2-(benzyloxy)phenyl)-2-oxazolines were not identified, it was found that treatment with a mixture of n-butyllithium and potassium tert-butoxide gave 2-aryl-3-aminobenzofurans in a process involving nucleophilic attack of the benzyl anion at the oxazoline C=N bond. Electron-withdrawing substituents on the benzyl ring, however, were not well tolerated. This methodology could also be extended to the syntheses of related 2-vinyl-3-aminobenzofurans, 2,2-diphenyl-2,3-dihydrobenzofuran-3-imines, spiro[benzofuran-3,2'-oxazolidines], spiro[benzo[b]thiophene-3,2'-oxazolidine] S,S-dioxides and the analogous 2-aryl-3-aminobenzo[b]thiophenes and indoles.

By replacing the oxazoline with a secondary amide group, selective [1,2]-Wittig rearrangement could be achieved. Treatment of 2-(benzyloxy)-N-butylbenzamides with 3.3 equivalents of n-butyllithium gave 2-(hydroxy(aryl)methyl)-N-butylbenzamides which readily lactonised to give 3-arylphthalides in low to excellent yields although, once again, electron-withdrawing groups were generally not well tolerated. Analogously, 2-(1-phenylethoxy)-N-butylbenzamide and 2-(prenyloxy)-N-butylbenzamide could be transformed to 3-methyl-3-phenylphthalide and 3-(2,2-dimethylvinyl)phthalide respectively. Preliminary investigations into the asymmetric [1,2]-Wittig rearrangement of o-substituted secondary benzamides have also been conducted. Similarly, 4-(benzyloxy)-N-butylbenzamides underwent [1,2]-Wittig rearrangement upon reaction with 3.3 equivalents of n-butyllithium, giving 4-(hydroxy(aryl)methyl)-Nbutylbenzamides in low to excellent yields. These observations suggest the operation of a stepwise intramolecular S_NAr mechanism.

The extension of these methodologies to analogous disubstituted thiophene systems was also investigated. It was found that treatment of 2-(3-(benzyloxy)thiophen-2-yl)-2-oxazolines and 2-(4-(benzyloxy)thiophen-3-yl)-2-oxazolines with the mixture of n-butyllithium and potassium tert-butoxide gave the expected thienofurans which were readily opened by moisture and air to give 2-alkylidenethiophen-3(2H)-ones and 4-(benzoyloxy)thiophene-3-carboxamides respectively. In contrast, 2-(2-(benzyloxy)thiophen-3-yl)-2-oxazolines underwent [1,2]-Wittig rearrangement when subjected to these conditions. Reaction of 3-(benzyloxy)thiophene-2-carboxamides with n-butyllithium gave 3-(hydroxy(aryl)methyl)thiophene-2-carboxamides.

The diverse reactivity of a novel 3-alkylidene-2(3H)-one (a stable heterocyclic analogue of an ortho-quinomethane), prepared by sequential treatment of a 2-(3-thienyl)-2-oxazoline with n-butyllithium and bis(trimethylsilyl) peroxide, towards a range of electrophiles and Diels-Alder dienes has also been assessed and the crystal structures of the products determined.

Date of Award	7 Dec 2017
Original language	English
Awarding Institution	University of St Andrews
Supervisor	R Alan Aitken (Supervisor)