Thienopyridine anmalogues of quinoline alkaloids

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Jones, A.W., 1979. Thienopyridine anmalogues of quinoline alkaloids. PhD, Nottingham Trent University.

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Abstract

This Thesis reports attempts to prepare thienopyridine analogues of simple quinoline alkaloids, and a study of aspects of the chemistry of various thieno[3, 2-b] and [3,4-b] pyridine derivatives that were obtained as a result.

In the first approach the intention was to prepare 6-methylthieno- [2, 3-b] pyridin-4(7H) one, from 2-aminothiophen, by a method described in the literature, with a view to elaborating the 6-methyl group. Nitration of thiophen under a variety of conditions always gave mixtures of the 2- and 3-nitro-compounds and various techniques were examined in attempts to obtain material enriched in the 2-isonier. Reduction, and reaction of the aminothiophen with ethyl acetoacetate gave N-(2-thienyl) 3-keto-butanamide and not the product previously reported. Cyclisation then led to 4-methylthieno [2, 3-b] pyridin-6(7H) one.

Approaches to isomer-free aminothiophens were next investigated. Both the Beckmann rearrangement of 2-acetylthiophen oxime and the nitration/reduction of thiophen-2-carboxylic acid and ethyl thiophen- 2-carboxylate failed to produce acceptable yields of pure aminothiophens Nitration of thiophen-3-carboxylic acid and its ethyl ester did provide isomer-free nitro derivatives, which, on reduction and subsequent reactions also gave thienopyridines isomeric with those required.

Next, the possibility of preparing thienopyridines by vapour phase techniques (that are successful for the synthesis of thiophen and benzothiophens) was explored. Although reaction of 2-vinyl pyridine with carbon disulphide did produce thienopyridines, the yields were too low to make the route synthetically useful.

Finally, the application of 3-amino-2-acylthiophens to the synthesis of thienopyridines was explored. Syntheses of the Camps and Friedlander types were unsuccessful. Although the 3-aminothiophen derivatives failed to form adducts with methyl tetrolate, the 2- methoxycarbonyl compound provided excellent yields of the Michael adduct on reaction with dimethyl acetylene dicarboxylate. The adduct could be cyclised either to a thieno [3, 2-b] or a thieno [3, 4-b] pyridine, according to the conditions employed. The chemistry of the thieno- pyridines obtained from this intermediate was explored, and analogues of the alkaloids echinopsine and echinorine were prepared. Similar adducts were formed by addition of the 3-aminothiophen to ethoxymethylene malonate, and these, too, were cyclised to thieno [3, 2-b] or [3, 4-b] pyridines.

Item Type:

Thesis

Creators:

Jones, A.W.

Date:

1979

ISBN:

9781369326017

Identifiers: