Exploring the functionalisation of the thieno[2,3-d]pyrimidinedione core: late stage access to highly substituted 5-carboxamide-6-aryl scaffolds

O'Rourke, K., Johnstone, E. S., Becker, H. M., Pimlott, S. L. and Sutherland, A. (2018) Exploring the functionalisation of the thieno[2,3-d]pyrimidinedione core: late stage access to highly substituted 5-carboxamide-6-aryl scaffolds. Tetrahedron, 74(30), pp. 4086-4094. (doi:10.1016/j.tet.2018.06.019)

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Abstract

The thieno[2,3-d]pyrimidinedione core is found as a component in a range of pharmaceutically active compounds, however, synthetic approaches to these scaffolds rely on access to functionalised, highly substituted thiophenes. Here we describe a new approach for the preparation of 5-carboxamide-6-aryl analogues that involves a two-step synthesis of the thieno[2,3-d]pyrimidinedione core from a readily available mercaptouracil derivative. Thio-alkylation with ethyl 3-bromopyruvate, followed by cyclisation and dehydration mediated by polyphosphoric acid allowed the scalable synthesis of the thieno[2,3-d] pyrimidinedione unit. The late-stage functionalisation of this core motif via bromination of the thiophene ring and a subsequent Suzuki-Miyaura reaction as the key steps permitted access to a novel library of 5-carboxamide-6-aryl analogues. The physicochemical properties of these compounds were determined, generating an insight into the potential bioavailability of these scaffolds. Based on these results, a selection of the novel 5-carboxamide-6-aryl analogues were tested as lactate uptake inhibitors of monocarboxylate transporters 1, 2 and 4 in Xenopus oocytes.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Pimlott, Dr Sally and Sutherland, Dr Andrew and O'Rourke, Kerry
Authors: O'Rourke, K., Johnstone, E. S., Becker, H. M., Pimlott, S. L., and Sutherland, A.
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
College of Science and Engineering > School of Chemistry
Journal Name:Tetrahedron
Publisher:Elsevier
ISSN:0040-4020
ISSN (Online):1464-5416
Published Online:12 June 2018
Copyright Holders:Copyright © 2018 The Authors
First Published:First published in Tetrahedron 74(30):4086-4094
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
608951Engineering and Physical Sciences Doctoral Training Grant 2012-16Mary Beth KneafseyEngineering and Physical Sciences Research Council (EPSRC)EP/K503058/1VPO VICE PRINCIPAL RESEARCH & ENTERPRISE