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Current Organic Chemistry

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ISSN (Print): 1385-2728
ISSN (Online): 1875-5348

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Research Article

Synthesis of 5-membered Heteroaryl-substituted Benzyloxy-benzaldehydes by the Suzuki-Miyaura Coupling Reaction

Author(s): Hedvig Bölcskei*, Német-Hanzelik Andrea and György Keglevich

Volume 26, Issue 18, 2022

Published on: 27 December, 2022

Page: [1725 - 1733] Pages: 9

DOI: 10.2174/1385272827666221219114255

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Abstract

In medicinal chemistry, benzyloxy-benzaldehyde is a valuable intermediate, to which the attachment of a five membered heterocycle may be advantageous from the point of view of drug design. The starting iodo-benzyloxy-benzaldehydes were synthesized by the Obenzylation of o-, m- and p-hydroxybenzaldehydes with 2-, 3- and 4-iodobenzylbromides in refluxing acetone or acetonitrile in the presence of potassium carbonate and potassium iodide. Starting from the corresponding iodo-benzyloxy-benzaldehydes, the Suzuki-Miyaura carboncarbon cross-coupling reaction was utilized to get five membered heteroaryl-substituted benzyloxy- benzaldehydes. Various methods for Suzuki cross-coupling were studied. The applied boronic acids were 2- and 3-thiophene-boronic acids, as well as 2- and 3-furan-boronic acids. The reactions were followed by TLC and HPLC-UV-MS analysis. The products were purified by column chromatography. The original Suzuki method comprising NaOEt/EtOH, tetrakis(triphenylphosphine) palladium, in toluene was applied only in a few cases, resulting in poor yields. In several cases, the Suzuki coupling of substituted aryl iodides with 2-furanboronic acid failed to result in the formation of the expected products using the palladium acetate/tri(o-tolyl)phosphine/aqueous tripotassium phosphate/dimethoxyethan system. But reacting 3-thiophene-boronic acids with the corresponding iodo-benzyloxybenzaldehydes, this method afforded the products in 76-99% yields. The more powerful tetrakis(triphenylphosphine)palladium/aqueous cesium carbonate/ dimethylformamide system seemed to be more successful in cases of 2-thiophene boronic acid as well as 2- and 3-furan-boronic acids, providing the desired products in 75-93% yield. Twenty-six new compounds were synthesized.

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