The Flögel-three-component reaction with dicarboxylic acids – an approach to bis(β-alkoxy-β-ketoenamides) for the synthesis of complex pyridine and pyrimidine derivatives

Mrinal K Bera,Moisés Domínguez,Paul Hommes,Hans-Ulrich Reissig

doi:10.3762/bjoc.10.37

Mrinal K Bera, Moisés Domínguez + Show 2 more

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https://doi.org/10.3762/bjoc.10.37

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Abstract

An extension of the substrate scope of the Flögel-three-component reaction of lithiated alkoxyallenes, nitriles and carboxylic acids is presented. The use of dicarboxylic acids allowed the preparation of symmetrical bis(β-ketoenamides) from simple starting materials in moderate yields. Cyclocondensations of these enamides to 4-hydroxypyridine derivatives or to functionalized pyrimidines efficiently provided symmetrically and unsymmetrically substituted fairly complex (hetero)aromatic compounds containing up to six conjugated aryl and hetaryl groups. In addition, subsequent functionalizations of the obtained heterocycles by palladium-catalyzed couplings or by oxidations are reported. We also describe the simple synthesis of a structurally interesting macrocyclic bispyrimidine derivative incorporating a 17-membered ring, whose configuration was elucidated by DFT calculations and by subsequent reactions.

Highlights

Multicomponent reactions (MCRs) generally allow a diversityoriented fast and efficient access to complex synthetic intermediates and are powerful tools for the assembly of smallmolecule libraries [1,2]
MCRs leading to functionalized N-heterocycles [3,4,5,6,7] have long been known before the general concept of MCRs was introduced, e.g. the Hantzsch dihydropyridine synthesis [8] or the Biginelli reaction [9] leading to dihydropyrimidinones or the corresponding dihydropyrimidinethiones
In the course of exploring the reactivity of alkoxyallenes and their utilization as C-3 building blocks [34,35,36,37] our group developed a highly flexible method to synthesize β-alkoxy-β-ketoenamides of type 1 that are remarkably versatile cyclization precursors for the synthesis of functionalized heterocycles such as 4-hydroxypyridines [38,39,40,41,42,43,44], furopyridines [45], 5-acetyloxazoles [46,47], pyrimidines [43,48,49] and their corresponding N-oxides [50] (Scheme 1). This approach – discovered and mechanistically elucidated by Oliver Flögel – features a three-component reaction that employs alkoxyallenes, nitriles and carboxylic acids: upon treatment with n-butyllithium the allene is lithiated in α-position to the alkoxy moiety; the addition of a nitrile as electrophile to this highly reactive nucleophile results in the formation of an iminoallene adduct [38] that is protonated and subsequently acylated by the addition of a carboxylic acid furnishing a β-alkoxy-β-ketoenamide 1

Summary

Introduction

Multicomponent reactions (MCRs) generally allow a diversityoriented fast and efficient access to complex synthetic intermediates and are powerful tools for the assembly of smallmolecule libraries [1,2]. In the course of exploring the reactivity of alkoxyallenes and their utilization as C-3 building blocks [34,35,36,37] our group developed a highly flexible method to synthesize β-alkoxy-β-ketoenamides of type 1 that are remarkably versatile cyclization precursors for the synthesis of functionalized heterocycles such as 4-hydroxypyridines [38,39,40,41,42,43,44], furopyridines [45], 5-acetyloxazoles [46,47], pyrimidines [43,48,49] and their corresponding N-oxides [50] (Scheme 1) This approach – discovered and mechanistically elucidated by Oliver Flögel – features a three-component reaction that employs alkoxyallenes, nitriles and carboxylic acids: upon treatment with n-butyllithium the allene is lithiated in α-position to the alkoxy moiety; the addition of a nitrile as electrophile to this highly reactive nucleophile results in the formation of an iminoallene adduct [38] that is protonated and subsequently acylated by the addition of a carboxylic acid furnishing a β-alkoxy-β-ketoenamide 1. A detailed mechanistic proposal for this reaction has been disclosed in previous reports [38,39]

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