Abstract

The LANCA three-component reaction of lithiated alkoxyallenes LA, nitriles N and carboxylic acids CA leads to β-ketoenamides KE in good to excellent yields. The scope of this reaction is very broad and almost all types of nitriles and carboxylic acids have successfully been used. The alkoxy group introduced via the allene component is also variable and hence the subsequent transformation of this substituent into a hydroxy group can be performed under different conditions. Enantiopure nitriles or carboxylic acids can also be employed leading to chiral KE with high enantiopurity and dinitriles or dicarboxylic acids also lead to the expected bis-β-ketoenamides. β-Ketoenamides incorporate a unique combination of functional groups and hence a manifold of subsequent reactions to highly substituted heterocyclic compounds is possible. An intramolecular aldol-type condensation reaction efficiently furnishes pyridin-4-ols PY that can be further modified by palladium-catalyzed reactions, e.g., to specifically substituted furopyridine derivatives. Condensations of β-ketoenamides with ammonium salts or with hydroxylamine hydrochloride afford pyrimidines PM or pyrimidine N-oxides PO with a highly flexible substitution pattern in good yields. The functional groups of these heterocycles also allow a variety of subsequent reactions to various pyrimidine derivatives. On the other hand, acid-labile alkoxy substituents such as a 2-(trimethylsilyl)ethoxy group are required for the conversion of β-ketoenamides into 5-acetyl-substituted oxazoles OX, again compounds with high potential for subsequent functional group transformations. For acid labile β-ketoenamides bearing bulky substituents the acid treatment leads to acylamido-substituted 1,2-diketones DK that could be converted into quinoxalines QU. All classes of heterocycles accessed through the key β-ketoenamides show a unique substitution pattern – not easily accomplishable by alternative methods – and therefore many subsequent reactions are possible.

Highlights

  • Multicomponent reactions are known to create unique product skeletons in an atom economic, efficient and time saving fashion

  • During the exploration of alkoxyallene chemistry [11,12,13,14,15,16,17,18,19,20] we accidently discovered a new three-component reaction leading to β-ketoenamides that are uniquely functionalized alkenes and suitable for a variety of subsequent reactions, in particular in heterocyclic synthesis

  • By brief heating with trifluoroacetic acid β-ketoenamides KE with acid-labile alkoxy substituents OR1 underwent an unexpected formation of 5-acetyl-substituted oxazole derivatives OX (Scheme 22) [42,45]. This useful transformation proceeds with benzyloxy, p-methoxybenzyl, 2-tetrahydropyranyl- and 2-(trimethylsilyl)ethoxy-substituted β-ketoenamides KE as precursors and - mainly depending on the size of substituent R2 oxazoles OX and/or the simple hydrolysis products 1,2-diketones DK were isolated in moderate to excellent yields (Table 6)

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Summary

Introduction

Multicomponent reactions are known to create unique product skeletons in an atom economic, efficient and time saving fashion. The first reaction shown in Scheme 1 gave a mixture of β-ketoenamide 5 and its subsequent cyclization product pyridin-4-ol 6 in low yields. Scheme 4: Synthesis of β-ketoenamides KE by the LANCA three-component reaction of alkoxyallenes, nitriles and carboxylic acids.

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