Abstract
A convenient and general method for the direct synthesis of 2-aryl-6-(trifluoromethyl)-4-pyrones and 2-aryl-5-bromo-6-(trifluoromethyl)-4-pyrones has been developed on the basis of one-pot oxidative cyclization of (E)-6-aryl-1,1,1-trifluorohex-5-ene-2,4-diones via a bromination/dehydrobromination approach. This strategy was also applied for the preparation of 2-phenyl-6-polyfluoroalkyl-4-pyrones and their 5-bromo derivatives. Conditions of chemoselective enediones bromination were found and the key intermediates of the cyclization of bromo-derivatives to 4-pyrones were characterized. Synthetic application of the prepared 4-pyrones has been demonstrated for the construction of biologically important CF3-bearing azaheterocycles, such as pyrazoles, pyridones, and triazoles.
Highlights
4-Pyrone unit is an important heterocyclic motif, which is frequently present in numerous natural products that exhibit a wide range of important biological activities [1,2,3,4,5] and medicines, such as phenoxan [5] (Figure 1)
The ring-opening reactions of 2-RF-4-pyrones can be applied for the preparation of a wide range of trifluoromethylated azaheterocycles, such as indoles, regioisomeric pyrazoles, pyridines, benzodiazepines etc., [14,16,17,18]
We have developed a general method for the preparation of 2-aryl-6-polyfluoroalkyl-4-pyrones and their 3-bromo derivatives based on one-pot cyclization through the stage of bromination/dehydrobromination of enediones
Summary
4-Pyrone unit is an important heterocyclic motif, which is frequently present in numerous natural products that exhibit a wide range of important biological activities [1,2,3,4,5] and medicines, such as phenoxan [5] (Figure 1). The methods for the construction of 4-pyrones are actively developed, and in the literature there are three general approaches for the synthesis of 2-RF-4-pyrones based on (i) cyclization of tricarbonyl compounds or their derivatives prepared via Claisen condensation [19,20,21,22], (ii) cycloadditions of ketenes [23,24,25], and (iii) modification of substituted 2-RF-4-pyrones (usually for carboxylic acid derivatives) via side-chain transformations [26] (Scheme 1). Similar approach is the use of dibromo derivatives, which can react as synthetic equivalents of acetylenyl-1,3-diketones and undergo dehydrobromination reactions under basic conditions [34,35,36,37] This method was applied for the preparation of 2-aryl-4-pyrones bearing the methyl and carboethoxy substituents. The synthetic potential of the pyrones was demonstrated on the example of regioselective reactions with N-nucleophiles
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