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

Abstract

SummaryAn 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.

The Solvatofluorochromism of 2,4,6‐Triarylpyrimidine Derivatives

“…Two synthetic approaches for building the pyrimidine ring in compounds like diazines 1a–g have been described. The first of them employs condensation reactions from carbonyl and carbonyl‐masked compounds of already functionalized starting materials. The second approach, a more flexible one, is based on the use of palladium‐catalyzed cross‐coupling reactions of chloropyrimidines or pseudohalide derivatives .…”

Synthesis of highly functionalized 2,2'-bipyridines by cyclocondensation of β-ketoenamides – scope and limitations

“…As mentioned above β-ketoenamide 3i is a good precursor for 2,2´-bipyridine derivative 4i , but Scheme 4 also reveals that this intermediate could be converted into the expected pyrimidine derivative 7 by treatment with ammonium acetate [48–50] or into pyrimidine N -oxide 8 by employing hydroxylamine hydrochloride [51–52]. These products of simple condensation reactions may be regarded as azabipyridine derivatives and their synthesis demonstrates the versatility of β-ketoenamide such as 3i for the synthesis of highly functionalized heterocycles.…”

Recent Approaches to the Synthesis of Pyrimidine Derivatives

“…However, the authors showed that the alkoxy group could serve for post‐functionalization cross‐coupling reactions and that the methyl group could be efficiently oxidized to a carbaldehyde function. Other developments of this methodology include the use of α,β‐unsaturated carboxylic acids in the Flögel synthesis, as well as of dicarboxylic acids, which resulted in the preparation of conjugated bis(pyrimidine) derivatives …”