Attempted use of 3-arylglutaconic acids in the three-component version of the Castagnoli–Cushman reaction with amines and aromatic aldehydes resulted in an unexpected formation of 4,6-diaryl 1,6-dihydropyridine-2­(3H)-ones. These are of interest as representatives of a rare heterocyclic chemotype for de novo biological investigation. Alternatively, these compounds can be oxidized into their 2-pyridone counterparts, stereoselectively reduced to give cis-configured 4,6-diaryl 2-piperidones, or isomerized to 5,6-dihydropyridin-2­(1H)-ones. All the three scaffolds are well represented in the bioactive compound domain.

Significant expansion of heterocyclic product space accessible by the Castagnoli-Cushman reaction (CCR) has been achieved via the use of glutaric anhydride analogues containing endocyclic substitutions with oxygen, nitrogen, and sulfur. Incorporation of these heteroatoms in the anhydride's backbone results in enhanced reactivity and generally lower temperatures that are required for the reactions to go to completion. These findings are particularly significant in light of the CCR recently recognized as an efficient tool for lead-oriented synthesis.

The earlier reported three-component Castagnoli–Cushman-type synthesis of 1,4,6-trisubstituted 1,6-dihydropyridin-2-(3H)-ones from 3-arylglutaconic acids, primary amines, and aromatic aldehydes has been further investigated. It was shown to proceed via 3-arylglutaconic anhydrides, which, in turn, were found to give superior results in the two-component reactions with imines. The initial formation of the Castagnoli–Cushman carboxylic acids was shown to be the case, and their decarboxylation was found to follow a complex, “forked” pathway, which was confirmed by deuterium incorporation experiments.

Unlike its trans counterpart, the cis-configured scaffold derived from the Castagnoli-Cushman reaction (CCR) is scarce and has not been explored in bioactive compound design. We found that conducting this reaction in DMF (in contrast to conventional toluene or xylene) led to a significantly higher proportion of cis-configured lactams in the diastereomeric product mixture. This allowed us, for the first time, to obtain and thoroughly characterize both stereoisomers of a significant number of lead-like CCR lactams. Simple rules for 1 H NMR-based stereochemical assignment have been devised and correlated with the single-crystal X-ray structures obtained for pure cisand transconfigured lactams.Scheme 1 Castagnoli-Cushman reaction of succinic and glutaric anhydrides.

The first application of multicomponent chemistry (the Castagnoli-Cushman reaction) toward the convenient one-step preparation of cyclic hydroxamic acids is described. Cyclic hydroxamic acids are close analogues of bacterial siderophores (iron-binding compounds) and form stable complexes with Fe ions as confirmed by spectrophotometric measurements. These compounds are potential components for the design of chelating agents for iron overload disease therapy, as well as siderophore-based carrier systems for antibiotic delivery across the bacterial cell wall.