Lactone Enolates of Isochroman-3-ones and 2-Coumaranones: Quantification of Their Nucleophilicity in DMSO and Conjugate Additions to Chalcones.

Owing to stereoelectronic effects, lactones often deviate in reactivity from their open-chain ester analogues as demonstrated by the CH acidity (in DMSO) of 3-isochromanone (pKa = 18.8) and 2-coumaranone (pKa = 13.5), which is higher than that of ethyl phenylacetate (pKa = 22.6). We have now characterized the reactivity of the lactone enolates derived from 3-isochromanone and 2-coumaranone by following the kinetics of their Michael reactions with p-quinone methides and arylidenemalonates (reference electrophiles) in DMSO at 20 °C. Evaluation of the experimentally determined second-order rate constants k2 by the Mayr-Patz equation, lg k2 = sN(N + E), furnished the nucleophilicity parameters N (and sN) of the lactone enolates. By localizing their position on the Mayr nucleophilicity scale, the scope of their electrophilic reaction partners becomes predictable, and we demonstrate a novel catalytic methodology for a series of carbon-carbon bond-forming reactions of lactone enolates with chalcones under phase transfer conditions in toluene.

Nucleophilicity of 4-(Alkylthio)-3-imidazoline Derived Enamines.

Imidazolidine-4-thiones (ITOs) are cyclic, secondary amines that were considered as potential prebiotic organocatalysts for light-driven α-alkylations of aldehydes by bromoacetonitrile (BAN). Recent studies showed that the initially supplied ITOs represent the pre-catalyst because they undergo S-alkylation with BAN to give 4-(alkylthio)-3-imidazolines (TIMs). Given that the same reagent mix that undergoes light-driven α-alkylations is also effective in the dark, we synthesized ten ITO- or TIM-derived enamines of aldehydes and characterized their nucleophilic reactivities by kinetic studies in acetonitrile. The experimental second-order rate constants k2 for reactions of enamines with benzhydrylium ions (reference electrophiles) were evaluated by the Mayr-Patz equation, lg k2 (20 °C)=sN (N+E). The determined nucleophilicities N (and sN ) reveal the reactivity profiles of these enamines under prebiotically relevant conditions as well as their potential for use in organocatalytic synthesis.

The effect of S-alkylation on organocatalytic enamine activation through imidazolidine-4-thiones.

Imidazolidine-4-thiones have been suggested as potential prebiotic organocatalysts for light-driven α-alkylations of aldehydes by bromoacetonitrile. However, imidazolidine-4-thiones react with bromoacetonitrile to give S-cyanomethylated dihydroimidazoles. Kinetic studies show that enamines derived from these cyclic secondary amines and aldehydes are more nucleophilic than enamines derived from aldehydes and MacMillan organocatalysts.

Substituted α-Alkylidene Cyclopentenones via the Intramolecular Reaction of Vinyl Cations with Alkenes.

Substituted α-alkylidene cyclopentenones are formed in up to 93% yield by the intramolecular capture of vinyl cations with pendent alkenes. An increased level of substitution at the ß-position of the ß-hydroxy-α-diazoketone starting material changed the course of the reaction to instead give a lactone product. A reaction path that involves bond reorganization via an acylium ion intermediate is proposed to explain these results. Substrate scope studies showed that more stable vinyl cations gave higher α-alkylidene cyclopentenone yields. This study provides a mild and efficient method to form α-alkylidene cyclopentenones that complements C-H insertion and Nazarov cyclization strategies.

Migratory Aptitudes in Rearrangements of Destabilized Vinyl Cations.

The Lewis acid-promoted generation of destabilized vinyl cations from ß-hydroxy diazo ketones leads to an energetically favorable 1,2-shift across the alkene followed by an irreversible C-H insertion to give cyclopentenone products. This reaction sequence overcomes typical challenges of counter-ion trapping and rearrangement reversibility of vinyl cations and has been used to study the migratory aptitudes of nonequivalent substituents in an uncommon C(sp2) to C(sp) vinyl cation rearrangement. The migratory aptitude trends were consistent with those observed in other cationic rearrangements; the substituent that can best stabilize a cation more readily migrates. However, density functional theory calculations show that the situation is more complex. Selectivity in the formation of one conformational isomer of the vinyl cation and facial selective migration across the alkene due to an electrostatic interaction between the vinyl cation and the adjacent carbonyl oxygen work in concert to determine which group migrates. This study provides valuable insight into predicting migration preferences when applying this methodology to the synthesis of structurally complex cyclopentenones that are differentially substituted at the α and ß positions.

Remote C-H insertion of vinyl cations leading to cyclopentenones.

We report a Lewis acid catalyzed reaction sequence involving a 1,2-shift and subsequent C-H insertion that gives monocyclic and fused bicyclic cyclopentenone products. This reaction sequence, which is initiated by treating ß-hydroxy-α-diazo ketones with a Lewis acid, proceeds through vinyl cation intermediates that insert at non-activated gamma C-H bonds. This reaction represents an alternative strategy to exploit the diazo functional group in an intramolecular C-H insertion, and can provide products not accessible by transition metal catalyzed C-H insertions. This remote C-H activation process provides good yields of bicyclic cyclopentenone products that contain 7- and 8-membered rings, and monocyclic prostaglandin analogs.