Three-Component Reaction of Homophthalic Anhydride with Carbonyl Compounds and Ammonium Acetate: New Developments

The earlier described reaction of homophthalic anhydrides with aromatic ketones and ammonium acetate was tested for cyclic ketones (yielding spirocyclic motifs) and aliphatic aldehydes. In contrast to previous findings, the reaction was found to require no catalyst at all and to be applicable, in the non-catalyzed format, to these new carbonyl substrates as well as aromatic ketones. The reaction typically proceeds with high diastereoselectivity; if not, the initial diastereomeric mixture can be quantitatively equilibrated into a single, trans-diastereomer on treatment with aqueous base.

Aldazines in the Castagnoli–Cushman Reaction

Aldazines were employed in the Castagnoli–Cushman reaction of homophthalic anhydride for the first time. The reaction proved to be distinctly diastereoselective when conducted at room temperature in acetonitrile, yielding predominantly the kinetic cis-configured adduct as a racemate. Thermodynamically more stable trans-configuration could be attained either via heating the cis-configured product in DMSO or via the action of a base (imidazole) in the course of CDI-promoted esterification or amidation of the carboxylic acid function in the initial adducts. Further manipulation of the remaining N-acylhydrazone moiety in the latter led to N-alkyl- or fully unprotected N-aminolactams.

Facile Access to 3-Unsubstituted Tetrahydroisoquinolonic Acids via the Castagnoli–Cushman Reaction

Hitherto undescribed 3-unsubstituted tetrahydroisoquinolonic acids (isolated as their respective methyl esters) were accessed for the first time by the uncatalyzed, thermally promoted Castagnoli–Cushman reaction (CCR) of homophthalic anhydride (HPA) and a series of 1,3,5-triazinanes. The moderate yields observed in some cases are most likely associated with a persistent impurity also formed in these reactions. The new scaffold is expected to find novel medicinal utility (compared to the traditional CCR adducts) because it lacks a substituent at the 3-position.

A speedy route to sterically encumbered, benzene-fused derivatives of privileged, naturally occurring hexahydropyrrolo[1,2-b]isoquinoline

A series of 15 benzene-fused hexahydropyrrolo[1,2-b]isoquinolonic acids with substantial degree of steric encumbrance has been prepared via a novel variant of the Castagnoli–Cushman reaction of homophthalic anhydride (HPA) and various indolenines. The employment of a special kind of a cyclic imine component reaction allowed, for the first time, isolating a Mannich-type adduct between HPA and an imine component which has been postulated but never obtained in similar reactions.

The interaction of homophthalic anhydride with (triphenylphosphoranylidene)acetates

In the study of the interaction of homo­phthalic anhydride and methyl (triphenyl­phosphoranylidene)­acetate, along with (1-oxo-1H-isochromen-3‑yl)acetate obtaining, two minor products – (1,3-dioxo-1,2,3,4-tetrahydronaphthalene-2-yl)acetate and 2‑((1‑oxo-1H-isochromen-3-yl)methyl)benzoic acid – had been isolated. The action of tert‑butyl (triphenyl­phosphoranylidene)­acetate on homo­phthalic anhydride didn’t lead to Wittig reaction; the encumbered ylide demonstrated only its basicity, and products of homo­phthalic anhydride self-condensation – 2‑((1‑oxo-1H-isochromen-3-yl)methyl)-benzoic acid and 12-hydroxy-5H-dibenzo[c,g]chromen-5-one – were formed.