Dimerization and comments on the reactivity of homophthalic anhydride

Abstract

Homophthalic anhydride (HPA) dimerizes under the influence of base to provide, sequentially, the (3-4’)-C-acyl dimer, a pair of chiral diastereomeric bis(lactones), 3-(2-carboxybenzyl)isocoumarin-4-carboxylic acid, and finally, 3-(2-carboxybenzyl)isocoumarin. The structures of the bis(lactones) were misassigned in 1970 based on the (presumed) cis thermal decarboxylative elimination reaction of the lower melting one. The preferred pathway should be trans-anti, however, and crystallographic analysis of one of the bis(lactones) reverses the earlier assignment. The formal cycloaddition reaction of HPA with imines occurs in preference to HPA dimerization; the mechanistic implications of this reactivity difference are discussed.

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

“…Any appreciable conversion led to predominant formation of HPA dimer 11 and product of its decarboxylation 12 ( Scheme 1 ). The formation of these two products (observed by 1 H NMR) was recently reported by Knapp et al [ 35 ] as a result from the treatment of HPA with a strong base (which was absent in our case). The failure to activate sterically hindered indolenines toward the CCR using forcing conditions justifies conducting the reaction at room temperature, which led to clean conversions and good product yields despite the excruciatingly long reaction times ( Table 1 , entries 14 and 15).…”

Stereochemistry and reactivity of the HPA-imine Mannich intermediate

“…Organization of the reaction components 2 and 3 by an intermolecular hydrogen bond 13,22 could take place in two different configurations (Scheme 2). The “boat” configuration ( 7 ) places the aryl group away from the benzo ring, and ought to be favored for small N-substituents R .…”

“…For the electron-withdrawing trifluoroethyl N-substituent ( 23 → 24 ), prior N-protonation of the imine would not be favored, but the hydrogen-bonded pathway could still be operative without showing a clear stereochemical preference. 22 The cis, cyclic imines 29 and 31 could proceed through the open transition state of Scheme 3 without showing a strong stereochemical preference, since steric hindrance is reduced for both possibilities. Addition of a sub-stoichiometric amount of trifluoroacetic acid increased the amount of trans isomer 30 slightly.…”

“…Despite earlier considerations of alternative mechanisms, 2,14,21 more recent analysis of the HPA-imine reaction seems to have settled on a two-step process centered on Mannich-type amino-anhydride intermediate 5 , 3,13,15,22 the stereochemistry of which translates to the C-3 and C-4 stereocenters of the THIQ product. Under certain conditions, elimination of amine from 5 to afford a Knoevenagel-type alkene product 6 has been observed.…”

Tautomers of homophthalic anhydride in the ground and excited electronic states: analysis through energy, hardness and vibrational signatures

“…It is a wellknown oxygen heterocycle, considered a structural motif for a variety of natural products [16]. These are extensively used in pharmacology [17,18] for various activities including its specific use as a precursor of an antimalarial drug [19]. The antioxidant properties of one of its derivatives, 4-acyl isochroman-1, 3-diones, are well established by Saba et al [20].…”