The photodecarboxylative addition of carboxylates to phthalimides as a key-step in the synthesis of biologically active 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones

Abstract

The synthesis of various 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones was realized following a simple three-step process. The protocol utilized the photodecarboxylative addition of readily available carboxylates to N-(bromoalkyl)phthalimides as a versatile and efficient key step. The initially obtained hydroxyphthalimidines were readily converted to the desired N-diaminoalkylated 3-arylmethylene-2,3-dihydro-1H-isoindolin-1-ones via acid-catalyzed dehydration and subsequent nucleophilic substitution with the corresponding secondary amines. The procedure was successfully applied to the synthesis of known local anesthetics (AL-12, AL-12B and AL-5) in their neutral forms.

Continuous Flow Photochemical and Thermal Multi-Step Synthesis of Bioactive 3-Arylmethylene-2,3-Dihydro-1H-Isoindolin-1-Ones

“…This procedure caused near complete isomerization to the Z-isomers, presumably via an acylaminium cationic intermediate [32]. The same isomerization was also observed during alternative column chromatographic purification of compounds 6a-e on silica gel [6].…”

“…Subsequent acid-catalyzed dehydration [16], followed by amination with the corresponding secondary amines (5) [17] yields the desired target compounds 6. Under batch conditions, the photodecarboxylation, dehydration, and amination steps were performed in three different solvents, i.e., acetone/pH 7 buffer, dichloromethane and DMF [6]. To avoid a switch of solvents under continuous flow conditions, a common solvent for all three reaction steps was desirable.…”

“…Under batch conditions, the photodecarboxylation, dehydration, and amination steps were performed in three different solvents, i.e., acetone/pH 7 buffer, dichloromethane and DMF [6]. To avoid a switch of solvents under continuous flow conditions, a common solvent for all three reaction steps was desirable.…”

“…The integrated assembly provided the desired target compounds 6a-e in good overall yields of 73%-77%, among them the local anesthetic AL-12 in its neutral form (entry II). The acidic workup conditions caused near complete conversion into the Z-stereoisomer of 6a-e (Z:E ≥ 9:1) [6].…”

“…Among the many synthetic pathways developed, the photodecarboxylative benzylation of phthalimides represents a mild and efficient access to these important target compounds [3,4]. Subsequently, this photobenzylation has been successfully applied as a key step in the synthesis of the cardiovascularly active AKS-186 and the local anesthetic AL-12 (Scheme 1) [5,6]. The syntheses protocols involved utilize conventional step-by-step batch procedures.…”