Highly Stereoselective Synthesis of Isoindole Derivatives Containing an Azetidinone Ring

Abstract

Isoindole derivatives containing an azetidin-2-one moiety were prepared from phthalic anhydride by an approach that involves a [2π+2π] cycloaddition of an imine to a novel ketene generated in situ, and an electrocyclic reaction of a zwitterionic intermediate. The reactions were highly stereoselective and trans-β-lactams were obtained as the sole observed products.

Phthalic anhydride (PA): a valuable substrate in organic transformations

“…(114) in the presence of glacial acetic acid in reuxing dioxane (Scheme 40). 151 Simijonovic in 2020 described green aqua-mediated synthesis of benzamide-dioxoisoindoline derivatives (117) via the reaction of PA and benzoyl hydrazides (116) at 80 °C under ultrasonic irradiation. All compounds were subjected to experimental determination of their antioxidative potential.…”

“…The reaction was found to be highly stereoselective, and the trans -isomers of (E) were obtained as the only products ( Scheme 15 ). 117 …”

“…The reaction was found to be highly stereoselective, and the trans-isomers of (E) were obtained as the only products (Scheme 15). 117 Chandrasekhar and coworkers in 2009 identied (33) as an N-alkyl imide of PA from a microwave-assisted (450 W) procedure of polymer bound g-amino butyric acid (36) (1 mmol) and PA (1.25 mmol) in the presence of activated silica gel and TaCl 5 - SiO 2 (Scheme 16). 118 The organic product was isolated from the resin-silica mixture using TFA.…”

Intramolecular [2 + 2] Cycloadditions of Alkyl(phenylthio)ketenes: Total Synthesis of (+)-Sphaerodiol

“…It has been reported that activation of carboxylic acid with Mukaiyama’s reagent is superior to the corresponding acid chloride for the in situ generation of ketene and subsequent cyclization . Mukaiyama’s reagent (2-chloro- N -methyl­pyridinium iodide) is an effective reagent to generate ketenes in situ for subsequent [2 + 2] cycloadditions with alkenes, allenes, aldehydes, imines, and hydrazones . Although initial studies on the acid 3c with Mukaiyama’s reagent failed to yield desired intramolecular cycloadduct 4a , when the phenylthio-substituted acid 3d and 3f were added to a solution of Mukaiyama’s reagent and Et 3 N in refluxing CH 3 CN, cycloadducts 4b and 4f were obtained as single diastereomers in 70% and 62% yields, respectively (entries 4 and 6, Table ).…”