REACTION OF ORTHO-PHTHALALDEHYDE AND THIOLS WITH PRIMARY AMINES - FORMATION OF 1-ALKYL(AND ARYL)THIO-2-ALKYLISOINDOLES

The fluorogenic reaction of o-phthalaldehyde (OPTA) and β-mercaptoethanol (MERC) with primary amino acids gives a l-alkylthio-2-alkylisoindole as the product. The structure of this group of previously unknown isoindoles was determined (1) from an in situ analysis of the adducts formed in solution from OPTA, MERC or ethane-thiol (ET), and n-propylamine, (2) from the characterization of solid derivatives of these MERC and ET adducts, and (3) from the studies of two isolable isoindoles (an OPTA/tert-butylthiol/n-propylamine adduct and a dimeric adduct formed from OPTA, ethanedithiol, and n-propylamine). The reaction is found to be quite general as OPTA and numerous thiols rapidly react with n-propylamine or leucine to give isoindoles in excellent yield. Most adducts were not isolated, but their physical properties in solution were qualitatively identical with those of the tert-butyl and dimeric ethanedithiol adducts. Analyses of the chemical shifts of the isoindole alkyl substituents in the NMR spectra support the previous conclusions that these heterocycles have relatively low levels of aromatic character. The addition sequence of the reaction is important; the best results are obtained by mixing OPTA and thiol before adding the amine. With some thiols, this procedure results in the initial formation of a l-alkylthio-3-hydroxy-l,3-dihydroisobenzofuran. However, these 1:1 adducts do not appear to be obligatory intermediates in the subsequent reaction with primary amines to form 1-thio-substituted isoindoles. © 1978, American Chemical Society. All rights reserved.