New synthesis of substituted isoindolines from furans via epoxyisoindolines

Abstract

The preparation of substituted N‐arylisoindolines 3 from simple furan derivatives 1 is reported. Oxatricycloadducts 2, readily accessible by intramolecular Diels‐Alder reaction are susceptible to acidic reagents yielding aromatized products 3 by a ring‐opening reaction via intermediate carbocation.

New compounds in ring‐opening reaction of 5‐substituted epoxyisoindolines

“…Under the same reaction conditions but with alumina instead of silica gel, the mixture of 3a (70%) and 4a (15%) was obtained. Separated hydroxyenone 4a was successfully aromatized by heating of the solution in the mixture of hydrobromic and acetic acid, with the yield comparable to those reported for direct reaction of 2a to 5a [3]. Hydroxyenones 4a and 4b obtained during the present reinvestigation were duly characterized by elemental analyses, ir, nmr and mass spectra.…”

“…From the dried etheral solution 5a was isolated on a silica gel column protected from light, using petroleumether/ether 5:1 as eluent. Colorless crystals (43 mg, 95%) melting at 159-160 °C proved to be identical with the original sample [3] by the comparison of their elemental analysis, ir, nmr and mass spectra. -4-methyl-5-nitro-3a,4,5,7a-tetrahydro-5,7a-epoxyisoindoline (6) with Hydrobromic Acid/Acetic Acid Mixture.…”

“…To explain the presence of the undoubtedly confirmed 5-hydroxy group in 10 and 11 we tentatively suggest the ring-opening reaction under nucleophylic attack at C7a [3,5], with formation of the corresponding very unstable geminal hydroxy-nitro intermediate, which possibly could lead to aromatized compounds 10 and 11. On the other hand, the attack at C7a and the ring-opening reaction, in case of saturated 7-bromo epoxy-compounds 8 and 9 must be more or less suppressed by the vicinity of bromine, preventing the expected aromatization and making possible the isolation of the corresponding 5-nitro-hexahydroepoxyisoindoline.…”

“…Recently we suggested a useful procedure to convert simple furans to substituted isoindolines via epoxyisoindolines (Scheme 1) [3]. The process includes the intramolecular Diels-Alder reaction of tertiary N-alkenyl-N-aryl-2furfurylamine [4] and subsequent aromatization of the formed oxatricycloadduct through the ring-opening reaction [5] by hydrobromic acid in glacial acetic acid.…”

“…The early example of intramolecular [4+2]cycloaddition with simple furans, that is N-alkenyl-N-aryl-N- (2furfuryl)amines, was reported from our laboratory more than three decades ago [6a]. Since that time the IMDAF reaction has been used by us [3,4,7] and others [8] as a simple synthetic step towards nitrogen containing heterocycles and for studies of substituent effects in cyclization reactions. Further reactions which include the epoxy-bridge of IMDAF adducts may lead to sometimes rare heterocycles or natural products difficult to approach by other procedures.…”