Stereochemistry of Lithium Dialkylamide Induced 1,4-Eliminations Leading to Substituted Isobenzofurans

Article abstract of DOI:10.1021/jo00370a019

The O-ethylation of 3-methyl- and 3-phenylphthalide followed by borohydride reduction was used to prepare cis/trans mixtures of 1,3-dihydro-1-ethoxy-3-methyl(or phenyl)isobenzofuran.The cis isomer is formed preferentially, presumably due to steric interference of hydride attack by the 3-substituent.Equilibrium mixtures of the 1-methoxy analogues, formed by acid-catalyzed transacetalization in methanol, slightly favor the trans isomer.Stereochemical assignments were made on the basis of long range coupling constants and difference NOE spectra.The stereochemistry of lithium diisopropylamide induced 1,4- elimination was examined with mixtures of cis/trans isomers, and preference for syn elimination was found for both the 3-phenyl and 3-methyl acetals.However, both isomers of each substrate react to form the isobenzofurans, showing that a formal anti elimination pathway is also energetically accessible.The LiNR2 reaction of the 3-phenyl acetal has been used to prepare 1-phenylisobenzofuran; although isolable, this material is very reactive, more closely resembling the unsubstituted parent than 1,3-diarylisobenzofurans in this regard.The base-induced (anti) elimination of the cis 3-methyl acetal is much slower than the reactions of the other substrates examined in this study, allowing recovery of pure cis isomer from incomplete reactions of cis/trans mixtures.When resubjected to base, however, this isomer also slowly formed 1-methylisobenzofuran.Lithation of the unsubstituted furan site occurs with these isobenzofurans, as shown by quenching with trimethylsilyl chloride and further characterization of silylated derivatives.Reaction of the 3-methyl acetal in the presence of trimethylsilyl chloride with lithium tetramethylpiperidide causes trimethylsilylation of both the furan site and the methyl group.After cycloaddition, the bridgehead silyl group was selectively removed by treatment with a fluoride ion source.The O-ethyl-3-substituted-phthalidium tetrafluoroborate salts were converted to the diethyl orthoesters by addition to alkoxide solutions.The standard Meerwein procedure (NaOR in ROH) is suitable for the 3-methyl derivative, but preparation of the 3-phenyl orthoester requires the use of aprotic conditions.LiNR2-induced eliminations were used to generate 1-alkoxy-3-methyl(or phenyl)isobenzofurans.Treatment of the 1-ethoxy-3-methylisobenzofuran with methanol gave, by preferred syn 1,4-addition, the cis-1-ethoxy-trans-1-methoxy orthoester.The opposite stereoisomer was prepared by similar syn 1,4-addition of ethanol to the 1-methoxyisobenzofuran analogue.The stereoisomerically enriched orthoesters synthesized in this manner were used to study the stereochemistry of the base-induced 1,4-elimination, which was found to occur with high syn selectivity.