1-Lithio- and 1,3-Dilithioisobenzofuran: Formation and Reactions with Electrophiles

Article abstract of DOI:10.1021/jo00176a017

The acetal 1 reacts with 1 equiv of alkyllithium in the presence of catalytic diisopropylamine to form isobenzofuran (2), which with an additional equivalent of alkyllithium gives 1-lithioisobenzofuran (3).Solutions of 3 have been treated with various electrophiles and the resulting products characterized by NMR and as cycloadducts formed on addition of dienophiles.Lithiation of 2 occurs cleanly at C-1, as shown by quenching with D2O.Both the metalation and subsequent alkylation reactions are more rapid in THF than in ether.Reaction of 3 with CH3I gives 1-methylisobenzofuran (6) as the major product, accompanied by some 1,3-dialkylated material.Further treatment of 6 with alkyllithium results in specific lithiation at C-3 to give 14, as demonstrated by deuteration and analysis of cycloadducts by 2H NMR.Ethylation of 14 gives 1-ethyl-3-methylisobenzofuran, illustrating the feasibility of a one-pot procedure for preparing unsymmetrically disubstituted isobenzofurans.Dilithiation of 2 occurs when excess base is employed in THF, and this allows the direct formation of some symmetrical 1,3-disubstituted isobenzofurans.The 1-alkyl- and 1,3-dialkylisobenzofurans are moderately stable in neutral or mildly basic solution, resembling the parent 2 in this respect.Exchange reactions demonstrate that isobenzofuran is more acidic than both furan and diisopropylamine.