Acetylene phthalide

A highly efficient synthesis of l-alkylidene-13-dihydroisobenzofurans and 3-alkylidene isobenzofuran-l(3//)-ones (phthalides) through Pd-Cu-catalysis using acetylenic carbinols as synthons was reported <99SL456>. 

A dimethyl 1-naphthol-2.3-dicartx)xylate compound has been synthesised from phthalide. Thus 2-methoxyphenyllithium, prepared from 2-bromoanisole and n-butyllithium, was reacted with phthalide in tetrahydrofuran solution at -78°C during 30 minutes and after the reaction mixture had attained ambient temperature during a further 30 minutes, 4 moles of dimethyl acetylene (DMAD) in dichloromethane were introduced. Following completion of reaction overnight, and removal of excess reagent, the crude product was aromatised by refluxing for 4 hours with a benzene solution of toluenesulphonic acid to afford dimethyl 1 -hydroxy-4-(2-methoxyphenyl)naphthalene-2,3-dicarboxylate (ref.53). 

Chiral 3-substituted phthalides are central structures in a number of biologically active compounds. The synthesis of chiral phthalides has been achieved by Witulski and Zimmerman, starting with enantiopure substituted propargylic alcohols 409 (Scheme 2-38). The chiral ester-linked diyne 410 was cyclotrimerized with acetylene by using RhCl(PPh3)3 as the catalyst to afford enantiopure phthalides 411 in good yields. 

Chiral 3-substituted phthalides were synthesized by RhCl(PPh3)3-catalyzed [2-I-2-I-2] cycloaddition of chiral ester-linked 1,6-diynes with acetylene without racemization (Scheme 4.25) [32]. 

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