Synthesis of functionalized hydroxyphthalides and their conversion to 3-cyano-1(3H)-isobenzofuranones. The Diels-Alder reaction of methyl 4,4-diethoxybutynoate and cyclohexadienes

Abstract

Several methods have been used in the preparation of functionalized hydroxyphthalides. Metalation of jV,lV-diethyl-3-methoxybenzamide, followed by reaction with dimethylformamide and hydrolysis, furnished 3-hydroxy-4-methoxy-l(3ii)-isobenzofuranone in 52% yield. Reaction of the metalation product of m-fluorobenzaldehyde dimethyl acetal with carbon dioxide, followed by hydrolysis, gave 3-hydroxy-7-fluoro-l(3if)-isobenzofuranone in 86% yield. Especially noteworthy is the excellent metalation result with fluorine as a directing group. However, metalation of 2,5-dimethoxybenzaldehyde dimethyl acetal followed by reaction with carbon dioxide gave 2,5-dimethoxy-4-formylbenzoic acid (62%), not the corresponding hydroxyphthalide. The key step in the preparation of the remaining hydroxyphthalides was the Diels-Alder reaction of methyl 4,4-diethoxybutynoate with 1,3-and 1,4-cyclohexadienes, followed by in situ aromatization with loss of ethylene. Hydrolysis of the resulting products furnished functionalized hydroxyphthalides in good yields. Conversion of the above hydroxyphthalides to their corresponding 3-cyano-l(3fí)-isobenzofuranones could not be conveniently effected by literature procedures. However, a unique procedure for cyclization of the corresponding cyanohydrins using oxalyl chloride and dimethylformamide did lead to a good preparation of the above mentioned systems.

Tandem reversible addition–intramolecular lactonization for the synthesis of 3-functionalized phthalides

“…23,24 Although the functionalized phthalides 3a-c are the most commonly used precursors in Hauser-Kraus annulations, there are only a few reports of synthetic modifications of these compounds. 18,19,25,26 In the present study, a new synthetic strategy is proposed for efficient formation of phthalides 3a and 3c. In this strategy, the advantage of using multi-step reactions of combined reversible-and irreversible processes in a single operation have been explored.…”

A multiply convergent platform for the synthesis of trioxacarcins

“…4-Methylsalicylic acid (13, 50 g) was transformed in a sequence of five chemical transformations using conventional synthetic techniques and a single, final chromatographic purification step to afford the 3,4-disubstituted salicylamide 15 in 74% yield (57 g). Protection of the phenolic hydroxyl group as a methoxymethyl ether and subsequent directed metalation-formylation (29) (30,31).…”

Oxalyl Chloride: A Versatile Reagent in Organic Transformations

“…After a couple of years, the Stadler's method was employed to cyclize the corresponding cyanohydrins 156 for the good preparation of a number of substituted derivatives of 3‐cyano‐1(3 H )‐isobenzofuranones 157 (Scheme ) …”