A-Methylglutaric anhydride

Pinho e Melo et al. (89) employed an intramolecular miinchnone cycloaddition to constmct several l/7-pyrrolo[l,2-c]thiazole derivatives from N-acylthiazolidines and acetic anhydride. Martinelli and co-workers (90,91) employed an intramolecular miinchnone cycloaddition to craft a series of 4-keto, 5,6,7-tetrahydroindoles (168-171) in two steps. The requisite acetylenic precursors were prepared from glutaric anhydride (or 3-methylglutaric anhydride). The overall sequence is illustrated for the synthesis of 168. An electrophilic acetylenic unit appears to be necessary for successful intramolecular 1,3-dipolar cycloaddition. 

The bis-fused 1,3-oxazepine derivative 35 can be made by treatment of amino alcohol 34 with the keto acid 33, the latter being prepared from a Grignard reaction with 3-methylglutaric anhydride. A 6 1 trans ds diastereomeric ratio was obtained with 35, which was then used in a new approach to a spiro heterocyclic system (Scheme 3) <2001SL1506>. 

Pure j3-methylglutaric anhydride melts at 46°.6 The jS-methylglutaric anhydride obtained in this preparation varies in its appearance at 25° from an almost completely crystalline mass to a mixture of about one-third solid and two-thirds liquid. However, the submitter has found that product of either appearance can be converted to methyl hydrogen /3-methylglutarate in 80-85% yield. Further purification is troublesome, and the product of the present procedure is pure enough for most purposes. 

S-Methylglutaric anhydride is obtained from the acid, which has been prepared by condensation of acetaldehyde with cyano-acetamide.7 8 The present method, which is a simplification of that published by Stallberg-Stenhagen,9 gives a higher yield and is much better adapted to the preparation of large quantities. 

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