Methylglutaric Anhydride

Triethyl 2-methyl-l,1,3-propanetricarboxylate (not isolated). A 1-1. three-necked flask is fitted with a mechanical stirrer, a reflux condenser protected by a calcium chloride tube, and a 250-ml. dropping funnel. All parts of the apparatus should be scrupulously dry. Three hundred milliliters of anhydrous ethanol (Note 1) is placed in the flask, and 14.1 g. (0.61 g. atom) of clean sodium, cut in pieces as large as will easily pass through a neck of the flask, is added rapidly. The neck of the flask is immediately closed, and the mixture is stirred until all the sodium has dissolved the cooling bath is removed, and heat is applied if the reaction becomes sluggish at the end. 

0-Methylglutaric anhydride. The residue described above is cooled in an ice bath during the successive addition of 200 ml. of water and 450 ml. of concentrated hydrochloric acid. The resultant mixture is heated under reflux, with stirring, for 8 hours (Note 4). The condenser is again set for distillation, the bath temperature is raised, and, with continued stirring, water and alcohol are distilled. The bath is finally heated to 180-190° until gas evolution ceases (usually about 1 hour). 

The stirrer is removed, 125 ml. of technical acetic anhydride is added to the residue, and, after thorough mixing, the mixture is heated on a steam bath for 1 hour. The condenser protected by a calcium chloride tube is left attached, and the other necks of the flask are closed. At the end of the heating period salt is removed from the cooled reaction mixture by filtering it with suction, using a filter aid mat, into a 250-ml. Claisen flask. The reaction vessel and filter are washed with a few milliliters of acetic acid. 

The combined filtrate and washings are distilled at reduced pressure, using a water pump, until all acetic acid and acetic anhydride have been removed. An oil pump is then connected, 

Commercial absolute ethanol from a freshly opened bottle is often satisfactory. Otherwise it can be dried by treatment with sodium,2 sodium ethoxide and diethyl phthalate,3 magnesium methoxide,4 or aluminum ferCbutoxide.6 

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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>. 

METHYL-2-EDROIC ACID, 39, 46 /3-Methylglutaraldehyde, 34, 72 35,88 3-Methylglutaric acid, 36, 88 3-METHYLGLUTARIC ANHYDRIDE, 38, 52 M ETH YLGLYOXAL-u-PHE X YLHYDRA-... 

Pure 8-methylglutaric anhydride melts at 46°. The /3-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. 

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