The lithiation of various methyl substituted isoxazoles, isothiazoles, pyrazoles, oxadiazoles, and thiadiazoles using 11-butyllithi~in~ has been studied. Three types of reactions, namely, lateral lithiation, ring cleavage, and addition of butyllithium to the ring, have been found. 3,5-Din~ethylisoxazole, 3-phenyl-5-n~ethylisoxazole, 3,4-dimethyl-1,2,5-oxadiazole, 2,5-dimethyl-l,3,4-thiadiazole, 3-phenyl-5-methyl-l,2,4-oxadiazole, and 3,5-dimethyl-l,2,4-thiadiazole all undergo lateral lithiation to give the respective acetic acids after carboxylation. I-Methyl-3,5-disubstituted pyrazoles form the I-lithiomethyl derivatives, while 1-phenyl-3,5-disubstituted pyrazoles are converted to the 1-ortholithiophenyl-3.5-disubstituted pyrazoles. 4-Methylisothiazole is lithiated nlainly at C-5, but also suRers ring cleavage to form I-tr-butylthio-2-cyanoprop-I-ene. Heteroaromatic compounds containing an N-S bond, such as 3,4-diiiiethyl-l,2,5-thiadiazole, 4-111ethyl-5-pl1enyl-l,2,3-thiadiazole, and 3,5-dimetl~ylisothiazole, undergo n~icleophilic attack at sulfur with resulting ring cleavage. 3,5-Din~ethylisothiazole produces 2-11-butylthiopent-2-en-4-one. 3-Methyl-5-phenyl-l,2,4-oxadiazole gave 3-niethyl-5-phenyl-5-1z-butyl-l,2,4-dih~-drooxadiazole by addition to the azon~ethine bond. The res~ilts of these lithiations are discussed. 3-Methyl-5-lithiomethylisoxazole was converted to various derivatives. Nuclear magnetic resonance spectral analysis was used to establish the identity of the products.Canadian Journal of Chemistry, 48, 2006Chemistry, 48, (1970 In connection with our work on semisynthetic 3-Methyl-5-lithiomethylisoxazole (2) was used penicillins (1), we required various five-membered as an example to study further synthesis with this heteroarylacetic acids. These acids have usually class of compound. Scheme 1 illustrates these been made by multistage processes (see for reactions. example refs. 1-4). It occurred to us that some of An Ivanov-type reagent (19) could be obtained the methyl substituted heteroaromatic com-from 3 and two equivalents of butyllithium. pounds would undergo lateral metalation with Reaction with methyl iodide gave 3-methylbutyllithium and that these lithioderivatives with isoxazole-5-a-methylacetic acid (4) in 70 % yield.carbon dioxide would form the desired acetic The structure of this acid was established acids. These lithiomethyl compounds could also unequivocally by elemental analysis, infrared give rise to other derivatives.(i.r.), and nuclear magnetic resonance (n.m.r.) Although the lateral metalation of six-spectral analysis. The thioketeneacetal 6 and the membered heteroaryl compounds has been in-'dimer' 7 are conveniently prepared from 2. vestigated (5-13), this reaction has not been applied to the simple five-membered heteroaromatic compounds, except for the thiazoles (14) and certain isoxazoles (15).
The IsoxazolesBowden et al. (15) have shown that while 3-methoxy-4,5-dimethylisoxazole is lithiated exclusively at the C5-methyl group, 3-methoxy-5-methylisoxazole reacts with butyll...