The syntheses and reactivity of 6- and 8-azaindolizines.

Shand, Charles Alexander

Abstract

Synthetic routes leading to indolitine and its mono-aza derivatives, and the reactivity of these systems have been briefly reviewed. A number of simple alkyl, aryl, methoxy and chloro substituted 6- and 8- azaindolizines have been synthesised via the Chichibabin reaction between suitably-substituted 2- or 4- methylpyrimidines and alpha-bromo ketones. The structures of the products obtained have been confirmed spectroscopically, principally by 'H NMR spectroscopy, and by formylation procedures. The reaction between 2,4,6-trimethylpyrimidine and phenacyl bromide has been showm to yield a 6-azaindolizine structure rather than an 8-azaindolizine structure as previously reported. The reaction between 2-methylpyrimidine and ethyl bromopyruvate gave 2-carbethoxy-8-azaindolizine, which gave the parent 8-azaindolizine system on hydrolysis and decarboxylation. Formylation of 6-azaindolizines bearing a C-5 methyl group gave - along with their formyl derivatives - 5-azacycl[3,2,2]azine structures, which were also synthesised by 1,3-dipolar addition reactions betvieen dimethyl acetylenedicarboxylate and 6- or 8- azaindolizines. An examination of the 'H NMR spectra of 6- and 8- azaindolizines in trifluoroacetic acid showed both systems to have a preference for protonation at their non-bridgehead nitrogen atoms, although partial carbon protonation at C-3 was observed in a number of alkyl derivatives. The protonation of 6- and 8- azaindolizinones and 5-azacycl[3,2,2]azines was also investigated. Formylation of 6- and 8- azaindolizines occurred preferentially at C-3 and then at C-1. A number of other electrophilic substitution reactions on 2,7-dimethyl-8-azaindolizine also occurred at C-3. Nucleophilic replacement of chlorine by methoxide from a 5-chloro-6-azaindolizine and a 7-chloro-8-azaindolizine occurred readily. Ammonolysis and hydrolysis were, however, only successful in the case of the former compound. These experimentally-determined sites of reactivity in 6- and 8- azaindolizines are in accord with those predicted from reported pi-electron density calculations. Formylation of 5-amino-7-methyl-2-phenyl-6-azaindolizine gave a 4,5-diazacycl[3,2,2]azine structure, and refluxing a solution of 7-methyl-2-phenyl-6-azaindolizin-5(6H)-one in phosphoryl chloride gave a peri-condensed di(6-azaindolizino)pyrazine.

Citation

SHAND, C.A. 1977. The synthesis and reactivity of 6- and 8-azaindolizines. Robert Gordon's Institute of Technology, PhD thesis. Hosted on OpenAIR [online]. Available from: https://doi.org/10.48526/rgu-wt-1993228

• Thesis Type: Thesis
• Deposit Date: Jun 22, 2023
• Publicly Available Date: Jun 22, 2023
• DOI: https://doi.org/10.48526/rgu-wt-1993228
• Keywords: Drug synthesis; Azaindolizines
• Public URL: https://rgu-repository.worktribe.com/output/1993228
• Award Date: May 31, 1977