{"id":{"repo_id":"rgu","oai_identifier":"oai:rgu-repository.worktribe.com:1993228"},"canonical_url":"https://search.dev.ndltd.org/etd/rgu/oai:rgu-repository.worktribe.com:1993228","repository":{"repo_id":"rgu","name":"Robert Gordon University","base_url":"https://rgu-repository.worktribe.com/oaiprovider"},"display":{"title":"The synthesis and reactivity of 6- and 8-azaindolizines.","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.","abstract_html":"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.","abstract_has_math":false,"creators":["Shand, Charles Alexander"],"institution":null,"degree_name":"PhD","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["M. Fraser, R. Buchan and A. Murray"],"committee_chairs":[],"committee_members":[],"year":1977,"date_issued":"1977","date_published":"1977","updated_at":"2026-07-24T04:10:03Z","subjects":["Drug synthesis","Azaindolizines"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["oai:rgu-repository.worktribe.com:1993228","https://doi.org/10.48526/rgu-wt-1993228"],"render_values":[{"text":"oai:rgu-repository.worktribe.com:1993228","href":null,"code":true},{"text":"https://doi.org/10.48526/rgu-wt-1993228","href":"https://doi.org/10.48526/rgu-wt-1993228","code":true}]}]},"links":{"outbound_url":"https://rgu-repository.worktribe.com/1993228/1/SHAND%201977%20The%20synthesis%20and%20reactivity","outbound_label":"Repository record","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["M. Fraser, R. Buchan and A. 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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."]},{"key":"dc:title","label":"Title","values":["The synthesis and reactivity of 6- and 8-azaindolizines."]}]}],"canonical_facts":{"dc:contributor.advisor":["M. Fraser, R. Buchan and A. Murray"],"dc:contributor.sponsor":["RGU Internal Funding"],"dc:creator":["Shand, Charles Alexander"],"dc:date":["1977-05-31"],"dc:date.issued":["1977"],"dc:description.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."],"dc:identifier":["oai:rgu-repository.worktribe.com:1993228","https://doi.org/10.48526/rgu-wt-1993228"],"dc:identifier.uri":["https://rgu-repository.worktribe.com/1993228/1/SHAND%201977%20The%20synthesis%20and%20reactivity"],"dc:language":["en"],"dc:relation.isreferencedby":["https://rgu-repository.worktribe.com/output/1993228"],"dc:subject":["Drug synthesis","Azaindolizines"],"dc:title":["The synthesis and reactivity of 6- and 8-azaindolizines."],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral"],"dc:type.qualificationname":["PhD"]},"updated_at":"2026-07-24T04:10:03Z"}