Preparation of Azacyclononanes

Abstract

The preparation of azacyclononanes derived from 1-azabicyclo-(4.3.0)nonane (indolizidine) was investigated. The first step of the overall synthesis entailed preparation of 9-substituted indolizidines from reactions between nucleophiles and either 9-cyanoindolizidine or Delta 4(9) -dehydroindolizidinium perchlorate. Nucleophiles derived from organometallic reagents generally gave 9-substituted indolizidines in high yield whereas weak nucleophiles such as cyanate, thiocyanate, and ethylxanthate failed to give the desired 9-substituted indolizidines. Azacyclononanes were prepared by ring opening or methiodide salts (A) prepared from 9-substituted indolizidines and methyl iodide. Three ring-opening methods were investigated. [Diagram] Abstraction of an electrophilic group (E of N-E in formula A) by a nucleophile was investigated as a general ring-opening method. Because of the difficulty encountered in preparing some compounds, the study was limited to abstraction of labile hydrogen. In a related example, ring opening was accomplished by decarboxylation (N-E = CH2COO-Na+. Ring opening of methiodide salts of 9-vinyl- and 9-ethynylindolizidine was effected by addition of nucleophiles to unsaturated groups (N-E of formula A) in SN2' reactions. The reaction of N-methyl- 9-ethynylindolizidinium iodide with lithium aluminum hydride led to an allene, and the reaction of propargylic quarternary ammonium salts with nucleophiles is suggested as a general synthesis of allenes. Ring opening of methiodide salts in which N-E of Formula A is an unsaturated group was also accomplished by reductive fission of the carbon-nitrogen bond using lithium and sodium in liquid ammonia. The mechanism of the reaction is considered in terms of the mode of initial electron addition and products obtained are explained on the basis of protonation of carbanions fanned in the reactions. Further applications of this reaction are suggested.