Indolizin-1-ols with Charged Electron Acceptors: A Direct Way to 3H-Indolizinium-1-olates with Donor Functions

The reaction of cyclopropenones with pyridines, having an attached integer-charged electron-withdrawing group (pyridinium, imidazolium, and phosphonium) was discovered to afford novel indolizin-1-ol derivatives in high yields with no chromatographic purification required. While being stable as solids, these indolizin-1-ols have a limited lifetime in solution. The study of reasons for such instability uncovered an aerobic oxidative pathway, eventually resulting in indolizine-1,7-dione dimers. The exploration of N-(1-hydroxyindolizin-7-yl)pyridinium salts' chemistry led to a reaction discovery, affording a new type of rare pseudo-cross-conjugated mesomeric betaines (3H-indolizin-4-ium-1-olates with an electron-donating function at C7 position) inaccessible by other means. In this reaction, a sequential introduction of nucleophiles takes place: the first one (Nu1) is represented by simple anilines, whereas Nu2 extends to primary, secondary, aliphatic, aromatic amines, and phenols. For the obtained betaines having unsymmetrical aliphatic amino groups at C7 position an increased order of the C7-Nu2 bond resulting in existence of amide type E/Z-forms (∼1:1 at room temperature) was demonstrated. For aryl amino groups, with typically reduced nitrogen's lone-pair donation, the barrier of rotation around the C7-Nu2 bond was lower, and for the C7-oxy betaines, no such E/Z-isomerism was revealed. Although primary amines (as Nu2) introduce a hydrogen atom in the conjugated betaine system, allowing prototropic tautomerism in this way, non-zwitterionic tautomers (3-amino-7-iminoindolizin-1-ones) were rejected by nuclear Overhauser effect spectroscopy experiments.