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

Abstract

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.

3-Thioxo-3H-indolizinium-1-olates and Related Pseudo-Cross-Conjugated Heterocyclic Mesomeric Betaines: Synthesis and Spectral Features

“…Instead, the betaine system was conserved, and restricted rotation around the C7−N bond was established. 11 Tropoquinone-containing PCC HMB type-B is noteworthy for the near IR range light absorption and its redox properties: B is easily reduced back to its blue 3-(tropolon-5-ylazo)-indolizin-1-ol precursor. 13 It is notable that in the overwhelming majority of cases, pyridines with an electron-withdrawing group (R were utilized.…”

“…Thus, the −OH coordinating solvents (e.g., DMSO), internal hydrogen bonding, and crystal packing are the factors that minimize such reactivity. 11 At the same time, covalent O-capping completely prevents the formation of paramagnetic forms of indolizin-1-ols, making them air-stable. Therefore we applied trapping of the intermediate [3] with an excess of Ac 2 O in pyridine under argon.…”

“…In these products, although HX and N + are connected with an effective conjugation chain, no uncharged quinoid tautomer was observed: the PCC HMB system persisted. 11 In regard to pyridines' reactivity, the presence of a phenyl ring between HX and pyridine's nitrogen is essential, as without it the reaction does not proceed (for example, with 4-aminopyridine 7aminoindolizin-1-ol intermediate is not even formed). However, to our surprise, 3,5-dimethoxypyridine, having two directly attached electron-donating groups, smoothly resulted in the 6,8dimethoxy-3-thioxo-3H-indolizinium-1-olate 6x.…”

“…Recently we reported a number of studies − on the chemistry of highly reactive C3-unsubstituted indolizin-1-ols. In our approach, we utilized an accidently discovered reaction of pyridines and mono substituted 3,3-difluorocyclopropenes in wet nonbasic solvents which resulted in C3-free indolizin-1-ols.…”

“…Recently synthesized PCC HMBs type- A were found to be unusual regarding prototropic tautomerism: while exocyclic proton (C7–NH) was anticipated to relocate with a formation of an uncharged quinoid tautomer, this did not happen. Instead, the betaine system was conserved, and restricted rotation around the C7–N bond was established . Tropoquinone-containing PCC HMB type- B is noteworthy for the near IR range light absorption and its redox properties: B is easily reduced back to its blue 3-(tropolon-5-ylazo)-indolizin-1-ol precursor …”