Synthesis and Aerobic Dehydrogenation of Indolizin-1-ol Derivatives

Abstract

The reaction between simple pyridines, Michael acceptors (cyclopentenone, N-methylmaleimide), and monoalkyl-3,3-difluorocyclopropenes affords 3-(1-hydroxyindolizin-3-yl)-succinimides or 3-(1-hydroxyindolizin-3-yl)-cyclopentanones in good yields. These air-sensitive products regenerate double bond in the incorporated Michael acceptors by selective and near-quantitative aerobic dehydrogenation, yielding intensively colored dyes. The purple 3-(1-hydroxyindolizin-3-yl)-maleimides are highly electrophilic and react smoothly with N-, S-, and P-nucleophiles at the maleimide double bond, which is again easily restored by aerobic dehydrogenation. In the particular case of hydrazine and hydroxylamine nucleophiles, their Michael adducts with the 3-(1-hydroxyindolizin-3-yl)-maleimides afford the novel pyrimido­[6,1,2-cd]­indolizin-5-one (5-aza[2.3.3]­cyclazin-1-one) heterocyclic core by the proposed double-dehydrogenation–6π-electrocyclization−β-elimination reaction sequence. O-Protected 3-(1-hydroxyindolizin-3-yl)-succinimides are air-stable and not electrophilic. Deprotection returns the ability of the succinimides for aerobic dehydrogenation, yielding the appropriate electrophilic maleimides. This property may be employed in design of the switchable covalent-binding tool, activated by chemical or enzymatic cleavage of the O-protective group. Electron-withdrawing group at the C7 position of the indolizine core directly affects the dehydrogenation rate; hence, it can be used for kinetic tuning. Additionally, new stable indolizinium-based zwitterionic 3-oxo-3H-indolizin-4-ium-1-olate (1-oxo-1H-indolizin-4-ium-3-olate) was accessed by TEMPO oxidation of the C3-free indolizin-1-ol, generated by 3-hydroxypyrrole ring annulation with monoalkylcyclopropenone in situ.

Radical and Ionic Reactions of Indolizin-1-ols: Synthesis of 3-Arylsulfanyl-, 3-(Tropon-2-yl)- and 3-(Tropolon-5-ylazo)-1-hydroxyindolizines from 3,3-Difluorocyclopropenes

“…This aerobic reaction, affording symmetric 3,3′-biindolizine-1,1′-diol 4 , was interpreted as the intermolecular recombination of 1-hydroxyindolizin-3-yl C-radicals. At the same time, (2,2,6,6-tetramethylpiperidin-1-yl)­oxyl (TEMPO), being a stable aminoxyl O-radical, acts as a competitive radical trap, leading to a stable heterocyclic mesomeric betaine 3t , after α,α′-tetramethylpiperidine part dissociation …”

“…Modulation of redox properties, decreasing air stability of the whole molecule, is a common feature of the indolizin-1-ol moiety, as could be seen, for example, from the oxidation series 3 → 4 → 5 (Scheme ) and our previous study . We were curious about the potential oxidation of 3-arylsulfanyl-1-hydroxyindolizines 6a – l and expected their further aerobic oxidation to form sulfoxides but found them quite stable in DMSO or solid state under ambient conditions.…”

Multiple-fold C–F bond functionalization for the synthesis of (hetero)cyclic compounds: fluorine as a detachable chemical handle

“…Inspired by this innovative work, the same group later demonstrated an aerobic multicomponent reaction between monoalkyl-3,3-difluorocyclopropenes, pyridines, and C-/S-/ N-nucleophiles (e.g., arylthiols, O-tosyltropolone, and 5-tropolonediazonium tetrafluoroborate) (Scheme 36a-c). 71 Very recently, cyclopentenone and N-methylmaleimide were also introduced as Michael acceptors for the flexible installation of alkyl functional group at C3 position of indolizin-1-ols (Scheme 36d). 72 The double bond in air-sensitive product 36-10 could be easily restored in near-quantitative yield by aerobic dehydrogenation.…”

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

“…From a chemical point of view, they strongly tend to react with nucleophiles, 12 however, they are also able for protonation, as was illustrated in the example of PCC HMB type-C. Mesomeric betaine type-D (R�Ph, R 1 �H) was first obtained as a single example (9% yield) in 1988 by Potts et al 17 in the reaction of pyridine-2-yl lithium with (chlorocarbonyl)phenylketene, and since then only a little progress on this type of HMBs was reported. 14 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.…”