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

The first example of the synthesis of 3-thioxo-3H-indolizinium-1-olates, which further expands a limited class of pseudocross-conjugated heterocyclic mesomeric betaines isoconjugate to odd nonalternant hydrocarbon anion, is reported. These unique, moderately colored heterocyclic products result from a developed three-component reaction of cyclopropenones, pyridines, and sulfur. The protocol is distinguished by simple and mild reaction conditions that avoid expensive reagents or exotic catalysts, exhibiting high functional group tolerance. The broad scope of the reaction is particularly remarkable in light of the dramatic influence of pyridines' substituents on the reactivity of corresponding indolizin-1-ols, the key intermediates that proved to be highly thiophilic. In addition, an oxidative coupling of indolizin-1-ol in situ with p-tropoquinone oxime acetate is discovered. The reaction involves the C3 and C5 positions of the indolizin-1-ol and results in unusual indolizine-aminotropolone combinations. For the 3H-indolizinium-1-olate type of PCC HMBs, some general considerations concerning light absorption and NMR regularities were formulated.

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.

Unique Pseudo-Cross-Conjugated Mesomeric Betaines via an Iodate-Promoted Reaction of 3,3-Difluorocyclopropenes, Pyridines, and Anilines.

A simple method for the synthesis of (E)-3-arylimino-3H-indolizin-4-ium-1-olates by an iodate-promoted multicomponent reaction between 3,3-difluorocyclopropenes, pyridines, and anilines was discovered. The reaction products belong to a limited and underexplored class of pseudo-cross-conjugated heterocyclic mesomeric betaines isoconjugated with odd nonalternant hydrocarbon anions, whose properties were studied. Reversible nucleophilic addition at the C5 position was revealed as their main chemical feature, which had an access to novel fully conjugated 1,5-dioxo-3-arylamino-1,5-dihydroindolizine and tetracyclic 4-oxo-4,6-dihydrocyclopenta[4,5]pyrimido[2,1,6-cd]indolizine ring systems in one step. Both the synthesis of betaines and their transformations demonstrate a high level of functional group compatibility, allowing the ready preparation of a number of structurally attractive compounds for materials or medicinal chemistry.

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.

An aerobic multicomponent reaction between monoalkyl-3,3-difluorocyclopropenes, pyridines, and arylthiols has been discovered to afford 3-arylsulfanyl-1-hydroxyindolizines. This reaction proceeds via intermediate C3-free indolizin-1-ols, easily forming free radicals in air. In the presence of arylthiols, potent radical traps, incorporation of arylsulfanyl substituent occurs at the C3 position of indolizin-1-ols by radical recombination. On the contrary, in an inert atmosphere, intermediate 1-hydroxyindolizines react with C- and N-electrophiles in a one-pot fashion. Novel, intensively colored 3-(tropon-2-yl)-indolizin-1-ols and high absorption coefficient 3-(tropolon-5-ylazo)-indolizin-1-ol dyes were synthesized in a multicomponent manner in 50-80% yields. The presence of an O-uncapped indolizin-1-ol moiety modulates the redox properties of the whole molecule, facilitating free radical formation, which is susceptible to further transformations. Three such examples were demonstrated: oxidative recyclization of 3-(2-hydroxyphenylsulfanyl)-indolizin-1-ol, auto-oxidation of substituted 3,3'-biindolizine-1,1'-diol, and diacetoxyiodobenzene (DAIB)-mediated dehydrogenation of 3-(tropolon-5-ylazo)-indolizin-1-ol. The latter reaction affords 3-((4,5-dioxocyclohepta-2,6-dien-1-ylidene)hydrazono)-3H-indolizin-4-ium-1-olate, a mesomeric betaine, strongly absorbing light on the borders of the visible range and showing a solvatochromic effect.

Synthesis and Aerobic Dehydrogenation of Indolizin-1-ol Derivatives.

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-ß-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.

Three-Component Reaction of 3,3-Difluorocyclopropenes, s-Tetrazines, and (benzo) Pyridines.

A new three-component reaction leading to 1-α-(pyridyl-2-[1,2,4]triazolyl)-2-alkyl-ethanones has been discovered while studying the reactivity of monosubstituted 3,3-difluorocyclopropenes in an inverse electronic demand Diels-Alder (IEDDA) cycloaddition-cycloreversion sequence with s-tetrazines. The reaction involving the above-mentioned reactants and (benzo)pyridine as a third component results in a complex transformation proceeding in mild conditions in a stoichiometric ratio of reactants and has high functional group tolerance (phenols, amides, ethers, carboxylic acids, ketones, and acrylic esters). As a result, simple pyridines are selectively functionalized at the α-position in good isolated yields. The reaction mechanism includes a rare azaphilic [4 + 2]-cycloaddition step between s-tetrazine and intermediate 1-hydroxyindolizine, suggested after byproduct identification and tracked with a deuterium label. To date, it is only the third known example of skewed azaphilic cycloaddition of tetrazine. The reaction is truly three-component and cannot be effectively performed stepwise.

Synthesis of Carbosilane and Carbosilane-Siloxane Dendrons Based on Limonene.

In this work, carbosilane dendrons of the first, second, and third generations were obtained on the basis of a natural terpenoid, limonene. Previously, we have shown the possibility of selective hydrosilylation and hydrothiolation of limonene. It is proved that during hydrosilylation, only the isoprenyl double bond reacts, while the cyclohexene double bond does not undergo into the hydrosilylation reaction. However, the cyclohexene double bond reacts by hydrothiolation. This selectivity makes it possible to use limonene as a dendron growth center, while maintaining a useful function-a double bond at the focal point. Thus, the sequence of hydrosilylation and Grignard reactions based on limonene formed carbosilane dendrons. After that, the end groups were blocked by heptamethyltrisiloxane or butyllithium. The obtained substances were characterized using NMR spectroscopy, elemental analysis and GPC. Thus, the proposed methodology for the synthesis of carbosilane dendrons based on the natural terpenoid limonene opens up wide possibilities for obtaining various macromolecules: dendrimers, Janus dendrimers, dendronized polymers, and macroinitiators.