NMR Spectra of indolizines and their σ complexes

New and previous data on the¹H and¹³C NMR spectra of indolizines with electron-withdrawing groups at C(¹), C(³), C(⁶), and C(⁸) obtained in our laboratory are reviewed. The chemical shifts in the¹³C NMR spectra were compared with the total atomic charge values calculated by the MNDO method. Feasibility was demonstrated for the use of PMR spectroscopy to identify isomers for pairs of 1(3)- and 6(8) -substituted indolizines and to establish the protonation site of such compounds. Evidence was obtained for the unexpected ipso protonation in 3-substituted indolizines. The spectral properties of cationic and anionic sigma complexes involving indolizines were discussed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1235–1244, September, 1995.     

Pd-Catalyzed C-3 functionalization of indolizines via C-H bond cleavage

New transition metal-catalyzed methods for the arylation of indolizines by the direct cleavage of C-H bonds have been developed. A wide range of aryltrifluoroborate salts react with indolizines in the presence of Pd(OAc)(2) catalyst and AgOAc oxidant to give the arylated indolizines in high yields. Both electron-donating and electron-withdrawing groups perform smoothly while bromide and chlorine substituents are tolerated. In addition, the indolizines display similar reactivities in the Pd-catalyzed reaction with 3-phenylpropiolic acid to afford the corresponding C-3 alkynylated indolizines. These methods allow the direct functionalization of indolizines in one step.     

Preparation of new nitrogen-bridged heterocycles. 59. Syntheses and intramolecular interactions of 3-(acylmethylthio)- and 3-[(3-ethoxycarbonyl-2-propenyl)thio]thieno[3,4-b]indolizine derivatives

Various thieno[3,4-b]indolizine derivatives having an acylmethylthio or (3-ethoxycarbonyl-2-propenyl)thio group at the 3-position which could not be obtained by a conventional method were prepared by a new procedure using cyanoethyl group as a protecting group and their intramolecular arene-pi interactions were investigated. In the (1)H-NMR spectra of these thieno[3,4-b]indolizines, the low-field shifts (delta 0.10-0.33 ppm) for the 5-protons were observed in comparison with those of 3-(methylthio)thieno[3,4-b]indolizines as a standard. The UV spectra also exhibited a characteristic absorption band at 425-445 nm attributable to the arene-pi interaction but their intensities were generally lower than those of 3-(arylmethylthio)thieno[3,4-b]indolizines. In their X-ray analyses, the anti conformation for 3-(acylmethylthio)thieno[3,4-b]indolizines and the gauche one for the 3-(3-ethoxycarbonyl-2-propenyl)thio derivatives were exhibited.     

Catalytic Asymmetric Conjugate Addition of Indolizines to α,β-Unsaturated Ketones

A catalytic enantioselective conjugate addition of indolizines to enones is described. The chiral phosphoric acid (S)-TRIP activates α,β-unsaturated ketones, thereby promoting an enantioface-differentiating attack by indolizines. Using this reaction, several alkylated indolizines were synthesized in good yields and with enantiomeric ratios of up to 98:2.     

New route synthesis of indolizines via 1,3-dipolar cycloaddition of pyridiniums and alkynes

A convenient synthesis of 2,3-di and 1,2,3-trisubstituted indolizines has been achieved via a 1,3-dipolar cycloaddition of pyridiniums and alkynes. Various alkynes and diynes were used instead of dimethyl acetylenedicarboxylate (DMAD) and its analogues in the traditional method. The corresponding 1,2,3-trisubstituted indolizines are useful building blocks for the construction of complex indolizine derivatives.     

Palladium-Catalyzed Direct C-3 Alkynylation of Indolizines with (2,2-Dibromovinyl)arenes

The direct C-3 alkynylation of indolizines with (2,2-dibromovinyl)arenes in the presence of palladium catalyst has been developed. This novel protocol showed wide substrate scope with respect to both indolizines and dibromoalkenes. Also this method was characterized with high efficiency and good functional group tolerance.     

Synthesis and reactivity of 5-Br(I)-indolizines and their parallel cross-coupling reactions

Poorly available 5-iodo- and 5-bromoindolizines were prepared via regioselective lithiation of indolizines followed by halogenation. 5-Halogenoindolizines were found to be passive toward nucleophiles, whereas they may be trifluoroacetylated at C-3 and involved in reaction with DMAD giving cycl[3.2.2]azine. The first successful Suzuki-coupling of 5-bromo(iodo)indolizines with different arylboronic acids (performed as a parallel synthesis) led to a series of 5-arylindolizines; the effect of substituents on the reaction yield was examined.     

Acid-catalyzed reactions of 1- and 3-(α-hydroxybenzyl)indolizines

Treatment of 1-(α-hydroxybenzyl)- and 3-(α-hydroxybenzyl)indolizines with trifluoroacetic acid in dichloromethane gave phenylbis(α-indolizinyl)methanes, bis[α-(indolizinyl)benzyl] ethers and indolizines, depending upon the presence or absence of the substituent at the 2- or 5-position and the reaction conditions used.     

A convenient synthesis of 8-substituted indolizines as precursors to 5-substituted cycl{3.2.2}azine derivatives

The synthesis of 8-substituted indolizines is described via a two step process in which a 1,4-diketone, containing a rerf-butyl group, is cyclocondensed with a trialkylsilyl protected pyrrole to provide 5,8-disubstituted indolizines in higher yields than the identical reaction with unprotected pyrrole. Cleavage of the tert-butyl group from the indolizine 5-position, by treatment with 85% phosphoric acid, provides 8-substituted indolizines in good yields. Treatment of 8-substituted indolizines with dimethyl acetylenedicarboxylate, in the presence of palladium-on-carbon, provides novel 5-substituted cycl{3.2.2) derivatives.     

Visible-Light-Induced Insertion of Sulfur Dioxide Mediated by Electron Donor–Acceptor Complex: Synthesis and Photophysical Properties of 3-Sulfonyl Indolizines

This work investigates a light-driven 3-component sulfonylation reaction of indolizines without needing any external photocatalyst. The mechanistic investigations support the formation of an electron donor–acceptor (EDA) complex in situ. This transformation offers a mild and sustainable approach with high functional group tolerance for the synthesis of 3-sulfonylated indolizines. This compound class has valuable photophysical properties and represents promising candidates in various applications related to fluorescence.     

Electrochemical studies of biologically active indolizines

The electrochemical behavior of indolizine ethers, esters, tosylates, sulfonates and other indolizine and azaindolizine derivatives has been investigated by cyclic voltammetry and preparative electrolysis. The cyclic voltammetric data show that the E° values, taken as the midpoints between the anodic and cathodic peak potentials, are sensitive to the identities of the substituents at C-1, C-2 and C-7 positions. The E° values have been correlated with the Hammett substituent parameters. As expected, low E° values are seen for electron donating substituents and higher E° values are seen for electron withdrawing substituents. The cyclic voltammograms of indolizine derivatives with an oxygen atom connected to the C-1 position exhibit a one-electron reversible oxidation and a further, less well-defined, one-electron irreversible oxidation at higher E° values. The cyclic voltammograms of indolizines with hydrogen atom or thienyl substituents connected to the C-1 position exhibit only a one-electron irreversible oxidation. Electrochemical bulk oxidations of indolizines with an oxygen atom at the C-1 position afforded oxoindolizinium salts in decent yields, whereas indolizines with a hydrogen atom at C-1 afforded 1,1′ dimers of indolizines as products in good yields. Bulk oxidation of 1-(α-hydroxybenzyl)-2,3-diphenylindolizine-7-carbonitrile afforded an unexpected ketone product in which the carbonyl group of the indolizine is connected at C-8 instead of at the C-1 position of the starting material. The findings described herein support our hypothesis that certain indolizine derivatives may inhibit lipid peroxidation by an electron transfer mechanism.     

Pt-catalyzed cyclization/migration of propargylic alcohols for the synthesis of 3(2H)-furanones, pyrrolones, indolizines, and indolizinones

Several heterocycles such as furanones, pyrrolones, and indolizines, which are of pharmacological importance, are easily accessed via the Pt(II)-catalyzed heterocyclization/1,2-migration of propargylic ketols or hydroxy imine derivatives. This method sidesteps the challenges of traditional heteroaromatic oxygenation strategies such as regioselectivity and functional group tolerance in the syntheses of these heterocycles.     

Synthesis of indolizines starting from pyrylium salts

β-N-Pyridinium acetaldehydes with alkyl substituents in the 2 and 6 positions of the pyridinium ring, obtained from the corresponding pyrylium salts, cyclise in alkaline medium to new indolizines. This high-yield reaction sequence is optimal for indolizines unsubstituted in the five-membered ring which are difficultly accessible by other methods.     

4-甲基吡咯并[2,1,5-cd]中氮茚的合成

以2-乙基吡啶生成的叶立德为原料,采用1,3-偶极环加成反应,得到了一系列3-乙酰基(或苯甲酰基)-5-乙基中氮茚衍生物,后者与KOH在加热条件下发生分子内缩合,得到了一系列4-甲基吡咯并[2,1,5-cd]中氮茚.     

Tandem Michael addition/amino-nitrile cyclization from 2-formyl-1,4-DHP in the synthesis of novel dihydroindolizine-based compounds

A simple and efficient methodology for the synthesis of a small library of substituted indolizines with different degrees of saturation starting from the racemic 2-formyl-1,4-DHP reagent was described. The large synthetic possibilities of this reagent as well as of its Knoevenagel corresponding 2-dicyanovinyl-1,4-DHP reagent were investigated using four kinds of activated methylenes as nucleophiles. The key step of the sequential reaction was based on the highly diastereoselective tandem Michael addition/intramolecular amino-nitrile cyclization catalyzed by an organic base, which resulted in the formation of 1,7-dihydroindolizines in a diastereoselective manner. The process seems to be a straightforward one and can be extended to numerous active methylenes such as malononitrile, 1,3-diketones, and alkyl acetoacetates. The 1,3-hydrogen shift of partially hydrogenated indolizines was accomplished easily with a base at room temperature, giving rise to the corresponding 7,8-dihydroindolizines in very good yields. Interestingly, when the active methylene bears a leaving group, the latter process could not be accomplished because a rare cis-elimination of phenylsulfinic acid and nitrous acid preceded the hydrogen shift. The resulting 1,7-dihydroindolizines bearing an exo-methylene group at C1 were not isolated in all cases, as they turned rapidly to indolizines as the thermodynamically more stable products. During these investigations, oxidization of 1,7-dihydroindolizines with CuCl(2) resulted in the formation of polysubstituted pyridines. Also, the epimerization of certain 1,7-dihydroindolizines was evidenced in the solution studied by NMR spectroscopy, whereas in the solid state, they existed only in a unique form as shown by X-ray diffraction analysis of a representative structure. Finally, all products reported herein bear a primary amine and a nitrile function crucial for further transformations. These include the introduction of various pharmacophore groups at either NH(2) or CN groups as well as at both groups at the same time to access the more elaborated indolizines fused to N- or N,N-heterocycles.     

The reaction of indolizines with tetracyanoethylene

Tetracyanoethylene (TCNE) reacts with indolizines ( 1a-c ) to give mixtures of 1- and 3-sub-stituted tricyanovinylindolizines, respectively. The isomers are identified by nmr spectroscopy. The occurrence of intramolecular charge-transfer bands in the visible spectra is discussed.     

Preparation of 3-(2H-pyran-2-on-6-yl)indolizines and the diels-alder reactions with some olefinic and acetylenic dienophiles

3-(2H-Pyran-2-on-6-yl)indolizines 6a-d were prepared by 1,3-dipolar cycloaddition reactions of N-(2H-pyran-2-on-6-yl)methylpyridinium bromides 5a,b with dimethyl acetylenedicarboxylate (DMAD). All of the cycloaddition reactions of 6b with N-phenylmaleimide, p-benzoquinone, and DMAD took place at the 2-pyrone ring to give 3-substituted indolizines.     

A novel and efficient approach to highly substituted indolizines via 5-endo-trig iodocyclization

A new approach to indolizines has been developed using a 5-endo-trig iodocyclization of allylic esters followed by isomerization and dehydroiodination facilitated by triethylamine at rt. This mild procedure enabled us to synthesize a number of highly substituted indolizines in good yields.     

Electrochemically Induced Hetero-[4+2]-Cycloaddition Reactions Between 2-Vinylpyrroles and β-Acceptor-Substituted Enamines

An efficient route to indolizines is provided by radical-cation-initiated cycloaddition reactions between 2-vinylpyrroles acting as heterodienes and enamines (below; SET = single electron transfer).     

Synthesis and reactions of 1,2-fused 3-cyanoindolizines

With the intention that annulation of carbo- or heteroaromatic rings at the 1,2-positions can activate 3-cyanoindolizines as 1,3-dipolar species, 6-cyanobenz[a]indolizines, pyridazino[4,5-a]indolizines and 5-cyano-1,3-diphenylthiopheno[3,4-a]indolizine were prepared. 6-Cyanobenz[a]indolizines smoothly -underwent 1,3-dipolar cycloaddition on to dibenzoylacetylene and diacetylacetylene to afford the corresponding indolizino[3,4,5-ab]isoindoles, whereas 5-cyano-1,4-diphenylpyridazino[4,5-a]indolizine reacted with dimethyl acetylenedicarboxylate to give the 1:2 adduct. Only a 3% yield of 5-cyano-1,3-diphenylthiopheno[3,4-a]indolizine formed upon phosphorus pentasulfide treatment of 1,2-dibenzoyl-3-cyanoindolizine.