Substituted indolizines

The base-induced cyclization of Ar-(oxoethyl(pyridinium salts of 2-picolines, known as the Tschitschibabin indolizine synthesis, is a classical method of preparation of indolizines from pyridines. The ready isolation of the products by decanting or filtration has allowed for the recent development of a parallel synthesis of a wide range of 2-substituted indolizines <2003SL2086>. 

Substituted indolizines 18 are formed in Chichibabin reactions of l-[alkyl(aryl)carbonylmethyl]-2-alkylpyridinium halides 17 (Scheme 11) <1972AJC1003>. Various modifications of this method are used for the preparation of many other pyrrolo[l,2-< ]azines and pyrrolo[l,2- ]azoles. Indolizines can also be made by intramolecular Michael additions, e.g., by the cyclization of 2-acylpyridine 19 (Scheme 12). 

Detailed one- and two-dimensional NMR spectroscopic analysis of 2-substituted indolizines has facilitated interpretation of H and C NMR spectra <93JCS(Pl)1809>. 

Two trifluoromethylsulfenyl groups were introduced into the 1,3-positions of indolizines by reaction of F3CSO2CI with indolizine and 2-substituted indolizine derivatives <81JFC(19)67>. 

Substituted indolizines (61) were formed in a Chichibabin reaction of l-(ethoxycarbonylmethyl)-2-methylpyridinium chloride (Equation (2)) <81MI 809-01>. 

In a reversal of this intramolecularized side-chain reactivity (effecting annulation of a five-membered ring to the N/C-2-position of pyridine) the Baylis-Hillman reaction of pyridine-2-aldehydes with acceptor-substituted alkenes, e.g. acrylates, in the presence of DABCO gives rise to formation of products 74, which can be cyclized to 2-substituted indolizines, e.g. indolizine-2-carboxylates 75 [54]. 

Whereas reaction of the cyano-substituted indolizine 251 with a base results in the tf-fused product (Equation 34), the diester 255 reacts to give only the Afused product 256 <1987CL2043> (Equation 37). Similarly, when the acylindolizines 257 are prepared (Equation 38), very small amounts of the thienoindolizines are found in the product mixture. When such indolizines are substituted with both cyano and keto groups, treatment with a base gives a mixture of products resulting from reaction of the ester enolate with either of these electrophiles <1989BCJ119> (Equation 39). 

Several pyridyl-substituted indolizines are fluorescent and their photophysics have been studied <1999MI155, 2002MI279>. This property has found application in the synthesis of indolizine-substituted /3-cyclodextrins <2005T3939> used as fluorescent chemosensors for organic guest molecules <2005CAR1706, 2005JFC385>. 

The radical cyclization can also involve an acrylate to obtain C02Me-substituted indolizine derivatives 57 (Scheme 18) <2000TL10181>. 

A highly efficient access to diversely substituted indolizines using a new three-component condensation of activated methylene compounds, aldehydes, and isonitriles is described <2006QSAR504>. 

An efficient method for the synthesis of IV Group metals substituted indolizines from diverse propargyl-substituted pyridines in the presence of Au-catalyst, has been developed <2006JA12050>. 

Substituted, particularly hydroxyphenylmethyl- or hydroxyalkyl substituted, indolizines have shown activity against Mycobacterium tuberculosis <2006MI26>. 3-Substituted indolizine-l-carbonitrile derivatives displayed activity against MPtpA/MPtpB phosphatases which are involved in infectious diseases <2006BMCL59>. 

Nitration of benzof/jjthiophene (HN03/AcOH) yields mainly the 3-nitro derivative. Under these conditions the p to a ratio of substitution is approximately 5 1, which is significantly less than for indole itself which undergoes almost exclusive (3 substitution. Indolizines are readily nitrated, e.g. brief treatment of 2-methylindolizine with a mixture of concentrated nitric and sulfuric acids gives 2-methyl-l-nitroindolizine (66). 

It has been shown, by NMR studies, that the protonation of indolizines takes place exclusively at the 3-position when this position is unsubstituted. Depending on the nature and positions of the substituents, 3-substituted indolizines give mixtures of 1- and 3-protonated salts (Table 8). In 3,5-disubstituted indolizines, intramolecular overcrowding is reduced by protonation at the 3-position. 

Table 8 Percentage Composition of Solutions of 3-Substituted Indolizines in Trifluoroacetic Acid (66jcs(B)44)...

The Mannich reaction, however, is an easily accomplished substitution, occurring in the 1- and 3-positions. The biological activity of numerous Mannich bases of indolizines has been investigated. The 1-substituted indolizines (34) and (35), which have been prepared using a Mannich reaction, may serve as examples (Scheme 6). 

A Michael-type addition reaction of substituted ethylenes (39) with 2-phenylindolizines yields 3-substituted indolizines (40) <66AC(R)752). Arylation occurs on treatment of an indolizine with the salt (41) (67TL4321) or with diphenylcyclopropenone (68TL5537), yielding the tetrafluoroborate (42). 

Substituted indolizines have been hydrogenated to give 5,6,7,8-tetrahydroindolizines (72) using Raney nickel or a platinum catalyst at ambient temperature and pressure. The hydrogenation of the pyrrole ring of indolizine to (73) was successful with palladium on charcoal in aqueous hydrogen bromide. It is almost certain (see Section 3.08.3.1) that the 3H-indoIizinium cation is formed initially. 

The Tschitschibabin reaction represents the most versatile way to substituted indolizines. It fails only in the case of indolizines bearing no substituents on the five-membered ring. Usually the intermediate quaternary salt (108) is isolated, but in some cases a one-pot reaction has been performed. The cyclization of (108) normally proceeds directly to the indolizine (110). A carbinol intermediate (109), however, has been isolated from the reaction of 2-picoline and 2-bromopropiophenone in the absence of a solvent (73JCS(P1)2595). 

This synthesis, originally devised by Tschitschibabin,8 is still the most widely used because it can easily be modified to yield substituted indolizines. The synthesis involves the quaternization of a 2-substituted pyridine, normally using an a-halo carbonyl compound, followed by intramolecular cyclization of the quaternary salt with a mild base, usually aqueous sodium bicarbonate (Scheme 1). 

A new synthesis leading to a previously unknown 8-substituted indolizine involves initially the formation of the dihydropyridopyranyl ether (81) by reaction between a vinyl ether and a Mannich base obtained from 3-hydroxypyridine treatment with dilute hydrochloric acid... 

In view of the diversity of these reactions, they will be subdivided according to the type of substituted indolizine produced. 

A large number of thioamide derivatives have been obtained by Mirek and associates by allowing substituted indolizines to react with an aryl171,172 or aroyl173 isothiocyanate in a refluxing inert solvent. If a diisocyanate or a carbodiimide is used, products such as 109 and 110 are formed.17 ... 

Substituted indolizines have been shown to undergo cycloadditions with suitably substituted alkenes to give pyrroloindolizines.202 Thus, 2,6-dimethylindolizine with methyl acrylate gives 136. The reactions presumably involve [8 + 2] cycloadditions, with subsequent 1,5-proton shifts. 

Substituted indolizines such as 144 may be hydrogenated to their 5,6,7,8-tetrahydro derivatives using Raney nickel or occasionally platinum catalysts at ambient temperature and pressure.151,152,205 A series of derivatives of the type 145 were found to have various kinds of CNS activity.205... 

Methyl propiolate and EPP add to indolizine giving 43 and 44 the structure of the latter was confirmed by hydrolysis and decarboxylation to a known compound.597 Substituted indolizines react as well Boekel-heide and Fahrenholtz converted 2-phenylindolizine (47) into 48 under these same conditions.599... 

Triphenylphosphine was employed as a nucleophilic catalyst for the umpolung addition of azoles (225) to the electron-deficient allenes (226 R1 = H, R2 = OEt, R3 = H, Et) to afford the addition products (227). This organocatalytic methodology has been extended to addition-cyclization reactions between electron-deficient allenes or alkynes and pyrrole-2-carboxaldehyde in the presence of a catalytic amount of tri-butylphosphine, giving the substituted indolizine-7-carboxylates (228 R2 = OEt, Me R3 = H, Et).265... 

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