Indolizines substitution

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>. 

Half-wave oxidation potentials (E1/2) in MeCN at a platinum electrode, and gas-phase ionization potentials (P) were measured for 15 indoles and 12 indolizines substituted at the 5-membered ring. Except for a few compounds, a linear correlation of , 2 and P was found. Deviations of linearity were discussed in terms of conformation differences between the two phases <86JCS(P2)1229>. 

The review is organized in the following way. First, indolizines with substiments at pyrrole fragment are covered. This includes indolizines substituted at positions 3 and 1 (since these positions are most easily substituted), and then 2-substituted derivatives. Then, indolizines substituted at pyridine ring are covered structures with 6(8)-perfluorinated groups are reviewed, and finally, 7- and 5-derivatives are discussed. Major attention is paid to indolizines benzo-derivatives are also included. 

Fluorinated indolizines remained relatively rare class of compounds. In contrast to indolizines substituted at pyrrole fragment the structures having a perfluoro-substituent in the pyridine ring are less available. This is caused by the fact that 3... 

Jug and co-workers investigated the mechanism of cycloaddition reactions of indolizines to give substituted cycl[3,2,2]azines <1998JPO201>. Intermediates in this reaction are not isolated, giving evidence for a concerted [8+2] cycloaddition, which was consistent with results of previous theoretical calculations <1984CHEC(4)443>. Calculations were performed for a number of substituted ethenes <1998JPO201>. For methyl acrylate, acrylonitrile, and ethene, the concerted [8+2] mechanism seems favored. However, from both ab initio and semi-empirical calculations of transition states they concluded that reaction with nitroethene proceeded via a two-step intermolecular electrophilic addition/cyclization route, and dimethylaminoethene via an unprecedented two-step nucleophilic addition/cyclization mechanism (Equation 1). 

All compounds reported within the review period are indolizines or their hetero-substituted derivatives, fused through the a- or -edge to a five-membered heterocyclic ring. 

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). 

Compounds in this section comprise indolizines and their hetero-substituted analogues which are fused through the /-edge to a six-membered heterocycle. Where the fused six-membered ring is pyridine, however, these compounds are named not as fused indolizines but as pyrrolonaphthyridines. 

Electron-rich heterocyclic systems such as indolizines react readily with DEAZD (and PTAD) to give substitution products (Eq. 16).141 None of the formal [8 + 2] cycloaddition products (e.g., 89) are observed. This is in direct contrast to the reaction of indolizines with electrophilic acetylenes which gives high yields of cycloaddition products, presumably via a stepwise mechanism, in the presence of palladium on charcoal.142 This example of... 

Indolizine is an electron-rich system and its reactions involve mainly electrophilic substitutions, which occur about as readily as for indole and go preferentially at the C-3 position, but may also take place at the C-l. Consistent with their similarity with pyrroles rather than pyridines, indolizines are not attacked by nucleophiles nor are there examples of nucleophilic displacement of halide-substituted systems. 

Indolizine is much more basic than indole (p Ta = 3.9 vs. —3.5), and the stability of the cation makes it less reactive and resistant to acid-catalyzed polymerization. Protonation occurs at C-3, although 3-methylindolizine protonates also at C-l. Introduction of methyl groups raises the basicity of indolizines. Electrophilic substitutions such as acylation, Vilsmeyer formylation, and diazo-coupling all take place at C-3. Nitration of 2-methylindolizine under mild conditions results in substitution at C-3, but under strongly acidic conditions it takes place at C-l, presumably via attack on the indolizinium cation. However, the nitration of indolizines often can provoke oxidation processes. 

Using benzotriazole methodology, it was possible to obtain indolizine compounds by cycloaddition of benzotria-zole-substituted /V-ylidcs to bromoalkenes and acetylene derivatives <1999JOC7618>. 

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

Allene-substituted lactams or cyclic imines are useful intermediates in the synthesis of indolizine derivatives. While the former are stable and need a Pd(0) catalyst and the presence of phenyl iodide to react < 1997TL6275>, the latter are produced in situ and react immediately (Scheme 37) <2001JA2074>. 

The Chichibabin reaction for the synthesis of indolizines has been revisited and some variations have been proposed. The modified benzotriazole 168 reacted with substituted pyridines 167 in refluxing dimethylformamide (DMF). The indolizine 169 bears a triazole moiety that proved useful for the construction of benzo-annulated indolizines <2000JOC8059>. Also, cyclic iminium ylides like 170 can be used in the Chichibabin reaction. Their solvolysis produced the corresponding indolizinones 171 (Scheme 40). 

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>. 

Indolizines, aromatic heterocycles with 12-jr-elec-tron system salts, isomeric with indole and isoindole, are prepared in good yields from pyrylium salts with active a-methylene groups.215 216 Aromatics derived from pyrylium salts by substitution of one or two fi-CW group(s) with a heteroatom are also possible. 

A new selective thermal cascade ring-enlargement process of 4-chloro-substituted spiro[cyclopropane-l,5 -isoxazolidines], leading to a new method for the synthesis of the indolizine skeleton, has been reported (see Scheme 17). Apparently, the process is made possible by the presence of a chlorine substituent on the carbon a to the spirocyclopropane ring which facilitates a cyclopropyl-to-cyclobutyl ring enlargement mediated by a polar solvent. 

The sulphur TT-electron analogue of indolizine, pyrrolo [2,1-6 ]-thiazole [ 178], and some methyl substituted derivatives protonate in... 

Indolizines were arylated under similar conditions selectively in the 3-position (6.90.). A detailed mechanistic study of the transformation revealed that in this reaction the arylpalladium species, formed in the first step of the catalytic cycle, is attached to the indolizine core in an electrophilic substitution step, which is followed by reductive elimination. The presence of alternate routes such as Heck-type insertion, oxidative addition of the C-H bond, or transmetalation were excluded on the basis of experimental evidence.121... 

Further substitution of the peripheral carbon atoms of the cyclazines by heteroatoms (N, S, etc.) is indicated in this chapter according to the replacement nomenclature system (aza, thia, etc.). Although, strictly, this runs contrary to the rules,lc since it is a heterocyclic, not a hydrocarbon, system which is replaced, the connection between closely related compounds can more clearly be seen. It should be noted that Chemical Abstracts employs the systematic fusion nomenclature I, for instance, is pyrrolo[2,l,5-cd]indolizine. 

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