Indolizines, formation

Indolizines, formation from pyridine acetates, 355-357 formation from pyridine side-chain carboxylic acids, 355-357, 481-488 5-methyl, synthesis, 352 N-(2- (3-Indolyl)ethyl]-2-halo (or ethoxy) pyridinium bromide, hydrolysis, 787 ring closure by fusion, 787... 

Reduction of isoindoles with dissolving metals or catalytically occurs in the pyrrole ring. Reduction of indolizine with hydrogen and a platinum catalyst gives an octahydro derivative. With a palladium catalyst in neutral solution, reduction occurs in the pyridine ring but in the presence of acid, reduction occurs in the five-membered ring (Scheme 38). Reductive metallation of 1,3-diphenylisobenzofuran results in stereoselective formation of the cw-1,3-dihydro derivative (Scheme 39) (80JOC3982). 

The same principle of sequential cyclopentene-opening RCM resulting in the formation of a dihydropyrrole ring was the key step in Blechert s novel approach to the polyhydroxylated indolizine alkaloid (-)-swainsonine (378) via RRM of 375 (Scheme 73) [157]. 

Tominaga and coworkers have reported the formation of indolizine by the reaction of azomethine ylide with l-nitro-2-phenylthioethylene (Eq. 10.86).146... 

Recently, dipolarophile 1)13 (fumaronitrile) (777) has been used in the synthesis of indolizine lactone (677). Both, intermolecular and intramolecular cycloadditions were studied. Intermolecular 1,3-cycloaddition of nitrone (671) to D13 led to the formation of isoxazolidine (672). Subsequent deprotection and esterification of the obtained alcohol (673) with (674) gave isoxazolidine (675) in 65% yield. Ester (675), when refluxed in xylene for 10 min, after elimination of fumaronitrile by cyclo-reversion, underwent spontaneously intramolecular cycloaddition to give the tricyclic cycloadduct (676) in 84% yield (Scheme 2.291). 

Hydrogenation of 85a gives the tetrahydro derivative (88). A cycloadduct (89) may be obtained with V-phenylmaleimide. Heating 85a in toluene results in formation of a dimer containing two indolizine parts easily distinguished one from the other by PMR spectroscopy. 

Acetic and other anhydrides have been shown to promote the formation of indolizines from pyridinium salts in a cyclization reaction in which the 2,3-bond if formed. Some practicable ways are given in Scheme 18. 

Substituted vinylindolizines sometimes polymerize spontaneously and also copolymerize with styrene. Polymers of similar structure have been prepared by formation of indolizines on the polymer chain using methods outlined in Sections 3.08.3 and 3.08.6 (see Scheme 36 for an example). Moreover, indolizine dyes such as (214) have been bound to an ethyl acrylate/acrylic acid copolymer by heating to give dyes that do not migrate in photographic colour film emulsions. 

Most of the methods of formation of [2.2.3]cyclazines have been described already the intramolecular condensation of indolizines in Sections 3.08.1 and 3.08.4, the cycloaddition to indolizines in Section 3.08.3.5, the cycloaddition to methylenepyrrolizines in Section 3.08.6.2.1 and a multistep synthesis from 2-formylpyrrole and l,2-bis(hetero) substituted ethylenes in Section 3.08.6.3.1. 

Although this method is rarely used because of the poor yields often associated with it, acetic and other anhydrides have been shown to promote the formation of indolizines from pyridine quaternary salts in a cyclization reaction in which the 2,3-bond of the indolizines is formed.3141-45 This route starts from a quaternary salt of general formula 11 which is acylated and dehydrobrominated in one step to give 12. Heating 12 under reflux with acetic anhydride gives the indolizine 13a or 13b (Method A) (see Scheme 4).31 Alternatively, the quaternary salt can be converted directly into the indolizine by employing triethylamine (Method B).41 Some idea of the scope of the reaction can be gained from Table I. 

There are a few examples of the formation of indolizines from pyrroles. Thus pyrrole condenses with acetonylacetone in the presence of zinc acetate to give 5,8-dimethylindolizine (74) as the major product.87,88 3,4-Diethylpyrrole similarly gives 75.89 This same compound undergoes self-condensation in the presence of zinc acetate to give 76 in 24% yield.89 In another example tetramethine compounds (77) obtained from... 

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... 

This section is concerned with reactions that result in the fusion of one or more additional rings to the indolizine system. Of course, an indoli-zine synthesis can be designed in which the functional groups are oriented for cyclization. An example is the formation of the indolizino-[l,2-c]quinoline 132 (Scheme 17).199... 

The formation of cycl[3,2,2]azines from indolizines has its parallel in the saturated system with a reaction reported by Japanese workers.275 The indolizidinone ester 238 gives the tricyclic compound 239 on distillation with soda lime. This reaction is of potential importance in view of the number of alkaloids containing fused systems similar to 239. 

---