Indolizines ring synthesis

In another example of heterocyclic ring synthesis, pyridinium salts 816 require only Et3N for deprotonation, the resulting ylides 817 add to esters of 2-bromo-2-alkenecarboxylic acids or analogous benzonitriles to give intermediate betaines 818 which, via intramolecular nucleophilic attack, give indolizines 819 (Scheme 174) <1999JOC7618>. 

The traditional ring synthesis of imidazo[l,2-a]pyridines is based on the Chichibabin route to indolizines... 

The ring synthesis of imidazo[l,2-a]pyridines is based on the Chichibabin route to indolizines (Section 25.1.2), but using 2-aminopyridines instead of 2-alkylpyridines. The initial reaction with the halo-ketone is regioselective for the ring nitrogen, so isomerically pure products are obtained. 2-Oxoimidazo[l,2-a]pyridines are the products when an o-bromo-ester is used instead of a ketone. 

Nitrogen Systems.—Monoaza-compounds. Treatment of the azapentalene anion (745) with dichloromethane and butyl-lithium yields a mixture of indolizine (746 R = H) and compound (747) it has been established that the latter is not a precursor of indolizine.3-Diethylaminoindolizine (746 R = NEt2) is formed by the reaction of 2-bromopyridine with propargyl alcohol and diethylamine in the presence of bis(triphenylphosphine)palladium(ll) dichloride and copper(i) iodide. The pyridinium ylide (748) undergoes 1,5-dipolar cyclization to the tran -dihydroindolizine (749). As in previous years, there have been several reports on the synthesis of the indolizine ring system from pyridinium ylides the methide (750 R = H, R = Ph) adds benzylideneacetophenone to form the tetrahydroindolizine (751), the action of phenyl vinyl sulphoxide. 

The Diels-Alder reaction of 1-azadienes has been used to construct indolizines and homologous systems. Hence, acyl azadienes (122), prepared by thermal elimination of acetic acid from N-acyl-O-acetyl-N-allylhydroxylamines, undergo intramolecular Diels-Alder cyclization to form indolizidine (123) and related ring systems. A closely related paper describes the synthesis of the indolizine ring system (124) by utilization of an imino Diels-Alder cyclization. 

The synthesis of 2-azacycl[3.2.2]azine (imidazo[2.1.5-c /]-indolizine), 334, by Paudler et al. <1975JOC1210> (Scheme 97) is apparently the only successful synthesis to date, and is in effect a variant of the Vilsmeier-Haack-Arnold method of Scheme 90. All attempts to synthesize the ring system by cycloadditions to imidazo[l,5- ]pyridine have been unsuccessful. 

Attempts to synthesize l,2-diazacycl[3.2.2]azines (l,2,4-triazolo)[3,4,5-ti/]indolizines, for example, 337, have met with very limited success. To date the ring system is known only when fused on its ef-faces to a cycloheptatriene ring (see Section 12.16.6.4). It may be that the 1,2-diazacyclazine system is more strained than that of the parent cyclazines, since the N-N bond of the triazole ring is expected to be shorter than a C-C or C-N bond. Similarly, all attempts to form the N-N bond as the final step in a synthesis of the 1,2,4-triazacyclazine ring system, 359, have been unsuccessful <1987J(P1)1159>. 

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 reaction of pyridines with alkynic compounds provides a useful synthesis of indolizines containing ester groups in the five-membered ring (78AHC(23)263). 

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... 

An ingenious method for the construction of the pyridine ring based on the tert-amino effect was used (1990RTC481) in the synthesis of a series of [3,2-Z>]-annu-lated thienoazines. Prolonged refluxing of diene aminodinitriles 166 in butanol affords thieno[3,2-Z>]indolizines and thieno[2,3-e]quinolizines of general formula 167. 

Singlet oxygen oxidation of 3-substituted indoles in the presence of alcohols followed by treatment with sodium borohydride gives 2-alkoxy-3-hydroxyindolines in high yields. Further reaction with a nucleophile and a Lewis acid forms the basis of a synthesis of 2-substituted indoles (Scheme 70). This represents an alternative approach to CC bond formation at the 2-position of indoles to that involving the reaction of 2-lithioindoles with electrophiles. Isoindoles and indolizines are also preferentially oxidized in the five-membered ring to give phthalic acid and picolinic acid derivatives, e.g., 168, respectively. 

An unusual synthesis of ( )-septicine (866) from dimethyl squarate (878) exploits rearrangement of a 4-(l-pyrrolo)cyclobutenone 879 to the indolizine-5,8-dione 880, presumably via a ketene intermediate formed by electrocyclic ring opening of 879 (Scheme 113) (584). Partial reduction of 880 yielded the 4-hydroxypyridone 881, the triflate ester of which was deoxygenated with a palladium(II)-formic acid system to yield the l,2,3,5-tetrahyi oindolizin-5-one 882. Mild reduction with aluminum hydride completed the synthesis of ( )-866 in an excellent overall yield of 27% from 878. 

This procedure parallels the classical indolizine synthesis <69CB669>. A 2-methyl cycloiminium ion provides the four-membered chain which is joined to the five-membered ring by condensation with phosphorus trichloride <955361 >. 

The key step of a synthesis of the alkaloid septicine involves ring expansion of the pyrrolyl-cylobutenone (79) to the corresponding indolizine-5-8-dione (80) <94T6173>. 

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