Indolizines esters

Indolizine esters containing electron-withdrawing groups in the 5-position are useful fluorophores which react with amines at the ester function to produce amides of use in the construction of... 

In methanol, isoquinoline and the ester gave the benzo[fif]indolizine [(121), cf. Section II,D,3] while in ether the labile adduct, tetra-methyl llbH-benzo[a]quinolizine-l,2,3,4-tetracarboxylate (122) was obtained. The labile adduct is much less easily isoraerized than the 9-methyl-9aH-quinolizines derived from pyridines (Section III,F,1) but with boiling xylene or, better, with sulfuric-acetic acids the cor-... 

A study of the photochemical reactions of some ylides of compound 1 showed the expected fragmentation to give, from compound 258 for example, 3-methyl-triazolopyridine and the products 259 and 260 postulated as derived from a carhene intermediate (00MI2). Ester 261 gives a hydrazone, and ylide 262 an indolizine. Thermal reactions of ylides are in Section IV. I. 

Reaction of the nitrone 4-184 with allenic esters 4-185 as described by Ishar and coworkers led to the benzo[b]indolizines 4-186, together with small quantities of 4-187 (<5%) (Scheme 4.40) [63]. The first transformation is a 1,3-dipolar cycloaddition this is followed by four further steps, including a [4+2] cycloaddition of an intermediate 1-aza-l,3-butadiene. 

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). 

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). 

Cyclic amino acids 139, when heated in acetic anhydride, probably form initially mesoionic oxazolium 5-oxides (munchnones) subsequent 1,3-dip olar cycloaddition of 1,2-dicyanocyclobutene, loss of carbon dioxide, and opening of the cyclobutane ring lead to dinitriles 140 (80JHC1593). Pyridone 141 is the by-product (together with an indolizine) of the mono-cyclic pyridone dicarboxylate and acrylic ester (73JHC77). 

Ring contraction to form the indolizine ring system is another side-reaction in the alkaline hydrolysis of a quinolizine ester. Acheson etal.30 have studied in detail the conversion of tetramethyl 4Zf-quinolizine-1,2,3,4-tetracarboxylate into the corresponding indolizine derivative. 

Indolizines can also be produced from pyridine and acetylenedicarboxylic ester (Section 3.2.1.3.7). 

Information concerning the effect on 5-values of aza substitution as well as of methyl groups and electron attracting ester and nitrile groups may be obtained from the examples given in Tables 2, 3 and 4. Using Tables 8 and 9 of Section 3.01.4.1, a comparison of the NMR spectra of indolizine, indole and isoindole is possible. 

Table 4 Chemical Shifts of Ring Protons of Esters and Nitriles Derived from Indolizine...

Acylation of the highly reactive indolizines may be achieved at the 3-position and, less easily, at the 1-position using acid chlorides, anhydrides and even esters (48CRV(42)6ll). 3-Acetylation of indolizine, 1,3-diacetylation of indole and 2,5-diacetylation of pyrrole have been effected with acetic anhydride at 140-200 °C (see Section 3.02.2.4.8 for details). The indolizines (49) and (50) are formed with ethyl chloroformate and ethyl benzoylacetate respectively. 

Indolizine-l-acetic acid has been prepared by reaction of 3-benzoylindolizine with diazoacetic ester followed by basic hydrolysis <68AC(R)1206). 

Using an a-bromo ester instead of an a-bromo ketone the 2-hydroxyindolizine (111) has been obtained from ethyl 2-pyridylacetate (63JCS3277, 80JOC5100). By variation of R1 in (106), 1-cyano-, 1-amino-, 1-hydroxy- and 1-nitro-indolizines have been obtained. 

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 same enol betaine was obtained by Flitsch and Gerstmann,46 who also found that benzoylation of the quaternary salt of 2,6-lutidine with phenacyl bromide at room temperature gave the enol ester 24. Benzoylation at elevated temperature or treatment of 24 with base gave the expected indolizine 25 [Eq. (7)]. 

Crabtree, Johnson, and Tebby55 have studied the reaction of pyridine with methyl propiolate and found that the major product is 31, high-pressure hydrogenation of which resulted in loss of the acrylic ester side chain to give indolizidin-3-one, whereas treatment with piperidine gave a product (32) believed to be the indolizine [Eq. (8)]. 

The position of the equilibrium of Eq. (13) depends markedly on the nature of R. When R = H the product is entirely the ketone, whereas when R = CH3 the product can be shown from IR and NMR spectroscopic data to be completely enolized. Whichever form predominates, Schotten-Baumann benzoylation gives the indolizine / -nitrobenzoate ester (67). Acetic anhydride instead of perchloric acid with 65 gives the 1-acetamidoindolizine which is also available from the 1-acetyl compound via the Schmidt reaction. 

A shorter method has been used to prepare indolizine-1-acetic acid (88) by reaction with diazoacetic ester followed by base hydrolysis and acidification.139... 

Ames and co-workers have reported the synthesis of some aminoethyl indolizines.141 Workers at Keele University have investigated the preparation of hydroxymethyl and aminomethyl derivatives.142 They obtained the 2-, 3-, and 6-hydroxymethyl compounds by lithium aluminum hydride (LAH) reduction of the esters. However, compound 93 gave inseparable mixtures on reduction, and whereas the 2-amino-methyl compound could be made by reduction of the corresponding... 

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. 

The course of the reaction between DMAD and alkoxycarbonyl-cyanopyridinium methylides (79 X = CN, Y = C02R) is strongly solvent dependent.284 In dimethylformamide or benzene, indolizines (e.g., 80) are obtained, but in acetonitrile the reaction is stated to give 81, an ester shift285 having taken place. Douglass and Wesolosky286 reacted the ylids 79 (X = E, Y = CN) with DMAD and isolated 82. 

In rather unreliable reactions, pyridine and its 3-methyl and 3,5-dimethyl derivatives with MP and 1 mole of methanol yield 2-methoxy-1,2-dihydropyridines (e.g., 122).292 This contrasts with DMAD which yields indolizines (e.g., 35 and 36), perhaps because the extra ester group encourages the methoxide ion to add to the exocyclic double bond, but 4-methylpyridine with MP gives the same products (see earlier) as obtained in the absence of added methanol.292 Replacing the methanol by water gave compounds exemplified by 123, where the 5 6 -double... 

This volume contains two articles which bring up to date older reviews in the Series. Progress in the chemistry of the 1,3-oxazines since they were covered by Eckstein and Urbanski in Volume 2 (1963) is described by the same authors. Acheson and Elmore review reactions of acetylenecarboxylic esters with nitrogen heterocycles, which have been the subject of much concentrated research in the years since Acheson s article in Volume 1. The review on indolizines (Swinboume, Hunt, and Klinkert) also concentrates on the advances of the last IS years and up-dates reviews published elsewhere. Anastassiou and Kasmai provide a critical account of the V-excessive heteroannulenes, and Fletcher and Siegrist deal authoritatively with the olefin-forming condensations of anils with methyl groups, the Anil Synthesis. ... 

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