Indolizines preparation

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). 

Thienoindolizines can be prepared by treatment of the alkenylindolizine 261 with bromine and a base, whereby bromination of the indolizine ring also occurs. Alternatively, reaction of 261 with a tetraalkylammonium tribromide and a base gives the tricycle 262, which can then be brominated to 263 by treatment with molecular bromine <2004CPB279> (Scheme 71). 

Pyrano[3,2 ]indolizines such as 120 can be prepared from the reaction of N-( 1 -benzotriazolylmethyl)indolines with 3,4-dihydro-2//-pyran under acidic or Lewis-acidic conditions (Equation 26) <2001T4933>, and a simpler analogue 122 is the end product of an annulation process starting from the enamine 121 and ethyl acrylate <1996H(43)1391> (Scheme 34). Pyrano[4,3-/]indolizinetriones, for example, 124, result from the hydrolysis of protected 2,3-dihydro-l//-indolizincdioncs 123 (Equation 27) <2000H(53)771>. 

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. 

When the reaction of enaminone (223) and dimethyl methoxymethy-lenemalonate was carried out in THF in the presence of butyllithium, pyrrolidinomethylenemalonate (224) was obtained in 4% yield. When this reaction conducted in DMF in the presence of potassium tert-butylate, pyrrolidinomethylenemalonate (224) and 2,3-dihydro- l//-indolizin-5-one (225) were prepared in 21 and 46% yields, respectively (88AP345). 

Aminoester 121a and isomeric indolizine 121b (Scheme 31) are the products of the [1,2] and [2,3] rearrangement, respectively, of ene-endo-spirocyclic, didehydropiperidine-derived ammonium ylide 120 that was in situ prepared from the diazoester (050L2075). Acyclic ta-iodo-... 

Azo derivatives of indolizines are readily prepared since the arenediazonium ion is a good electrophile. Compounds of this type are sometimes used as dyes (73AC(R)95>. Another method of preparing azobisindolizines is by reaction of indolizines with tosyl or picryl azides thus compound (33) has been obtained from 2-methylindolizine by this route. Redox characteristics of such compounds have been studied (71LA(752)182, 71LA(752)196). 

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). 

The indolizines (36)-(38) have been prepared because of their similarity to the naturally occurring tryptophan, gramine and heteroauxin respectively. 

The reaction of indolizines with aldehydes and ketones in the presence of acids yields coloured salts, two of which (43 and 44) are given here for illustration. The salts (45) and (46) have been obtained from the reaction of the pertinent indolizines with formaldehyde and glyoxal respectively. Polymethine dyes, some of which have found application in photography, have been prepared from indolizines and malondialdehyde derivatives or vinylogous dialdehydes (47) was prepared from 1,2-dimethylindolizine and /3-ethoxy-acrolein diethyl acetal (48). 

Little work has been carried out on halogenation of indolizines. Only the preparation of iodo derivatives appears to be straightforward (71MI30800). Thus iodination of the 3-position of l-acetyl-2-methylindolizine was achieved by treatment with iodine and sodium acetate (69YZ1020). 

There are only a few reports on oxidations which leave the indolizine nucleus intact. The reaction of the 3,3 -methylenediindolizine (61), which was prepared by reaction of the... 

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

The reaction of 2-acylpyridinium bromides (117) with hydrazine hydrate provides an excellent method for the preparation of 1,2-disubstituted indolizines (119). The yields are generally better than in the corresponding Tschitschibabin reaction. The reaction may proceed via the derivative (118), which loses nitrogen to give the indolizines (Scheme 17). 

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. 

If an allyl halide is used as the quaternizing agent, an intramolecular 1,5-cyclization of the ylid may take place. In this way, various dihydro-indolizines, which are prone to oxidation and thus difficult to prepare, have been made.67 The probable mechanism is shown in Scheme 9. 

Diphenylcyclopropenone has proved to be a useful synthetic reagent for preparing indolizines.91 It reacts readily with pyridine to give the indolizine 79 in 50% yield, and the yields of cyclized compounds tend to be greater when pyridazines and pyrazines are used instead of pyridines to give azaindolizines. 

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... 

Some indolizines (90-92) have been prepared because of their structural similarity to naturally occurring indoles tryptophan, gramine, and heterauxin, respectively. 

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... 

Nitration of indolizines is seldom attempted in view of accompanying oxidation reactions. Thus the synthesis of 6- and 8-nitro-2-phenyl-indolizine has been achieved by the cyclization of appropriately substituted 2-methyl-1-phenacylpyridinium bromide.179 However, 1-nitro and 1,3-dinitro compounds have been prepared.4 From the behavior of the indolizine nucleus toward other electrophiles, 3-nitroindolizine might be expected to be the primary product. This compound has been synthesized using a dilute solution of nitric acid in acetic acid at - 70°C where the substrate could well be the base and not the 3-protonated cation as in a nitric acid-sulfuric acid mixture.180... 

Not surprisingly, azo derivatives of indolizines are readily prepared since the aryl diazonium ion is a good electrophile. Many compounds of this type (e.g., 129188) have been synthesized,183 188,189 some of which are used as dyes.190... 

Cyclazines are an interesting class of compounds that can be synthesized by intramolecular cyclization to the 3-position of the indolizine ring.200 The reactivity of the methyl group in 5-methylindolizine is similar to that in 2-picoline, and this provides the means of preparing cycl[3,2,2]azines. Thus, the reaction of 5-methyl-2-phenylindolizine with butyl lithium followed by JV,JV-dimethylbenzamide yielded the 5-(phenacyl) derivative, which could be ring-closed to 133 by heating... 

Theil, F. Sonnenschein, H. Kreher, T. Lipase-catalyzed resolution of 3,3 -bi-indolizines the first preparative access to enantiomerically pure samples. Tetrahedron Asymmetry 1996, 7, 3365-3370. 

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