Indolizines acylation

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. 

The monosubstitution products of the Friedel-Crafts reaction and of the nitration reaction have been interrelated to show that the substituent group is introduced at the same position in each case. A further correlation with the adduct (Id) from indolizine and methyl propiolate provides evidence that this is the 1-position as predicted.56 Acylation of 2-methoxycarbonyl-3-phenylcycl[3,2,2]azine (Is) takes place in the pyrrole part of the molecule.51... 

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. 

Heating of acyl- or ethoxycarbonyl-methines (123) with anhydrides yields the indolizines (120), (121) and (122). The 2-diacylmethylenepyridines (124) are thought to be intermediates in these reactions. 

A novel microwave-mediated three-component coupling of a-acyl bromides, pyridine and internal alkynes was carried out in the absence of a solvent on activated basic alumina to provide a collection of indolizines (Scheme 3.5)7. It was proposed that the reaction proceeded via in situ generation of a dipole from an N-acyl pyridinium salt, followed by a [3+2] cycloaddition reaction. A dedicated laboratory microwave system was... 

The indolizines constitute the core structure of many naturally occurring alkaloids, such as (-)-slaframine, (-)- dendroprimine, indalozin 167B and coniceine. There are a number of different routes to the synthesis of indolizines and they are most commonly synthesised by sequential N-quaternisation, intramolecular cyclocondensation reactions or the cycloaddition reaction of /V-acyl/alkyl pyridinium salts. 

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. 

In favorable cases, the reaction gives good yields of the 1-acyl-indolizine 13a. However, where either the carbonyl or —N+CH2— group is not sufficiently activated, unexpected products are formed [e.g., 14 -> 15 but 16 -> 17 Eqs. (5) and (6)]. Both Melton and Wibber-... 

A similar mercaptoacetate addition reaction to 5-acyl-4,7-dioxo-4,7-dihydrobenzo[i]thiophene-2-carboxylates followed by cyclization and oxidation to give benzo[ 1,2-6 5,4-ft ]dithiophene-4,8-dione derivatives 29 has been shown <03H1689>. Nitrogen bridged heterocycles, 3-(benzylthio)thieno[3,4-6]indolizine derivatives 30 have been synthesized and intramolecular arene-arene interactions within these compounds were reported <03CPB75>. The arene-arene interaction leads to significant shifts in the proton NMR signals and red shifts in the absorption maxima. 

Reviews - Acyl anion equivalents,1 2 crown ethers in synthesis,3 intramolecular 1,3-dipolar additions,11 oxazolines in synthesis,5 oxidation-reduction condensations,6 oxythallation,7 transition metals in synthesis,8 9 and ynamines in synthesis.10 Also reviewed are syntheses of pyridines,11 pyrroles,12 and indolizines.13 Other reviews are in specific sections. 

Ohler, E., El-Badawi, M., and Zbiral, E., Dialkyl (l,2-epoxy-3-oxoalkyl)phosphonates as synthons for heterocyclic carbonyl compounds. Synthesis of acyl-substituted thiazoles, indolizines, imidazo[ 1,2-fii]pyridines and imidazo[l,2-fii]pyrimidines, Chem. Ber., 118, 4099, 1985. 

Indolizines. Cycloisomerization of 7-(2-pyridyl)propargylic esters catalyzed by Ptl2-Ph3P is found to be affected by substituents at the a-position and the acyl group. Perhaps formation of two different types of products is determined by the degree of loosening of the propargyloxy bond. ... 

Yet another procedure used to prepare fused pyrroles is three-component condensation of an acyl bromide, pyridine, and an acetylenic compound, catalyzed by basic alumina, to give the corresponding indolizines 42 in 87-94% yield (Scheme 17.31) [84]. The mixture was irradiated for 8 min in a monomode MW reactor vdth a temperature limit of 250 °C. 

Six articles cover general aspects of heterocyclic chemistry 1,3-dipolar cycloreversions, syntheses with arylnitrenes and a-metallated isocyanides, and photo-oxygenation of nitrogen heterocycles,while others deal with more specialized subjects, i.e. preparation and use of halogeno-lactones, aspects of the chemistry of furan, 1-hydroxy-indoles, ring-opening of azoles by the action of amines, " the use of 2-chlorobenzoxazolium (1) and other heterocyclic onium salts for dehydration and condensation reactions," the synthesis of monosub-stituted tetrathiafulvalenes (2), cycloadditions of azoles containing three heteroatoms,sydnone imines (3), the conversion of acyl-benzofuroxans into nitro-indazoles (cf. p. 199), and advances in the chemistry of pyrrolizidine " and indolizine." ... 

Novel 2-acyl-6-aryl substituted indolizines were obtained starting from 4-acyl-p)rrrole-2-carbaldehyde and a, (3-unsaturated esters, in the presence of K2CO3 in DMF, with pelds between 42 and 68% after 8-12 h at 50°C [26]. 

Zhang et al. effected palladium-catalyzed oxidative C3-vinylations of indol-izine-l-carboxylates 136 with various styrenes (Scheme 10.45)."° Use of the bidentate nitrogen ligand bipy was key to formation of the branched a-product regioisomer 137 over the linear P-product. The authors later demonstrated that the same indolizine-l-carboxylates could be C3-acylated with a variety of a,P-unsaturated carboxylic acids via C—H and C—C double bond cleavage under oxidative conditions (138). "... 

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. 

Electrophilic substitution on indolizine takes place at C-3, such as acylation (e.g., AC2O/ACOH), ViLSMEiER formylation (DMF/POCI3), or diazo coupling (Ar — N ). 

The first example of a stable pyridinium yhde of type 80 is the pyridinium phenacylide (80, A = CH2COPh), obtained from the N-phenacylpyridinium ion (79, A = CH2COPh) by deprotonation with Na2C03 [97]- The reactivity of the pyridinium betaines is determined by their electron distribution (80a-c). Thus, they can be smoothly alkylated or acylated at the N-substituent ( 81) as 1,3-dipoles, they undergo dipolar cycloadditions with activated alkynes or alkenes [98] for example, the sequence 80 —> 82 83 establishes an efficient principle of indolizine synthesis (cf. p. 154). 

Bobiovskii SI, l.iLshnikov DE, Bundel YuG (1989) De-acylation, le-acylation and isomerization of 2-methyl-3-trihalogenacetyl indolizines. Zh Oig Khim 10 2251-2252 (Russ)... 

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