Indolizines

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. 

It was found that basic alumina worked well as the basic catalyst for the in situ dipole generation from the AT-acyl pyridinium salt. A three-component mixture of phenacyl bromide (1 mmol), pyridine (1.2 equiv.) and the acetylene (1.2 equiv.) was thoroughly mixed in basic alumina (1 g) and then irradiated for 8 min at 80% power in a domestic microwave. The products were formed in 87-94% yields when running the reaction under solvent-free conditions and in 60-71% yields when using anhydrous toluene as the solvent. 

The aromatic character of indolizine is expressed by three main mesomeric contributors, two of which incorporate a pyridinium moiety other structures (not shown) incorporating neither a complete pyrrole nor a pyridinium are less important. 

Aromatic indolizines are very rare in nature, but the fully reduced (indolizidine) nucleus is widespread, particularly in alkaloids, of which swainsonine is a typical example. Synthetic indolizines have found use in photographic dyes. 

Indolizine is an electron-rich system and its reactions are mainly electrophilic substitutions, which occur about as readily as for indole, and go preferentially at C-3, but may also take place at C-1. Consistent with their similarity to pyrroles, rather than pyridines, indolizines are not attacked by nucleophiles, nor are there examples of nucleophilic displacement of halide. 

Indolizine, pA a 3.9, is much more basic than indole (pA a -3-5) and the implied relative stability of the cation makes it less reactive and thus indolizines resistant to acid-catalysed polymerisation cf. Section 17.1.9). Indolizine protonates at C-3, but 3-methylindolizine protonates mainly (79%) at C-1 the delicacy of the balance is further illustrated by 1,2,3-trimethyl- and 3,5-dimethylindolizines, each of which protonate exclusively at C-3. Electrophilic substitutions such as acylation, Vilsmeier 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-1, presumably via attack on the indolizinium cation. 

Heterocyclic Chemistry 5th Edition John Joule and Keith Mills 2010 Blackwell Publishing Ltd 

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Pyridazinium and phthalazinium dicyanomethylides give indolizines as primary adducts with 1,2,3-triphenylcyclopropene, either by [4 + 2] cycloaddition or by 1,3-dipolar addition of the ylide to triphenylcyclopropene (81JCS(P1)73). 

The major internal comparisons to be made within this chapter are between (13) pyrrole (1), furan (2), thiophene (3), selenophene (4) and tellurophene (5) b) pyrrole (1) and indole (6) (c) indole (6), benzo[6 Jfuran (7) and benzo[6]thiophene (8) d) indole (6), isoindole (9) and indolizine (10) and (e) benzo[6] and benzo[c] fused systems. The names of relevant heterocyclic radicals are given with the structures of the parent heterocycle. 

Although it has not been possible to study the protonation of isoindole itself, it is clear that isoindoles are more basic than indoles or pyrroles. For example, 2,5-dimethyl-1,3-diphenylisoindole (40) has a p/sTa of 4-2.05 protonation of isoindoles occurs at positions 1 or 3. The pK for protonation of indolizine (10) at position 3 is 4-3.94 and that for carbazole (41) for protonation on nitrogen is estimated at -6.0. 

It is of interest to compare the stability of the protonated forms of benzo[u], benzo[Z>] and benzo[c] fused pyrroles, i.e. the cations derived from indolizines, indoles and isoindoles. Indolizine gives a stable pyridinium ion and does not polymerize in the presence of acid. 

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 acid catalyzed condensation of benzaldehydes with 2-acetyIpyridine provides access to hydroxy- or amino-indolizines (Scheme 58a) (71CB1629,71CB1645). A remarkable synthesis of fused pyrrolidines in which aldehydes also provide C-2 is exemplified in Scheme 58b... 

UV, 4, 179 <77JPC12), 449 <57JCS4510) Indolizine, 3-benzoyl-6-bromo-l-(2-pyridyl)-X-ray, 4, 445 (76MI30800)... 

Benzimidazolo[l,2-c]thiatri azoles synthesis, 6, 612 Benz[cd]indazole antiaromaticity, 5, 208 Benz[cd]indazole, dihydroaromaticity, 5, 208 Benz[e]indolizine synthesis, 4, 466 Benzipiperylon biological activity, 5, 296 Benz[/]isoindoles synthesis, 4, 266... 

Dieckmann reaction, 4, 471 Indolizidine alkaloids mass spectra, 4, 444 Indolizidine immonium salts reactions, 4, 462 Indolizi dines basicity, 4, 461 circular dichroism, 4, 450 dipole moments, 4, 450 IR spectra, 4, 449 reactivity, 4, 461 reviews, 4, 444 stereochemistry, 4, 444 synthesis, 4, 471-476 Indolizine, 1-acetoxy-synthesis, 4, 466 Indolizine, 8-acetoxy-hydrolysis, 4, 452 synthesis, 4, 466 Indolizine, I-acetyl-2-methyI-iodination, 4, 457 Indolizine, 3-acyloxy-cyclazine synthesis from, 4, 460 Indolizine, alkyl-UV spectra, 4, 449 Indolizine, amino-instability, 4, 455 synthesis, 4, 121 tautomerism, 4, 200, 452 Indolizine, 1-amino-tautomerism, 4, 38 Indolizine, 3-amino-synthesis, 4, 461, 470... 

Indolizine, 3-benzoyl-6-bromo- l-(2-pyridyl)-structure, 4, 445 In4olizine, 3-chloro-synthesis, 4, 470 Indolizine, 3-cyano-cyclazine synthesis from, 4, 460 Indolizine, 8-cyano-synthesis, 4, 469... 

Indolizine, 1 -cyano-2-(methylthio)-synthesis, 4, 465 Indolizine, 3,5-dialkyl-synthesis, 4, 475 Indolizine, dihydrosynthesis, 4, 467, 468 Indolizine, dimethyl-mass spectrometry, 4, 187 Indolizine, 1,2-dimethyl-oxidative dimerization, 4, 458 Indolizine, 2,6-dimethyl-cycloaddition reaction, 4, 460 reduction, 4, 459... 

Indolizine, hydroxy-conformations, 4, 451 GLC retention times, 4, 451 synthesis, 4, 121 tautomerism, 4, 198, 452 Indolizine, 2-hydroxy-synthesis, 4, 463 Indolizine, 8-hydroxy-conformation, 4, 452 Indolizine, 2-hydroxymethyl-synthesis, 4, 461 Indolizine, 3-hydroxymethyl-synthesis, 4, 461 Indolizine, 6-hydroxymethyl-synthesis, 4, 461 Indolizine, methyl-mass spectra, 4, 187, 450 NM 4, 448 Indolizine, 2-methyl-diazo coupling, 4, 454 mass spectra, 2, 529, 4, 450 nitration, 4, 50, 454 nitrosation, 4, 454 reaction with diaryl disulfide, 4, 460 reaction with nitroethane, 4, 460 Indolizine, 3-methyl-basicity, 4, 454 Indolizine, 5-methyl-acidity, 4, 461 synthesis, 4, 466 Indolizine, 6-methyl-mass spectra, 4, 450 Indolizine, l-methyl-2-phenyl-nitration, 4, 454 nitrosation, 4, 454, 455 Indolizine, 3-methyl-2-phenyl-reaction... 

Naphtho[2,3-h]indolizine-6,l 1-dione, 1, 337 Naphthoisocoumarin synthesis, 3, 831, 832 Naphtho[l,2-c]isothiazole, 3-amino-synthesis, 5, 136 2-Naphthol, l-(2-thiazolylazo)-analytical uses, 6, 328 Naphtholactam, 1, 326 Naphtholactone dyes, 1, 326... 

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