Indolizine

I I Indolizine contains an aromatic lOtt-system and thus is isoelectronic to the carbocycle azulene. Its mesomeric electron delocaHzation (described by resonance forms la-c) 

Indolizine is a base (plQ, = +3.9) much stronger than indole (pfQ, = -3.5). Indolizine is protonated at C-3 to give the indolizinium ion 2 its relative stability makes 2 less reactive and thus indolizine (in contrast to pyrrole) resistant to acid-induced polymerization  

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 ). 

Nitration occurs at different positions depending on reaction conditions. Thus, 2-methylindolizine in strongly acidic medium (concentrated HNO3/H2SO4) nitrates at C-1 (probably via attack at the indoUzinium ion), while in less acidic medium (ACONO2) the 3-position is attacked [214]  

Indolizine undergoes reduction by catalytic hydrogenation in acidic medium via the indoUzinium ion 2 depending on activity of the catalyst used, the pyridinium ion 3 (Pd/C) or indolizidine (4) (Pt) is obtained  

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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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