Pyrroles indolizines

Alkyl Ketones Phenols Ferrocenes Pyrroles, Indolizines... 

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). 

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

Alkenyl and alkynyl Fischer carbene complexes reacted with pyrrole imine 108 to give, through a 1,2- and 1,3-metal migration, respectively, indolizine derivatives at a different level of unsaturation (Scheme 29) <1999JA3065>. 

For example, rhodium catalyzed hydroformylation of 2-formyl-N-allyl-pyrrol gives an approx. 1 1 mixture of iso- and u-aldehydes. The latter cyclizes immediately in an aldol reaction followed by dehydration giving 7-formyl-5,6-indolizine in up to 46% (Scheme 29) [83]. Since here only one of the aldehyde groups can act as the enolate nucleophile this cyclization proceed with high regioselectivity (Scheme 29). 

Alekseeva et al. (1972b) have carried out a comparison of calculated values of localization energies and free valency indices of pyrrolo[ 1,2-a] imidazole, pyrrolo[l,2-a] benzimidazole and indolizine. In all these molecules the a-position of the pyrrole ring is calculated to be more reactive than the / -position. The free valence indices increase in the order indolizine < pyrrolobenzimidazole < pyrroloimidazole, which is also the order of increasing basicity. 

The HMO resonance energy per electron (REPE value5,48) using an appropriate reference structure was found to be 0.040 / (cf. pyrrole 0.039 / , indolizine 0.027 /3).s... 

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... 

The abstract of Russian work on the application of Hartree-Fock perturbation theory to the calculation of 7r-electron ring currents in inter alia pyrrole, indole, indolizine and carbazole reports agreement between calculated and experimental HNMR shifts... 

It seems useful to compare the chemical properties of indolizines with those of pyrroles, indoles and isoindoles. There is however one important exception, namely that cycloadditions involve the entire 7r-system of indolizines. 

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. 

Substituted indolizines have been hydrogenated to give 5,6,7,8-tetrahydroindolizines (72) using Raney nickel or a platinum catalyst at ambient temperature and pressure. The hydrogenation of the pyrrole ring of indolizine to (73) was successful with palladium on charcoal in aqueous hydrogen bromide. It is almost certain (see Section 3.08.3.1) that the 3H-indoIizinium cation is formed initially. 

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