Indolizine ring

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). 

Ring contraction to form the indolizine ring system is another side-reaction in the alkaline hydrolysis of a quinolizine ester. Acheson etal.30 have studied in detail the conversion of tetramethyl 4Zf-quinolizine-1,2,3,4-tetracarboxylate into the corresponding indolizine derivative. 

Figure 7 Averaged molecular geometry for the indolizine ring from X-ray diffraction data on (7)...

X-Ray data on the crystal structure of the indolizine (7) and the [2.3.4]cyclazine (8) showed that the indolizine ring system is nearly planar. Bond distances of (7) and (8) are given in Table 1. 

Hydrolysis of 8-acetoxyindolizine did not allow isolation of the corresponding indolizinol owing to spontaneous decomposition. A stabilization could be effected by introduction of electron withdrawing groups in position 3 of the indolizine ring (81JCR(S)366). 

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... 

Finally, the compounds in the margin form a medicinally important group of molecules, which includes antitumour compounds for humans and anthelmintics (compounds that get rid of parasitic worms) for animals. They are derived from a 6/5 fused aromatic ring system that resembles the ten-electron system of the indolizine ring system but has three nitrogen atoms. 

X-ray data of indolizine (2) indicate contributions of C=S -bonds in the molecular structure <85IZV2724>. An X-ray structural investigation of (3) reveals that it occupies a two-bladed propeller conformation with an anti relation between the methylene protons and the four methyl groups. In the crystal, the molecule lacks a C2 symmetry and is asymmetric rather than helical. Since the indolizine ring carries no substituents which conjugate, the structural results supply information about the geometry of indolizine itself <87CB23i>. 

Nitrogen Systems.—Monoaza-compounds. Treatment of the azapentalene anion (745) with dichloromethane and butyl-lithium yields a mixture of indolizine (746 R = H) and compound (747) it has been established that the latter is not a precursor of indolizine.3-Diethylaminoindolizine (746 R = NEt2) is formed by the reaction of 2-bromopyridine with propargyl alcohol and diethylamine in the presence of bis(triphenylphosphine)palladium(ll) dichloride and copper(i) iodide. The pyridinium ylide (748) undergoes 1,5-dipolar cyclization to the tran -dihydroindolizine (749). As in previous years, there have been several reports on the synthesis of the indolizine ring system from pyridinium ylides the methide (750 R = H, R = Ph) adds benzylideneacetophenone to form the tetrahydroindolizine (751), the action of phenyl vinyl sulphoxide. 

The NE region appears to be specifically recognized by a narrow groove on the binary enzyme-DNA complex, and both steric and electronic constraints of the indolizine ring system are therefore crucial for the potent Topo I inhibitory activity of camptothecin. 

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. 

Although the position 3 in the indolizine ring is the most reactive toward electrophilic attack, no direct fluorination of indolizines have been reported. Instead, in the recent work [2] 1,3-dipolar cycloaddition was studied to difluoro-substituted pyri-dinium ylides. 

Position 1 of the indolizine ring is the second one (after position 3) that can be attacked by electrophiles. However, there are no examples of direct fluorination of indolizine ring at position 1. Among the benzoindolizines there is such an example [15] where the desired F-containing scaffold 25 was obtained by use of Selectfluor. 

It is difficult to obtain pure isomers containing fluoro (or perfluorinated group) at 6- or 8-position. Since the substituents cannot be inserted directly into the pyridine fragment of indolizine ring, they should already exist in the precursors of the corresponding indolizines. However, this caused loss of regioselectivity (if )-substituted pyridinium salts were used) or necessity to use poorly available )-substituted a-picolines. 

Palladium-carbon/oxygen Indolizine ring opening... 

Benz[a]indolizine ring. Piperidine added with stirring to a mixture ofN-[(2,4,6-trinitrophenyl)phenacyl]pyridinium betaine and dimethyl sulfoxide, allowed to stand 3 hrs. with occasional stirring 6-benzoyl-7,9-dinitrobenz[a]indolizine. Y 96%. F. e. s. W. Augstein and F. Krohnke, A. 697, 158 (1966). 

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