3- Unsubstituted indolizines

Unsubstituted indolizines undergo oxidative dimerization in the presence of catalytic amounts... 

The most frequently used synthetic route to cycl[3.2.2]azines involves the reaction of an indolizine with a dienophile, for example, DMAD, in the presence of a dehydrogenating agent such as palladium-on-carbon (Scheme 85), although the scope of the reaction is limited by the presence of substituents in one or both of the reactants, and/or the reaction conditions. If C-3 and C-5 of the indolizine are unsubstituted, the cyclazine is the main product a 3,4-dihydrocyclazine may sometimes be isolated as a by-product (see below). 

It has been shown, by NMR studies, that the protonation of indolizines takes place exclusively at the 3-position when this position is unsubstituted. Depending on the nature and positions of the substituents, 3-substituted indolizines give mixtures of 1- and 3-protonated salts (Table 8). In 3,5-disubstituted indolizines, intramolecular overcrowding is reduced by protonation at the 3-position. 

The methods belonging to this section may provide indolizines unsubstituted in the five-membered ring, for which the Tschitschibabin reaction fails. Since they have been treated in great detail (76S209, 78AHC(23)103), only selected examples will be given here. 

This route has been particularly investigated to provide indolizines unsubstituted in the five-membered ring, for which the Tschitschibabin reaction fails. 

The protonation of indolizines in acidic media has been shown by NMR studies to take place exclusively at the 3-position when unsubstituted.102-104 3-Substituted compounds give mixtures of 1- and 3-protonated species depending on the nature and position of other substituents. Deuterium exchange also occurs preferentially in the 1-and 3-positions.108-107 It has also been reported recently that with 3-nitroso- and 3-phenylazo-2-alkyl indolizines, protonation occurs on the 3-substituent.108... 

The ultraviolet spectrum of the parent heterocycle in water shows three main peaks, at 221.5, 282, and 302 nm. The similarity of this spectrum to that of indolizine is apparently due to the fortuitous cancellation of the effects of the introduction of successive nitrogen atoms into indolizine. UV data are available for several quaternary derivatives of this heterocycle and their V-oxides." 2,3-Dihydroimidazo[l,2-a]pyr izine (5) has only two peaks, at 258 and 394 nm, in its ultraviolet spectrum in water. Both this compound and the unsubstituted aromatic heterocycle undergo large hypsochromic shifts on protonation. This contrasts with the bathochromic shift observed on protonation of aminopyrazines and is consistent with the hypsochromic effect obtained on protonation of the analogous imino compounds. These observations confirm the conclusion that protonation occurs at the 1-position in this heterocycle to give the cation 6. 

A similar addition reaction has also been reported for indolizine (429), which upon treatment with TADs gives monoadduct 430 [79H(12)787], Similarly, l-acetylimidazo[l,5-o]pyridine (431) gives with both MTAD and PTAD the corresponding Michael-type adducts 432. In contrast, unsubstituted imidazo[l,5-fl]pyridine, an aza analogue of 429, gives with TADs a 2 1 adduct (95JHC1525),... 

The 3-diazoniumtetrafluoroborates 64 were obtained in good yields via nitrosation of 3-aminoquinolizines 63. Treatment of 64 with anhydrous alcohol afforded a mixture of alkyl indolizine-3-carboxylates 67 and the 3-unsubstituted 4/f-quinolizin-4-ones 68. The product selectivity of this reaction depends upon the alcohol. The formation of indolizine 67 has been regarded as an aza Wolff rearrangement through ring contraction via 65 and... 

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