Aza-Indolizines

Note as can be seen from the examples above, numbering sequences vary with the number and disposition of the nitrogen atoms. 

Seven monoaza- and many more polyaza-indolizines (some are shown above) are possible, indeed compounds with up to six nitrogen atoms have been reported. Despite the rarity of such systems in nature, there is much interest in aza-indolizines stemming from their structural similarity to both indoles and purines. 

Apart from pyrrolo[l,2-(7]pyridazine, all the monoaza-indolizines protonate on the second (non-ring-junction) nitrogen, rather than on carbon. Alkylation similarly goes on nitrogen, however other electrophilic reagents attack with regioselectivity similar to indolizine itself - they effect substitution of the five-membered ring at positions 1 and 3 (where these are carbon). 

Electrophilic substitutions such as halogenation, nitration etc. go at C-3, or at C-5 if position 3 is blocked. Acylation does not require a catalyst.  

Of all the positional chloro isomers, nucleophilic displacement reactions are known only for the 5-isomer  

4-triazolo[4,3-a]pyridine imidazo[1,5-c]pyrimidine imidazo[1,5-d [1,2,4]triazine pyrrolo[1,2-a]pyrazine 

Of all the positional chloro-isomers, nucleophilic displacement reactions are known only for the 5-isomer 7-chloroindolizine, where one might have anticipated similar activation, is not reactive in this sense.  

Another useful method involves the intermediacy of a pyridinium ylid as a 1,3-dipole in a cycloadditionJ  

Base-catalysed deuterium exchange goes at C-3 and C-5 preparative lithia-tion occurs at C-3, or if C-3 is blocked, at C-5 or C-8 depending on other substituents.  

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Armarego109 has determined the pAa values of indolizines and aza-indolizines from their ultraviolet spectra. He found that indolizine itself has the same basic strength as a-naphthylamine (pAa 3.9) and that a methyl substituent increases the pAa by two to three units. Mason and Smith,110 studying the fluorescence spectra of various aromatic nuclei including indolizine, found no evidence to support the prediction that acid-base properties of aromatic hydrocarbons in the first electronic excited state should differ from those in the ground state. 

C. Schommer, Neue Synthese fur photochrome Dihydro(aza)indolizine, Thesis, Universitat des Saarlandes, Saarbriicken (1987). 

Reaction of the nitrone 4-184 with allenic esters 4-185 as described by Ishar and coworkers led to the benzo[b]indolizines 4-186, together with small quantities of 4-187 (<5%) (Scheme 4.40) [63]. The first transformation is a 1,3-dipolar cycloaddition this is followed by four further steps, including a [4+2] cycloaddition of an intermediate 1-aza-l,3-butadiene. 

The aza-tricyclic lactone 320 is an intermediate in the synthesis of the indolizidine 321, which is the indolizine analogue of the pyrrolizidine alkaloid platynecine <1995TL5109> (Scheme 84). 

Pyrimidine as the outer ring. Indolizines and their aza analogues fused to a uracil ring are produced in several ways (1) by thermal cyclization of 5-(2,2-dicyanoethenyl)-6-pyrrolidinouracil (Equation 66) <1998JCM502,... 

Numerous replacements for the indole core have been investigated, including imidazoles, thienoimidazoles, pyrroloimidazoles, quinolines, indolizines and several aza-indoles. Attachment of an N,N-dimethylacetamide side-chain to the thienopyrrole scaffold gives compound 34 with nanomolar enzyme activity (IC50 = 58 nM) and enhanced cell activity (EC50 = 2.9 pM) compared to the unalkylated scaffold [79]. 

The 1,3-dipolar cydoaddition reactions ([3-1-2]) are often used to synthesize five member aza- or azoxaheterocycles. Depending on the nature of the 1,3-dipoles employed in the transformation, different types of heterocycles such as isoxaza-zoles [270], isoxazolines (Scheme 3.22) [110], hydantoins [271], pyrrolidines [272], indolizines [273] or pyrazoles [274] are obtained. 

Further substitution of the peripheral carbon atoms of the cyclazines by heteroatoms (N, S, etc.) is indicated in this chapter according to the replacement nomenclature system (aza, thia, etc.). Although, strictly, this runs contrary to the rules,lc since it is a heterocyclic, not a hydrocarbon, system which is replaced, the connection between closely related compounds can more clearly be seen. It should be noted that Chemical Abstracts employs the systematic fusion nomenclature I, for instance, is pyrrolo[2,l,5-cd]indolizine. 

Several names have been used in the chemical literature for pyrrolo[l,2-a]pyridine including pyrrocoline, pyrindole, pyrrodine and 8-pyrrolopyridine, but the one which is now used by Chemical Abstracts, and which will be used in this chapter, is indolizine. The numbering of the system is shown in formula (1). The denomination of aza derivatives follows the replacement nomenclature system, e.g. 1-azaindolizine, etc. It should be noted that Chemical Abstracts follows the systematic fusion nomenclature 1-azaindolizine, for instance, is imidazo[l,2-a]pyridine. The cyclazine nomenclature is treated in Section 3.08.9.1. 

Quantum chemical calculations of indolizine and its aza derivatives have been reviewed (77HC(30)117). Attempts to correlate the results with various physical and chemical properties have not always been crowned with success. (A critical discussion of semi-empirical molecular orbital methods is given in Section 3.01.7.) A qualitative discussion using single structures may be appropriate. 

A rigorous theoretical treatment of the non-alternant and heterocyclic indolizine is extremely difficult and, even for the related isoconjugate hydrocarbon, far from conclusive. Many questions, however, in which experimentalists are interested may be answered in a satisfactory way on the basis of a perturbational treatment. This approach has been used for a discussion of the electronic spectra of indolizine and some azaindolizines (63JCS3999). Following first-order PMO theory the 7r-stabilization which follows from aza substitution at the different positions of the model molecule depends on the ir-electron density qt as well as the change in electronegativity Sat (B-75MI30801). The perturbations caused by aza substitution of the indenyl anion are depicted in Scheme 1. 

Information concerning the effect on 5-values of aza substitution as well as of methyl groups and electron attracting ester and nitrile groups may be obtained from the examples given in Tables 2, 3 and 4. Using Tables 8 and 9 of Section 3.01.4.1, a comparison of the NMR spectra of indolizine, indole and isoindole is possible. 

UV spectra of alkylindolizines and azaindolizines in water have been reported (64JCS4226), as well as a study of the fluorescence spectra of indolizines and aza analogues (77JPC12). 

The lone-pair electrons of bridgehead nitrogens in indolizine and its aza analogs [458] are delocalized, as concluded from carbon-13 shifts and in accordance with CNDO calculations All ring carbons of the parent indolizine except C-5 and C-9 (Table 4.67) are shielded (99-120 ppm) due to the (+ )-M electron releasing effect of the bridgehead nitrogen. 

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