7- Azaindole Mannich reaction

The Mannich reaction with azaindoles is of great importance as it leads to azagramines, which are useful as intermediates. Unfortunately, almost all of the work has been done with 7-azaindoles. 

Several modifications of the Mannich reaction were tried with 5-azaindole, but no isolatable product could be obtained. Since the Mannich conditions are usually acidic (pH 5-7), it seems the difference in reactivity between 5- and 7-azaindole can be accounted for by the greater basic strength (pK 8.26 ) of the former compared to the latter (pK 4.59 ). As noted above, protonation of the pyridine nitrogen has the effect of lowering the electron availability at the 3-position. Under the conditions of the reaction 5-azaindole would exist almost entirely in the protonated form (101), which is stabilized by resonance with the pnra-quinonoid canonical form (102), thus lowering the electron density of the pyrrole ring further. Protonation of 7-azaindole would be only partial, with mostly neutral molecule present. Also, the orfAo-quinonoid form (104) of the protonated species (103) is unimportant (see Section V,B,2). 

It was noted above (Section IV,C,3) that the failure of 5-azaindole to undergo the Mannich reaction could be accounted for by its high basic strength. Difficulty might be expected also for 6-azaindole, and less so for 4-azaindole. The only attempt reported was successful with ethyl 5-methoxy-6-azaindole-3-carboxylate, but the predicted pK for 5-methoxy-6-azaindole would be ca. 5.9, which may be lowered further by the electron-withdrawing ester group. It will be of interest to see how the parent azaindoles differ in these reactions. 

Reactions with electrophilic reagents takes place with substitution at C-3 or by addition at the pyridine nitrogen. All the azaindoles are much more stable to acid than indole (c/. section 17.1.1) no doubt due to the diversion of protonation onto the pyridine nitrogen, but the reactivity towards electrophiles at C-3 is only slightly lower than that of indoles. Bromination and nitration occur cleanly in all four parent systems and are more controllable than in the case of indole. Mannich and Vilsmeier reactions can be carried out in some cases, but when the latter fails, 3-aldehydes can be prepared by reaction with hexamine, possibly via the anion of the azaindole. Alkylation under neutral conditions results in quaternisation on the pyridine nitrogen and reaction with sodium salts allows A-1-alkylation. Acylation under mild conditions also occurs at N-1. The scheme below summarises these reactions for the most widely studied system - 7-azaindole. 

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