Synthesis of Aza-Indoles

Most syntheses of aza-indoles start from pyridines and parallel the standard indole syntheses discussed above. However, the Fischer reaction using pyridyl-hydrazones is much less consistent and useful than for arylhydrazones the Madelung reaction is also not as useful, however the Bartoli route (20.16.1.9) and the Gassman approach (20.16.1.12) can be used to effect. The most successful methods involve palladium-catalysed coupling of acetylenes with amino-halo-pyridines either as one- or two-step processes. The starting amino-halo-pyridines are generally available via directed metaUations. 

Syntheses utilising nitro-pyridines by Leimgraber-Batcho processes work well and can be modified by the introduction of a further substituent at the enamine stage.  

7-Aza-indoles can be prepared from 2,6-dichloropyridin-3-yl-epoxides by reaction with primary amines and 5-, 6-, and 7-azaindole-2-esters can be made via the Hemetsberger-Knittel route. Note that 4-aza-indoles cannot be made this way since cyclisation of the appropriate precursor takes place preferentially onto the ring nitrogen generating a pyrazolo[l,5-fl]-pyridine. 

The sequence below shows the assembly of a ring-closure precursor using a VNS (3.3.3) reaction.  

Synthesis from pyrroles is useful in particular cases.  

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A two-step, one-pot process has been developed for the synthesis of aza-indoles under dielectric heating conditions [31]. In the first step, aminopy-ridines and ketones were condensed either at room temperature (in the case of aza-indoles 19-20) or under dielectric heating at 160-220 °C to yield intermediate enamines 18. Subsequent microwave-assisted intramolecular Heck reactions furnished the corresponding 4-, 5-, 6- or 7-azaindoles in moderate to good yields (Scheme 9). 

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