The Fischer Reaction in the Synthesis of 2,3-Disubstituted 7-Azaindoles*

Abstract

We present the results of our study towards the synthesis of 2,3-disubstituted 7-azaindoles by cyclization of 2-pyridylhydrazones of aliphatic and alkylaromatic ketones under the conditions of Fischer reaction, catalyzed by polyphosphoric acid.

Synthesis of 2,3‐Disubstituted 5‐Iodo‐1H‐Pyrrolo[2,3‐b]pyridines via Fischer Cyclization

“…The Fischer reaction widely used for indole synthesis may be applied for the preparative synthesis of 7‐azaindole framework in polyphosphoric acid (PPA) at 160–180°C, as we have demonstrated previously for unsaturated and bromo‐substituted derivatives . The main purpose of present work is to extend the field of application of the Fischer indole synthesis under thermal conditions for the preparation of 2,3‐disubstituted 5‐iodo‐7‐azaindole moiety and to explore the influence of iodine atom in pyridine ring on the yields of the final products.…”

Understanding and Interrupting the Fischer Azaindolization Reaction

“…4 This transformation was first tested over 100 years ago. 5 It is now known, particularly via the studies of Parrick 4a,b and Robinson 4c that the azaindolization can proceed under extreme thermal conditions.…”

“…4 This transformation was first tested over 100 years ago. 5 It is now known, particularly via the studies of Parrick 4a,b and Robinson 4c that the azaindolization can proceed under extreme thermal conditions. For the corresponding acid-mediated process to take place, certain substituents on the hydrazine (e.g., methoxy, halides) can be used to improve reactivity, but the origins of such beneficial effects have remained unknown.…”

“…For the corresponding acid-mediated process to take place, certain substituents on the hydrazine (e.g., methoxy, halides) can be used to improve reactivity, but the origins of such beneficial effects have remained unknown. 4d–g …”

“…As noted earlier, it is known that introduction of a methoxy substituent on the pyridylhydrazine (e.g., see 9 , Figure 2) leads to improved yields in experimental studies. 4d–g This has previously been rationalized by a “push/pull” effect 4d which, in turn, makes the [3,3]-sigmatropic rearrangement more favorable. Instead, we suggest that the methoxy group reduces the basicity of the pyridine nitrogen, thus rendering the proton transfer/tautomerization more feasible.…”