Site‐Selective Decarboxylative Direct Formylation of Nitrogen Heterocycles (Azaindoles, Indoles, Pyrroles) and Anilines Utilizing Glyoxylic Acid

Abstract

A new method for formylation of nitrogen heterocycles overcoming the limitations of classical approaches using a cheap feedstock formylating agent especially under mild and neutral conditions is the subject of this current investigation. This work describes direct formylation of nitrogen heterocycles (azaindoles, indoles, pyrroles) and anilines using glyoxylic acid as the formyl source and K2S2O8 as the exclusive reagent. The key features include a general method for both C‐ and N‐formylation under neutral and mild reaction conditions. The application of the method is further demonstrated in the tandem synthesis of nitrogen heterocycles, pharmaceuticals, and a natural product. Unlike aroylation with arylglyoxylic acids, a previously unknown pathway for the direct formylation with glyoxylic acid in the presence of K2S2O8 is now unveiled.

K2S2O8‐Mediated C‐3 Formylation of Imidazopyridines Using Glyoxylic Acid

“…Following the inferences of control experiments (scheme 3) and prior literature reports, [5,[21][22][23][24] we tried to establish a plausible reaction mechanism of our developed methodology (Scheme 4). The reaction proceeds with the condensation of glyoxylic acid (2) to 1 a followed by its decarboxylation.…”

“…Laha et al also reported the generation of a similar condensation intermediate. [21] The decarboxylation of A was carried out by the sulfate radical anion (SO 4 À .…”

“…[20] Later, Laha et al reported formylation of various heterocycles (azaindoles, indoles, and pyrrole) using glyoxylic with potassium persulfate. [21] Although several reports are on the formylation of indoles and small heterocyclics, there is no such report on the use of glyoxylic acid for formylation of imidazopyridines. In continuation of our interest in the functionalization of imidazo[1,2-a]pyridines [5] and persulfate-based method developments, [22,23] herein, we report a highly efficient C-3 formylation of imidazo[1,2-a]pyridines by using glyoxylic acid and persulfate.…”

Recent Advances On Direct Formylation Reactions

“…Removal of an extra electron from adduct (69.5) by SO 4 *À followed by rearrangement of electrons in the system could result in the formation of 69.6 (Scheme 69). [33] 7. Miscellaneous…”