Selective, C-3 Friedel-Crafts acylation to generate functionally diverse, acetylated Imidazo[1,2-a]pyridine derivatives

Abstract

Carbon-carbon bonds are integral for pharmaceutical discovery and development. Frequently, C–C bond reactions utilize expensive catalyst/ligand combinations and/or are low yielding, which can increase time and expenditures in pharmaceutical development. To enhance C–C bond formation protocols, we developed a highly efficient, selective, and combinatorially applicable Friedel-Crafts acylation to acetylate the C-3 position of imidazo[1,2-a]pyridines. The reaction, catalyzed by aluminum chloride, is both cost effective and more combinatorial friendly compared to acetylation reactions requiring multiple, stoichiometric equivalents of AlCl3. The protocol has broad application in the construction of acetylated imidazo[1,2-a]pyridines with an extensive substrate scope. All starting materials are common and the reaction requires inexpensive, conventional heating methods for adaptation in any laboratory. Further, the synthesized compounds are predicted to possess GABA activity through a validated, GABA binding model. The developed method serves as a superior route to generate C-3 acetylated imidazo[1,2-a]pyridine building-blocks for combinatorial synthetic efforts.

BF3-Mediated Acetylation of Pyrazolo[1,5-a]pyrimidines and Other π-Excedent (N-Hetero)arenes

“…Acylation reaction is a fundamental and valuable transformation in organic synthesis and is often employed in manufacturing various pharmaceuticals, cosmetics, and agrochemicals. − Furthermore, acylated compounds are of great interest because they have demonstrated utility as functional substrates in constructing more complex structures with remarkable biological and physicochemical properties. − Many strategies have been developed to incorporate the acyl group into aromatic compounds, such as radical transformations, ,, metal acylation, − and the well-established Friedel–Crafts acylation. − However, except for formylation reactions, very few approaches are used to acetylate or acylate N -heteroaromatic rings. These scaffolds are of considerable interest due to their frequent biological and photophysical applications. − …”

Synthesis and site selective C–H functionalization of imidazo-[1,2-a]pyridines

“…The acetylated imidazopyridines 135 were foreseen to have gamma-aminobutyric acid (GABA) activity depicted through an authenticated, GABA binding model (Scheme 56). 114…”

Use of Imidazo[1,2‐a]pyridine as a Carbonyl Surrogate in a Mannich‐Like, Catalyst Free, One‐Pot Reaction

“…Significant advancement has been made to modify the C‐3 position of imidazo[1,2‐ a ]pyridine using alkylation, thiocyanation, nucleophilic addition,, arylation or alkenylation, fluorination, and acetylation . However, aminomethylation at the C‐3 position of imidazo[1,2‐ a ]pyridine is rare with only two reports in the literature , .…”

“…As part of our continued efforts to develop C‐C and C‐N bond formation reactions, particularly with imidazopyridines,, , we investigated the use of a Mannich‐like reaction for C‐3 aminomethylation of imidazo[1,2‐ a ]pyridines. Previously, the Mannich reaction has served as a tool to functionalize electron dense heterocycles and phenols using formaldehyde as a methylene source via acid catalyzed alkyl‐amination .…”