A Pummerer Reaction-Enabled Modular Synthesis of Alkyl Quinoline-3-carboxylates and 3-Arylquinolines from Amino Acids

Abstract

Concise synthesis of functionalized quinolines has received continuous research attention owing to the biological importance and synthetic potential of bicyclic N-heterocycles. However, synthetic routes to the 2,4-unsubstituted alkyl quinoline-3-carboxylate scaffold, which is an important motif in drug design, remain surprisingly limited, with modular protocols that proceed from readily available materials being even more so. We herein report an acidic I2–DMSO system that converts readily available aspartates and anilines into alkyl quinoline-3-carboxylate. This method can be extended to a straightforward synthesis of 3-arylquinolines by simply replacing the aspartates with phenylalanines. Mechanistic studies revealed that DMSO was activated by HI via a Pummerer reaction to provide the C1 synthon, while the amino acid catabolized to the C2 synthon through I2-mediated Strecker degradation. A formal [3 + 2 + 1] annulation of these two concurrently generated synthons with aniline was responsible for the selective formation of the quinoline core. The synthetic utility of this protocol was illustrated by the efficient synthesis of human 5-HT4 receptor ligand. Moreover, an unprecedented chemoselective synthesis of 2-deuterated, 3-substituted quinoline, featuring this reaction, has been established.

Rongalite as C1 Synthon in the Synthesis of Divergent Pyridines and Quinolines

“…During the last decade, conventional organic solvents such as dimethylformamide (DMF) or dimethyl sulfoxide (DMSO) have been used for the construction of pyridine and quinoline with different substitution styles. In addition, an array of other reagents such as aminoacetic acid, ammonium formate, and 2-methoxyethanol have also been proven to be applicable synthons in the synthesis of pyridines (Scheme A).…”

Facile Cleavage of Activated Ketones: An Access to Thioethers via In Situ Generation of Anhydrides by Pummerer-Type Rearrangement

“…Pummerer rearrangement is one of the most powerful tools in the transformation of a sulfoxide to α-substituted sulfide . In this context, DMSO is a common sulfoxide as well as solvent utilized in organic synthesis due to its low cost, relative stability, and efficient dissolving capacity.…”

Facile access to 3-sulfonylquinolines via Knoevenagel condensation/aza-Wittig reaction cascade involving ortho-azidobenzaldehydes and β-ketosulfonamides and sulfones

“…Moreover, numerous quinoline derivatives have been recently reported to possess intriguing pharmacological activities [3] including antiprotozoal [4][5][6][7], antitubercular [8,9], anticancer [10,11], anti-inflammatory [12], antioxidant [13], anti-HIV [14], antifungal [15], and an antineurodegenerative effect [16]. Hence, designing novel quinoline construction and functionalization techniques resulting in new or rare derivatives [17][18][19][20][21][22][23][24][25][26] is an important mission in the field of drug discovery and medicinal chemistry.…”