Tandem C–N Bond Formation through Condensation and Metal-Free N-Arylation: Protocol for Synthesizing Diverse Functionalized Quinoxalines

Abstract

Diverse functionalized quinoxalines were synthesized in good yields from arylamines and readily available β-keto oximes through condensation and metal-free N-arylation. The reaction was compatible with various functional groups, such as halides, cyano, and esters. A mechanism was proposed based on the experimental results. These quinoxalines were easily obtained on a gram scale and converted to various useful scaffolds. Compound LASSBio-1022 was prepared in 83% yield in two steps.

Synthesis of deuterium‐labeled 2‐quinoxalinecarboxylic acid and 3‐methylquinoxaline‐2‐carboxylic acid from deuterium aniline

“…The synthetic route to QCA‐ d 4 and MQCA‐ d 4 is shown in Scheme . The synthesis strategy follows a recently published method by condensing β‐keto oximes with aryl amines, and the resulting N ‐aryl keto oximes were converted to quinoxalines through Lewis acid–mediated intramolecular N ‐arylation . First of all, commercially cheap aniline‐ d 5 was used as the starting material, and reacted with ethyl‐2‐(hydroxyimino)‐3‐oxobutanoate ( 1 ) or 2‐oxopropanal oxime using acetic acid and POCl 3 as catalysts, thus obtaining ethyl 3‐methylquinoxaline‐2‐carboxylate‐ d 4 ( 2 ) and 2‐methylquinoxaline‐ d 4 ( 3 ), respectively.…”

“…The synthesis strategy follows a recently published method by condensing β-keto oximes with aryl amines, and the resulting N-aryl keto oximes were converted to quinoxalines through Lewis acid-mediated intramolecular N-arylation. 8 First of all, commercially cheap aniline-d 5 was used as the starting material, and reacted with ethyl-2-(hydroxyimino)-3-oxobutanoate (1) or 2-oxopropanal oxime using acetic acid and POCl 3 as catalysts, thus obtaining ethyl 3-methylquinoxaline-2-carboxylate-d 4 (2) and 2-methylquinoxaline-d 4 (3), respectively. According to Jiao et al, 8 the authors reported that the oximes used in this type of quinoxaline synthesis must contain electron-withdrawing (EWG) group.…”

“…Sodium nitrite (3.9 g, 56.4 mmol) in 8.5 mL of water was added to a mixture of ethyl acetoacetate (5.0 g, 38.4 mmol) and acetic acid (6.2 mL) in 0°C . The mixture was stirred at 0°C for 1 hour.…”

“…Sodium nitrite (3.9 g, 56.4 mmol) in 8.5 mL of water was added to a mixture of ethyl acetoacetate (5.0 g, 38.4 mmol) and acetic acid (6.2 mL) in 0°C. 8 The mixture was stirred at 0°C for 1 hour. After completion of the reaction, chloroform was added, and the mixture was washed successively with 10 wt% NaHCO 3 , brine, and then dried over sodium sulfate.…”

“…1 Ethyl2-(hydroxyimino)-3-oxobutanoate (5.25 g, 33 mmol) and deuterium aniline-d 5 (2.94 g, 30 mmol) were dissolved in 50 mL of benzene, and then 0.5 mL of acetic acid was added. 8 After the reaction mixture was refluxed for 2.5 hours, 5.7 mL of POCl 3 (75 mmol) in 70 mL of MeCN was added to the mixture at 0°C, which was heated to 100°C for another 4 hours. After completion of the reaction, the solution was poured into 100 mL of cool saturated aqueous NaHCO 3 .…”