Synthesis And Reactions Of Ethyl 2-bromomethyl Quinoxaline-3-carboxylate

Quinoxaline and its derivatives are important heterocyclic compounds which are widely distributed in natural alkaloids.Many quinoxaline-based compounds have been reported to display a significant range of biological activities and have been acted as a valuable pharmacophore for drug design.As a consequence,interest in the design and synthesis of novel and interesting types of quinoxaline-based derivatives continues unabated with the aim of enhancing the potency of this class of compounds.It has been found that 2-and 3-substituted quinoxaline derivatives have claimed to exhibit potent antibacterial and anticancer activities.In light of these findings,we felt that it would be of great interest to the construction of structurally novel and intriguing a series of 2,3-disubstituted quinoxaline derivatives.These newly synthesized compounds would likely possess significant biological activities and might be potentially applied for the development of biologically and pharmaceutically important drugs.The thesis is concerning the construction of novel types of 2,3-disubstituted quinoxalines and mainly consisted of six parts as follows:In the first part,a simple review involving the synthesis and biological activities of quinoxaline derivatives was conducted.In the second part,we selected readily synthesized ethyl 2-methyl quinoxaline-3-carboxylate as the starting material to subjected to the radical bromination reaction with 1.1 equiv.of NBS.The bromination reaction was effectively conducted using both 200W tungsten bulb and dibenzoyl peroxide?BPO?as the initiators in refluxing CCl₄ as the media,giving the desired monobromo ethyl 2-bromomethylquinoxaline-3-carboxlate?1?as the major product in 62.0%yield.In addition,the minor amount of byproduct was isolated and identified as ethyl 2-?dibromomethyl?quinoxaline-3-carboxylate in 21.0%yield.In the third part,with the newly-synthesized ethyl 2-bromomethyl quinoxaline-3-carboxylate?1?in hand,our attention was first focused on its applications in the reaction with various substituted salicylaldehydes for the one-pot construction of a series of novel 2-?benzofuran-2-yl?quinoxaline-3-carboxylic acids?3a-l?.The reaction was carried out in MeCN as the solvent with the presence of K₂CO₃ as the base and PEG-400 as the activated additive,providing the targeted products 3a-l in acceptable yields ranging60.1%to 73.4%.As a class of structurally novel quinoxaline derivatives,their structures were confirmed by IR,¹H NMR,¹³C NMR and HRMS.In the fourth part,with the use of ethyl 2-bromomethylquinoxaline-3-carboxylate?1?as the substrate,a simple and flexible three-step one-pot synthesis of a new series of?E?-2-styrylquinoxaline-3-carboxylic acids?5a–i?has been achieved for the first time in moderate to good yields involving successive Arbuzov with triethyl phosphate followed by in situ Horner–Wadsworth–Emmons?HWE?reaction with aromatic aldehydes and subsequent ester hydrolysis reaction procedure.The structures of the unreported 5a-i have been characterized by IR,¹H NMR,¹³C NMR and HRMS.In the fifth part,a simple and concise one-pot reaction of ethyl2-bromomethylquinoxaline-3-carboxylate?1?with various substituted phenols is described using K₂CO₃ as the base in refluxing MeCN,affording the corresponding 2-?aryloxymethyl?quinoxaline-3-carboxylic acids?7a-j?in good to high yields of 68.4-86.1%yields via Williamson reaction followed by ethyl hydrolysis procedure.The structures of the resulting 7a-j have been confirmed according to their IR,¹H NMR,¹³C NMR and HRMS.In the sixth part,ethyl 2-bromomethylquinoxaline-3-carboxylate?1?was subjected to the reaction with methylamine and aromatic amines using ethanol as the media through a tandem Williamson-type reaction and subsequent in situ intramolecular C-N bond cyclization process,affording the desired2-methyl/aryl-2,3-dihydro-1H-pyrrolo[3,4-b]quinoxalin-1-ones?9a-k?in moderate yields of 38.0-59.0%.Their structures were identified based on the spectral data(IR,¹H NMR,¹³C NMR)and HRMS.