New Synthetic Methods For Indolizine Media By Transition Metal

Indolizines and their derivatives have been comprehensively applied in biology, medicine, pesticide and so on. However, excess amounts of poisonous and harmful oxidant was used in the current synthetic method. We developed two kinds of synthetic methods to reduce the cost of synthesis and decrease the amount of harmful chemical waste.Firstly, we used sub-equivalent potassium dichromate as an oxidant for the one-pot synthesis of indolizines from electron deficient alkenes under base free conditions. According to the optimization of reaction conditions, we established the optimized reaction conditions as follows: pyridine?1 equiv? and 2-bromo-1-phenylethan-1-one?1 equiv? in 0.20 mL of ethyl acetate: the mixture were heated at 60 oC in a test tube with a stopper for 4h in situ, and then reacted with butyl acrylate?1.5 equiv? in the presence of potassium dichromate?0.75 equiv? under 80 oC for 8h with another 1.80 mL of DMF added as solvent. Then we studied the scope of pyridines, ?-halide carbonyl compounds and electron deficient alkenes. This synthetic method gave twenty-nine indolizines smoothly, and the yield ranged from 20 % to 100 %. The structures of twelve unknown compounds were characterized by FTIR, 1HNMR, 13 CNMR and HRMS.After that, we used copper salt as a catalyst and molecular oxygen as the final oxidant to develop a one-pot four-component reaction for synthesizing indolizines from pyridines, ?-halide carbonyl compounds, amines and maleic anhydride. According to the optimization of reaction conditions, we established the optimized reaction conditions as follows: anhydride?1.5 equiv.? and aniline?1.0 equiv.? were heated in 0.20 mL ethyl acetate at 60 oC for 4h, then pyridine?2.0 equiv.? and ethyl 2-bromoacetate?2.0 equiv.? were added and heated at 60 oC for another 5h, then copper bromide?0.30 equiv.?, K₂CO₃?2.5 equiv.? and 1.8 mL DMSO were added, the mixture was heated at 80 oC for 12 h under oxygen atmosphere?balloon?. Then we studied the scope of pyridines, ?-halide carbonyl compounds and amines. This synthetic method gave thirty indolizines smoothly, and the yield ranged from 17 % to 94 %. The structures of twenty-six unknown compounds were characterized by FTIR, 1HNMR, 13 CNMR and HRMS.Our study provides new methods for synthesizing indolizines. These new methods can reduce the cost of synthesis and greatly decrease the amount of harmful chemical waste.