Synthesis Of Poly-substituted Dihydropyridines And Pyrrolones Based On ?-oxoamides

Heterocyclic chemistry is an important branch of organic chemistry,especially in the construction of bioactive nitrogen-containing heterocycles which is a special field in organic synthetic chemistry.In recent years,environmental problems are becoming increasingly serious,and "green and sustainable chemistry"has become one of the hot spots of research.The use of cheap and readily available chemical reagents to synthesize complex heterocyclic compounds from simple compounds and developing environmentally benign synthetic methods and processes to produce simpler and safer experimental procedures have been the goals pursued by organic synthesis workers.At the same time,these green synthetic methods should take into account the high atomic economy,selectivity such as chemoselectivity,regioselectivity and stereoselectivity and how to efficiently convert to larger-scale preparations which are of crucial importance for industrial applications.?-Ketoamides as readily available raw materials and reagents are widely used to construct a variety of bioactive heterocyclic compounds.In the past few years,our research group has been dedicated to develop highly substituted and functional nitrogen-containing heterocyclic compounds utilizing ?-ketoamides as synthetic precursors.In this dissertation,new synthetic methods of poly-substituted dihydropyridines and pyrrolones were established by a one-pot and multicomponent reactions under the mild conditions with p-ketoamides as the main raw materials.At the same time,a simple and efficient new method for the synthesis of thiosulfonates has been unexpectedly discovered during the course of the synthesis of dihydropyridines.Based on the experimental results,the corresponding reaction mechanisms were investigated deeply.The details are as follows:(1)The synthesis of 4-alkenyl-N-sulfonyl-dihydropyridines compounds by the three-component one-pot reactions.Under mild conditions,the sulfonyl chlorides activated the pyridines to form pyridinium salts.The subsequent nucleophilic addition reaction of ?-ketoamides or its dehydrated products such as cyanide acetone or 3-carbonyl-3-phenylpropanenitrile to pyridinium salt occurred in the presence of pyridine as a base.4-alkenyl-N-sulfonyl-dihydropyridines derivatives were synthesized with high regioselectivity bearing valuable and reactive building blocks of dihydropyridine,acrylonitrile,and enol ester groups by a one-pot procedure.(2)The synthesis of poly-substituted pyrrolones.Under mild conditions,the highly substituted pyrrolidin-4-ones were efficiently synthesized with ?-ketoamides and amine hydrochlorides by a direct one-pot method.The mechanism was verified that pyrrolidin-4-ones were synthesized via single-electron-transfer forming nitrogen free radicals rather than positive nitrogen ion intermediates by loss of two electrons using cyclic voltammetry and theoretical calculation.It was confirmed that in situ generated TEMPO oxoammonium salt in the role of acid is the key to the successful transformation of the reaction.Under the combined action of TEMPO and acid,the synthesis of the cross-cyclisation product pyrrolidin-4-one was achieved by the reaction of the enaminone intermediate with p-ketoamides.(3)A new,simple and practical method for the synthesis of thiosulfonates.A series of thiosulfonates were synthesized by selectively reducing the arylsulfonyl chlorides with readily available and stable Cul catalyst and Na2SO3 or NaHSO3 reductants.The Cul-catalyst and the NaZSO3 and NaHSO3 reductants are all inexpensive and easily handled reagents,which are suitable for the large-scale production.Based on these facts,we tried to conduct a kilo scale reduction of tosyl chloride with Na2SO3 and confirmed the feasibility of this method preliminarily.