Cheap Metals Mn/al Promoted Synthesis Of N-Containing Heterocyclic Compounds Under Solvent-free Ball Milling

Pyrroles and 1,4-dihydropyridines are very important nitrogen-containing heterocyclic compounds,and their skeletons are widely found in many natural products and pharmaceutical structures with important biological activities.In addition,pyrrole and 1,4-dihydropyridine derivatives are also widely used as synthesis intermediates,drug structural units and various functional materials.Therefore,the development of methods to synthesize various substituted pyrroles and1,4-dihydropyridines has attracted more and more attentions from a large number of scientists.Presently,most of these approaches can achieve good results,but there are still some defects,such as involving special or expensive starting materials,the requirement of preparation of reaction intermediates or precursors,employment of noble-or heavy-metal catalysts,or toxic solvents,the need of harsh reaction conditions or long reaction time.In order to overcome these problems,it is necessary to develop a more environmentally-friendly and economical method for synthesizing pyrrole and 1,4-dihydropyridine compounds using conventional starting materials and cheap catalysts.Among them,the mechanical ball milling reaction effectively avoids the problem of using solvent in the reaction process.At the same time,Mn and Al catalysts have a wide range of applications in the field of organic synthesis because of their wide source,low cost and low toxicity.The main work of this dissertation is to explore new green methods for the synthesis of differently substituted pyrroles and dihydropyridines using Mn（OAc）₃ or AlCl₃ as catalyst under mechanochemical solvent-free milling,which can be summarized as the following:（1）Under solvent-free mechanical milling,a novel Mn（OAc）₃promoted condensation-cyclization cascade reaction of substituted aniline or ammonium acetate with 1,3-dicarbonyl compounds has been developed for efficient synthesis of 2,5-dimethyl-3,4-dicarboxylate-pyrroles through C-C and C-N bond formation.Employing this method,twelve polysubstituted 2,5-dimethyl-3,4-dicarboxylate-pyrroles were synthesized in good to excellent yield.Furthermore,some controlled experiments were performed to clarify the reaction mechanism.（2）A novel Mn（OAc）₃ catalyzed cascade reaction of substituted aniline or aliphatic amines with 1,3-dicarbonyl compounds has been investigated for efficient synthesis of N-substituted 3,4-diphenylpyrroles through C-C/C-N bond formation under mechanical milling.Following this protocol,a series of polysubstituted N-substituted-3,4-diphenyl-pyrroles was successfully synthesized.（3）An AlCl₃-catalyzed cyclization fromβ-keto derivatives with in situ generated enamines has been investigated under solvent-free high speed ball milling.This one-pot protocol furnished highly efficient synthesis of 33 structurally diverse polysubstituted 1,4-DHPs.The mechnism of the reaction chemoselectivity was also studied.In general,the yields of all these products are moderate to good under the optimized conditions.A wide range of functional groups are tolerant to the reaction conditions.Whether it is an electron-withdrawing or an electron-donating group,satisfactory results are obtained,and broader substrate scope is shown.All the obtained products were well characterized by ¹H NMR and ¹³C NMR,and unreported new compounds were futher characterized by HRMS.Comparing with traditional methods,these methods exhibit the advantages of higher chemoselectivity,significantly shorter reaction time,milder reaction condition and easier work-up.These merits make the present method a practical alternative to polysubstituted pyrroles and1,4-dihydropyridines.