Study On HNTf₂-catalyzed Intramolecular Cyclization Reaction Of Alkynes

Intramolecular cyclization of alkynes is a basic type of organic reactions.The alkyne cyclization reaction involving nitrogen atoms in the molecule is one of the important ways to construct nitrogen-containing heterocyclic compounds.Nitrogen-containing heterocyclic compounds are widely found in pharmaceutical molecules,natural products and organic functional materials.Tetrahydro pyranoisoindole and tetrahydro pyrroloquinoline derivatives have important applications in organic synthesis and medicinal chemistry,they have a wide range of pharmacological activities,such as treating nerve and cardiovascular tissue damage etc.This thesis mainly studies the intramolecular cyclization of alkynes catalyzed by HNTf₂,and has achieved the efficient synthesis of heterocyclic compounds of two important structures.In addition,the reaction constructed a new quaternary carbon center in the target product,providing a new synthetic strategy for the synthesis of natural products containing quaternary carbon centers.Most of the traditional methods of constructing this nitrogen-containing heterocyclic compound require relatively harsh conditions,such as precious metal catalysis,strong acid or strong base.Therefore,it is of great significance to develop some efficient methods for constructing such compounds.Reactions under metal-free catalysis conditions are still challenging.In this paper,an acid-catalyzed intramolecular cyclization reaction of alkynes was established.A method for synthesizing tetrahydro pyranoisoindole and tetrahydro pyrroloquinoline derivatives in dichloroethane（DCE）was established at 100℃using alkynyl N-methoxyamide as the reaction substrate and triflimide（HNTf₂）as the catalyst.Noteworthy,the substrate with a natural product fragment of estrone can also obtain the target product in a great yield.The reaction has the advantages of cheap and non-toxic catalyst,high atomic economy,high functional group tolerance,and suitability for heterocyclic systems.The possible reaction mechanism was studied by Hammett equation,it is proposed that the cyclization process is carried out through a Friedel-Crafts type reaction pathway.The C-O bond in tetrahydro pyranoisoindole compounds can be cleaved by NaH,and the N-O bond can be cleaved by SmI₂,which provides a new reaction pathway for the late modification of the compounds.The structures of all the synthetic target compounds were characterized by ¹H NMR,¹³C NMR and HRMS.The compound structure was confirmed by the X-ray single crystal diffraction analysis of compounds 6a.