The Study On Clauson-Kass Cyclization Reaction Promoted By MG(â…¡) And The Novel Synthesis Of Antiasthma Drug Salmeterol

This thesis aims at the study on Clauson-Kass cyclization of aromatic amine with2,5-dimethoxytetrahydrofuran promoted by Lewis acid MgI2and the synthetic method for antiasthma drug salmeterol. This dissertation consists of two parts as following:In the first part, we reviewed the methodology for the synthesis of pyrrole and its derivatives, which is focused on the typical Clauson-Kass reaction. We investigated the Clauson-Kass reaction of various aromatic amines with2,5-dimethoxytetrahydrofuran promoted by Mgl2etherate [MgI2·(OEt2)n], which afforded a variety of N-substituted pyrrole compounds. The effect of catalyst, solvent and temperature was studied, respectively. The experimental results demonstrated that the Clauson-Kass reaction shows a unique chemoselective to aromatic amine substrates in the presence of MgI2·(OEt2)n:(1) MgI2·(OEt2)n can be an effective catalyst for the reaction of aromatic amine or aromatic formamide with2,5-dimethoxytetrahydrofuran, but it doesn’t work to aliphatic amines or aliphatic formamide;(2) The crossover experiments of aromatic amines with2,5-dimethoxytetrahydrofuran shows that: aromatic amines with electron-donating substituent (i.e., o-or p-Me,-OMe) reacted much faster than aniline and electron-withdrawing substituent (i.e.,-Cl,-Br,-NO2) deactivated aromatic amines remarkably. This magnesium-catalyzed Clauson-Kass cyclization is mild, efficient and operationally simple. Iodide counterion, weakly coordinating peripheral ethereal ligands for Mg (II), and reaction media are critical factors for the unique reactivity of this catalytic system.In the second part, we introduced the classification of antiasthma drugs, which focused on the β2-agonist drugs. The various synthetic methods for salmeterol are reviewed. The synthetic route of salmeterol was designed and optimized. Starting from1-(4-hydroxyphenyl)ethanone, salmeterol xinafoate was prepared through10steps in an overall yield of9.5%. The yield and selectivity of mono-bromination was smoothly achieved by controlling the reaction temperature. One-pot reaction of amination, hydrolysis and reduction could simplify the procedure operatoin and efficiently improve the yield. This synthetic approach has some advantages such as readily starting material, simple operation and low cost, which is valuable to industrialization...