PEG-Supported Liquid-Phase Synthesis Of Nitrogen-Containing Heterocycles

Heterocycles are a class of organic molecule with important physiological function and potent pharmacological activity. The polymer-supported synthesis of heterocyclic molecules has been a subject of intense research activity. With the development of combinatorial chemistry, liquid-phase synthesis which profits from both the advantageous features of homogeneous solution chemistry and of solid-phase synthesis has presented an important approach to realize combinatorial chemistry. In this thesis, soluble polymer poly (ethylene glycol)(PEG) supported synthesis of small organic molecule libraries are reviewed and PEG-supported parallel liquid-phase synthesis of some nitrogen-containing heterocycles, incuding 1,2,4-oxadiazolines, pyrazolines, pyrazoles, furoquinolines, pyranoquinolines as well as indoles, are described. The research results are summarized below:1. The parallel liquid-phase one pot synthesis of oxadiazolines via 1,3-dipolar cycloaddition reaction on poly(ethylene glycol) support is developed. 1, 3-Dipolar cycloadditions of nitrile oxide generated in situ on soluble polymer with a variety of imines provided a 13-member library of 1, 2, 4-oxadiazolines with yields 79～93% and purity 89~98%. The solid phase synthesis of 1,2,4-oxadiazolines via 1,3-dipolar cycloaddition of nitrile oxide generated in situ on solid support with a variety of imines is also studied. The synthetic sequences performed in parallel one-pot fashion on Merrifield resin. Cleavage from the resin under two different mild conditions afforded a 20-member library of 1, 2, 4-oxadiazolines which exploited four sites of chemical diversity in good yields (64-96%) and purity (77-97%).2. Rapid parallel liquid-phase synthesis of pyrazoles and pyrazolines is developed. The 1,3-dipolar cycloaddition between nitrilimines generated in situ and soluble polymer-supported alkynyl or alkenyl dipolarophiles in parallel one-pot fashion gave the corresponding PEG-supported regioisomeric pyrazoles or regiospecific pyrazolines as indicated by NMR. Cleavage from the support under mild conditions afforded a 5-member library of regioisomeric pyrazoles with yields 70～93% and purity 93～99%, and a 9-member library of regiospecific 5-substituted pyrazolineswith yields 86~94% and purity 85~97%. The PEG-supported regiospecific pyrazolines was assuredly oxidated by DDQ to PEG-supported regiospecific pyrazoles. Cleavage from the support with transesterification afforded a 9-member library of regiospecific 5-substituted pyrazoles with yields 81 —93% and purity 92 ~3. A parallel liquid-phase protocol for the synthesis of furoquinolines and pyranoquinolines is developed. The one-pot three-component aza-Diels-Alder reaction of PEG-supported benzaldehyde, primary aryl amines and 2,3-dihydrofuran or dihydropyran under 2%TFA/CH3CN gave PEG-supported tetrahydroquinolines. Cleavage from the support with transesterification reaction afforded a 10-member library of cis and trans isomers tetrahydroquinolines with yields 69~90%, purity 78~90% and diastereoselectivity 81~93%. PEG-supported tetrahydroquinolines was assuredly oxidated by DDQ and then cleaved from the support to afford the novel heterocycles furoquinolines and pyranoquinolines. Using this method, a 10-member library of quinolines was prepared in yields 53~78 % and purity 69~94%.4. A parallel liquid-phase synthesis of indoles via palladium-mediated heteroannulation is developed. PEG-supported o-iodoaniline was afforded through nucleophilic substitution reaction between 4-amino-3-iodobenzoic acid and PEG-supported methyl sulfonate. The former was actived by methanesulfonyl chloride, then was treated with excessive terminal alkyne in the presence of 5% PdCl2(PPh3)2 and 10%CuI in DMF and Et3N at 80 °C for 16 h to afford PEG-supported indole through Sonogashira coupling and undergoes an intramolecular cyclization procedure. Under the same conditions, if the amino group of PEG-supported o-iodoaniline was not mesylated prior to coupling with a terminal alkyne, a internal alkyne instead of 2-substituted indole was isolated. The cleavage of PEG-supported indole with CH3ONa/CH3OH at reflux afforded N-unsubstituted indoles in yields 82~87% and purity 97~99%.