Syntheses Of Tetrahydroisoquinoline Alkaloids, Chiral Arylsulfinamides And Cis-IPP On Various Resolution Methods

This dissertation describes the study on some efficient resolution methods, such as half-equivalent resolution, recycling resolution and spontaneous crystallization. Syntheses of tetrahydroisoquinoline alkaloids, chiral arylsulfinamides and cis-IPP based on these efficient resolution methods are also discussed. The paper contains three parts as described below:Part one:A comparative study on resolution of1-phenylethylamine as a model reaction with half equivalent or one equivalent resolving agent was performed, and the results revealed that half-equivalent resolution is superior to the equal-equivalent. Then four racemic1-substituted1,2,3,4-tetrahydroisoquinolines (THIQs)(RS)-(±)-Ⅱ-4a-4d were efficiently prepared from homoveratrylamine in excellent yields by N-carboxylation, Bischler-Napieralski reaction and reduction of imines. Chiral resolution of these THIQs (RS)-(±)-Ⅱ-4a-4d with half equivalent of resolving agents smoothly afforded the desired enantiomerically pure (S)-(-)-norcryptostyline Ⅰ [(S)-(-)-Ⅱ-4a],(S)-(-)-norcryptostyline Ⅱ [(S)-(-)-Ⅱ-4b],(R)-(+)-salsolidine [(R)-(+)-Ⅱ-4c] and (S)-(-)-norlaudanosine [(S)-(-)-Ⅱ-4d] in45%,40%,41%and38%yields, respectively. The enantiomeric purities of the above obtained THIQs were determined by1H NMR method with CSAs. Base-catalyzed and redox methods were used for racemization of the undesired enantiomerically enriched THIQs,(R)-(+)-Ⅱ-4a,(R)-(+)-Ⅱ-4b,(S)-(-)-Ⅱ-4c and (R)-(+)-Ⅱ-4d, from the mother liquors, and the result indicated that undesired THIQs could be efficiently racemized via a one-pot redox protocol to afford the corresponding racemic THIQs (RS)-(±)-Ⅱ-4a-4d in98%,98%,97%and95%yields, respectively. Moreover,(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline (S)-Ⅱ-25, an important intermediate of solifenacin, was efficiently synthesized in38%yield by a half-equivalent resolution. The undesired (R)-II-25was efficiently racemized via the same method in98%yield. The obtained racemic Ⅱ-25could be used for further resolution. This "resolution-racemization" process could be conducted repetitively.Part two:Sodium arylsulfinates Ⅲ-1a-1d were converted into arysulfinyl chlorides, which were then treated with (R)-N-benzyl-l-phenylethanamine to afford diastereomeric mixtures of N-benzyl-N-(1-phenylethyl)-arylsulfinamides Ⅲ-3a-3d. By using a mixture of hexane and ethyl acetate (hexane/EtOAc=9:1) as the solvent, diastereomerically pure (R,Ss)-N-benzyl-N-(1-phenylethyl)-arylsulfinamides (R,Ss)-Ⅲ-3a-3d spontaneously crystallized in28%,29%,27%and31%yields, respectively. The diastereomerically pure compounds (R,Ss)-Ⅲ-3were then converted into four enantiopure (Rs)-methyl arylsulfinates (Rs)-Ⅲ-5, and finally into four enantiopure (Ss)-arylsulfinamides (Ss)-Ⅲ-6in good yields. Thus, a novel and simple process for the preparation of enantiomerically pure (Ss)-benzenesulfinamide (Ss)-Ⅲ-6a,(Ss)-p-toluenesulfinamide (Ss)-Ⅲ-6b,(Ss)-p-chlorobenzenesulfinamide (Ss)-Ⅲ-6c and (Ss)-p-fluorobenzenesulfinamide (Ss)-Ⅲ-6d has been developed. In addition, synthesis of diaryl disulfides via mild reduction of arylsulfinates and arylsulfinamides with hydrazine monohydrate in DMSO was achieved.Part three:A new process for the preparation of cis-IPP was developed. Using triethylamine as catalyst in a Michael addition, the yield of an intermediate compound Ⅳ-5was greatly increased from67%to92%. Mixture of cis and trans-IPP Ⅳ-6was obtained quantitatively via a thionyl chloride catalyzed etherification. The cis-IPP was readily precipitated from a mixed solvent of n-propanol and water (n-PrOH/H2O=1:2), which was based on the different of the solubility of the cis and trans diastereoisomers. The less active trans-IPP in the mother liquor could be epimerized into an equal-equivalent mixture of cis and trans-IPP under acidic conditions. In addition, a series of N-alkyl1-((6-chloropyridin-3-yl)methyl)-7-methyl-8-nitro-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridi n-5-amines Ⅳ-15were synthesized, and insecticidal activities of these compounds were evaluated. Compounds Ⅳ-15d, Ⅳ-15f and Ⅳ-15m showed high insecticidal activities against both sucking pest Nilaparvata lugens and lepidopteran Aphis medicaginis.