| Five-membered heterocyclic compound, which contain multiple chiral centers, can be synthesized by one step in the 1,3-dipolar cycloaddition reaction.The stereoselectivity of cycloaddition reaction can be controled effectively by the chiral catalysts, and the single chiral compounds with high stereoselectivity can be obtained. This preparation method provides a great convenience for the synthesis of chiral drugs and intermediates, which contains several chiral centers,so the catalytic study of 1,3-dipolar cycloaddition has been important research fields. The metal-bisoxazolines as chiral catalysts, the 1,3-dipolar cycloaddition reaction of diaryl ketone nitrate with N-?,?-unsaturated acyl-3,5-dimethyl pyrazole, which with the stereoselectivity is studied in this paper. The specific research content is as follows:1. In this paper, three chiral bisoxazoline ligands were synthesized.through three-step reactions: halogenation, nucleophilic substitution and condensation cyclization, dibenzofuran bisoxazoline ligand(DBFOX/Ph)was preparated, this method is simple, easy operating, and conditions is mild. On this basis, after improving the previous synthetic route, the dibenzothiophene-bis(oxazolines) and pyridine bis(oxazoline) were synthesized.2. Anhydrous Li Cl as catalyst, triethylamine as acid-binding agent,N-acryloyl-3,5-dimethyl-pyrazole and N-crotonic acyl-3,5-dimethyl-pyrazole were synthesized at room temperature. In this method, due to the utilization of anhydrous Li Cl as catalyst, the reaction time is shorten to 1/6, and the yield(90%) is increased by 50% compared with the previous method.3. The chiral organic metal catalysts can be formed with chiral ligands( DBFOX/Ph) and metal ions(Ni2+?Cu2+?Zn2+?Mg2+?Pd2+).And the 1,3-dipolar cycloaddition reaction of diphenyl nitrone and N-acryloyl-3,5-dimethyl-pyrazole was operated as the model, Based on the investigation of metal ions, the amount of catalyst and reaction temperature, the optimized conditions of this catalytic reaction was determined. Experimental study shows that:(1) The amount of catalyst has obvious influence on the stereoselectivity of this reaction: 2% of DBFOX/Ph-Ni2+, can make the regioselectivity(the proportion of 4- and5-) to 95:5, the de value(the proportion of endo and exo) to 99:1, and91% of enantiomer selectivity(ee value); with the amount of catalyst increase to 10%, the regioselectivity reach to 97:3, the de value and the ee value of the product reach to 99:1 and 94%, respectively.(2)The kind of metal ions have great influence on the reaction rate, regioselectivity and stereoselectivity. In the 1,3-dipolar cycloaddition reactions which diphenyl nitrone as dipole, 10% of Cu2+ as catalyst, the reaction rate was shorten from 24h(in the blank reaction) to 10 min, with regioselectivity(4-product) of 100%, but no enantiomer selectivity; in the reaction with chiral ligands DBFOX/Ph added, the reaction time was extended to 8 h,regioselectivity(4-product) is 100%, de value of 85:15, with no enantiomer selectivity. In the reaction of Ni2+ as catalyst, the reaction rate and regioselectivity is similar to that of Cu2+, but de value and ee value reached to 90:10 and 90%; while DBFOX/Ph-Pd2+ as catalyst,the catalytic results was opposite from that of Cu2+ and Ni2+, the regioselectivity(the proportion of 4- and 5-) is 15:85.(3)When the reaction temperature was reduced from room temperature to 0 ?, the regioselectivity and enantiomer selectivity have a slight increase, but the reaction rate was slower significantly. So the optimized conditions was determined as follows: at room temperature, with 10% mol DBFOX/Ph-Ni2+ as catalyst, 4- product was obtained in 90%, the proportion of endo : exo is 99:1, and ee value is 91%.4. At room temperature, 10%mol of DBFOX/Ph-Ni2+ as catalyst, the catalytic reactions of different diaryl nitrones with N-acryloyl-3,5-dimethyl-pyrazole was operated, the results show that the regioselectivity is 90:10~100:0, endo: exo is 97:3~100:0, ee value is82%~99%. |
PDF Full Text Request