A Study On Synthesis Of Fluorocyclopropane Derivatives And Reactions Of In Situ Generated Cyclopropenes

Development of new reactions and new methodologies is one of the most attractive areas in organic chemistry. Monofluorinated cyclopropane compounds, which combine both the feature of cyclopropane and fluorine, always have some special properties. As the increasing of bioactive molecules possessing monofluorinated cyclopropane unit, effective construction of these compounds become a meaningful study.In addition, cyclopropene, the smallest unsaturated cyclic molecule, has always attracted the attention of chemists for their extremely high ring strain and extremely diverse reaction types. This dissertation focused on the synthesis of monofluorinated cyclopropane compounds and the reaction of in situ generated cyclopropene. To date, we have achieved some useful results, the details are summarized below:1) We first studied the reactions between ethyl dihaloacetates and terminal electron-deficient alkenes in the presence of base. The results showed that halogen atoms have great influence on the reaction. The desired Michael-initiated ring closure reaction occurred between ethyl dichloroacetate and terminal electron-deficient alkenes, giving2-acyl-1-chlorocyclopropanecarboxylic esters in high yields (up to80%) and excellent diastereoselectivities (up to20:1). The stereostructure of the product was firmly confirmed by HMBC spectrum and X-ray analysis. While unexpected Morita-Baylis-Hillman reaction took place in the case of ethyl bromofluoroacetate or ethyl chlorofluoroacetate and terminal electron-deficient alkenes, the yield was up to89%.2) Reactions between the previously obtained2-acyl-l-chlorocyclopropanecarboxylic esters and various fluorinated reagents have been disclosed. These monochlorinated cyclopropanes can react effectively with alkali metal fluoride, such as KF, KHF2, giving monofluorinated cyclopropanes in high yield (up to85%). The stereostructure of the product was firmly confirmed by19F and HMBC spectrum. The main product was assigned to be thermodynamic stable trans-3.3) Mechanism study of the fluorinated reaction between2-acyl-1-chlorocyclopropanecarboxylic esters and alkali metal fluoride showed that the reaction proceeded through an elimination-addition pathway. The most important intermediate was the cyclopropene with two electron-withdrawing groups on the C=C bond.4) A cascade reaction between2-acyl-l-chlorocyclopropanecarboxylic esters and double functional compound salicylaldehyde has been developed. The reaction was initiated by1,2-elimination of monochlorinated cyclopropane, then proceeded through a cascade oxa-addition/aldol reaction giving the potential bioactive tetrahydrocyclopropa[b]chromene compounds in high yield (up to95%) under mild reaction conditions. The main product was assigned to be trans-13which was further confirmed by NOESY and X-ray analysis. Furthermore, we explored the influence of Lewis acid additive on the reaction. The addition of additive caused the reverse of the diastereoselectivities of the reaction.5) We broadened the scope of the double functional compounds. The cascade reaction between salicylaldimine and2-acyl-l-chlorocyclopropanecarboxylic esters has been disclosed. This methodology allows an efficient synthesis (up to98%yield and up to>20:1diastereoselectivities) of diverse and structurally complex4-aminobenzopyran compounds through cascade oxa-addition/Mannich reaction. The main product was assigned to be cis-16which was further confirmed by NOESY and X-ray analysis.6) A series of quinolizine derivatives were obtained in moderate yields (48%-60%) through the reaction between2-acyl-l-chlorocyclopropanecarboxylic esters and1,3-dipole pyridine ylide. We have proposed a possible reaction mechanism based on literatures and the preliminary reaction results.