Synthesis Of Planar Chiral Amino Thiourea Bifunctional Derivatives Based On [2.2]Paracyclophane And Their Application In Asymmetric Catalysis

Asymmetric catalysis is one of the most active branches of contemporary chemistry. Because of these catalysts contain at least one chiral element and have the effect of chiral inducement. The planar, axis, central and helical chirality are the elements of building chiral catalysts. Many catalysts derived from [2.2]paracyclo-phane are the typical planar chiral catalysts. More and more scientists have deep interest in such compounds. It is found that we can modify the [2.2]paracyclophane ring with substituents such as oxygen, nitrogen, sulfur and phosphine to afford a series of new catalysts. Since the beginning of the end of the1990s, many chemists began to apply this type of catalysts in asymmetric catalysis. The [2.2]paracyclophane ring has a lot of features such as:1, The convenience of introducing chiral factors. As long as only one substituent is introduced to [2.2]paracyclophane backbone, a planar chirality is formed.2, A good chemical stability:the skeleton is less prone to racemize and has a high degree of stability to most acids, bases, oxidants and reducing agents.3. A good chira) environment. At the same time, in recent years, with the development of organometallic catalysis, metal-free organic catalysis has been used in asymmetric catalysis. Based on the top of these reasons, we are committed to synthesize a series of catalyst containing amino thiourea, and try to apply these catalysts to asymmetric catalysis. Thesis includes the following contents:1. Synthesis of (RP)4-Benzhydrylideneamino-12-amino[2.2]paracyclophane(1), p-methylbenzyltrimethyllammonium under NaOH in DMSO, by the way of the elimination of quaternary ammonium base mechanism, we get [2.2]paracyclo-phane. Then under dry Dichloromethane, iron powder and bromine,[2.2]paracyclo-phane was bromination to give4,16-dibromo[2.2]paracyclophane. Under228℃,4,16-dibromo[2.2]paracyclophane transformed to4,12-dibromo[2.2]paracyclophane in n-dodecane. (2), In a glovebox, an oven-dried Schlenk flask were charged with Pd-DPPF,4,12-dibromo[2.2]paracyclophane, benzhydrylideneamine, sodium t-butoxide and toluene (0.60mL). The mixture was stirred at110℃under nitrogen for8hours to give4-Benzhydrylideneamino-12-bromo[2.2]paracyclophane, as a yellow solid. Then add HCl(aq) to give4-amino-12-bromo[2.2]paracyclophane.1R-(-)-camphorsulfonic acid was used in the resolution of4-amino-12-bromo[2.2]paracyclophane.2. Synthesis&resolution of4-Formyl-12-bromo[2.2]paracyclophane.(1), To a solution of4,12-dibromo[2.2]paracyclophane in dry THF, n-BuLi was added at-78℃under argon, and4h later dry DMF was added. We get4-Formyl-12-bromo[2.2]paracyclophane. Under xylene refluxing,4-Formyl-12-bromo-[2.2]paracyclophane reacted with optically pure4-amino-13-bromo-[2.2]paracyclophane to give two diasteroenantiomers. The use of different solubility of these two substances in ethanol, we get optically pure isomer, and recovered the corresponding optically pure4-amino-13-bromo[2.2]paracyclophane. The advantage of this method is few synthetic steps. But the particular amines,4-amino-13-bromo-[2.2]paracyclophane, as the resolving agent is the obvious limitation.(2). At presence of40%fluoroboric acid and isopropyl nitrite, optically pare4-amino-12-bromo[2.2]paracyclophane was transformed to a diazonium salt. This diazonium salt was decomposition to give optically pure4,12-dibromo [2.2]para-cyclophane. With the same method as above,4,12-dibromo[2.2]paracyclophane reacted with n-BuLi and DMF consecutively to give optically pure4-Formyl-12-bromo[2.2]paracyclophane.3. Synthesis of catalysts containing amino thiourea based on two [2.2]paracyclo-phanes, as well as thiourea containing prolinamide and [2.2]paracyclophane.(1), Synthesis of amino thiourea based on two [2.2]paracyclophanes.(RP)-4-Formyl-12-bromo[2.2]paracyclophane was treated with hydroxylamine hydro chloride and dimethyl sulfate, then was reduced by borane to give (RP)-4-aminomethyl-12-bromo[2.2]paracyclophane.(RP)-4-aminomethyl-12-bromo- [2.2]paracyclophane was condensed with (RP)-4-Formyl-12-bromo[2.2]para-cyclophane to give the desired imine, and RP-bis (12-bromo[2.2]paraclophane-4-methylene)amine was obtained by reductive amination in one-pot. After Buchwald-Hartwing amination, hydrolysis and protection of alkylamine, a Boc-protecting diamino[2.2]paracyclophane was gained and used to react with3,5-bis-(trifluoromethyl)phenyl isothiocyanate and TFA successively to give the final product.(2), Synthesis of amino thiourea derived from prolinamide based on [2.2]para-cyclophane. By Buchwald-Hartwing amination, amidation with N-Boc prolylchloride and deprotection of benzhydrylideneamino with hydroxylamine hydrochloride,(RP)-4-amino-12-bromo[2.2]paracyclophane was changed to (RP,S)-4-(N-BOC)prolinamido-12-amino[2.2]paracyclophane, then (RP,S)-4-(N-BOC)prolinamido-12-amino[2.2]-paracyclophane reacted with3,5-bis(trifluoromethyl)phenyl isothiocyanate and TFA successively to give the target product.4. Their application in Asymmetric catalysis.Isatin derivatives are one of most potent anticonvulsant agent of natural origin. It has display potent anticonvulsant effect in a wide variety of preclinical anticonvulsant models. Till date various isatin derivatives have been synthesized and evaluated for anticonvulsant activity.We have screened the solvents, additives by used (RP,S)-4-prolinamido-12-[2.2]paracyclophanylamino thiourea as catalyst, isatin and acetone as substrates. After that, we screened other catalysts and substrates.Innovations of this thesis.1. A family of novel [2.2]paracyclophane-based amino thioureas was synthesized and applied in asymmetric catalysis. We found a new method for resolution of4-Formyl-12-bromo[2.2]paracyclophane. 2. These new organic catalysts containing [2.2]paracyclophane-bsed amino thiourea was first used in asymmetric condensation of ketones and isatins along with a high yields and good enantioselectivties.