Study On Asymmetric Conjugation Cyanation With 3,5-Dimethylacylpyrazole As Substrate

Cyano groups are important organic functional groups,which widely exist in the molecules of chemicals such as medicines,pesticides,and dyes,and are also very important active groups.Cyanide products with optical activity occupy a prominent position in in the field of medicine.The asymmetric cyanidation reaction of?,?-unsaturated carbonyl compounds is an important method to introduce cyano functional groups into molecules.The optically active ?-cyano compound obtained by asymmetric conjugated cyanide addition can be easily converted into important compounds with therapeutic effects,such as GABA analogs and 1,2-dicarboxylic acid,which play a vital role in the treatment of neurological diseases.Therefore,it is of great significance to study the asymmetric conjugated cyanidation reaction of?,?-unsaturated compounds.This paper mainly studies the asymmetric conjugated cyanide reaction by using TMSCN as the cyanide source and3,5-dimethylacylpyrazole as the substrate.The specific research contents are as follows:1.Synthesis of chiral ligands.Three kinds of(R)-BINOL ligands(L1,L2,L3)were synthesized with R-configuration binaphthol as the raw material.Two kinds of Salen ligands(L4,L5)were synthesized with trans(1R,2R)cyclohexanediamine and salicylaldehyde as raw materials.Malononitrile was used as raw material,and reacted with hydrochloric acid ethanol solution to produce diethyl aminomalonate hydrochloride,which then underwent condensation reaction with chiral aminoindanol,and then reacts with different bromides to produce 13 chiral bisoxazolines Ligand(L6-L18).2.Determination of the best catalytic method.A model reaction was established by using trimethylsilyl cyanide as the cyanogen source and cinnamon pyrazole as the substrate.The optimum reaction conditions were determined by the research on some factors,such as the types of chiral ligands,the types of metal reagents,the ratio of ligand to metal reagent,the amount of catalyst,the solvent and the reaction temperature.Results showed that when bisoxazoline ligand L13 and dibutylmagnesium(molar ratio 2:1)was used to generate chiral catalyst in situ in1,2-dichloroethane,the amount of catalyst was 10 mol%,and the reaction temperature was-32?,the catalytic effect of asymmetric conjugated cyanidation reaction of TMSCN with cinnamon pyrazole was the best,with a yield of 95% and an er value of 93:7,The absolute configuration of the product is determined as S.3.Research on the applicability of the catalytic method.The catalytic method above was applied to the conjugation cyanation reaction of 10 kinds of aromatic3,5-dimethylacylpyrazole derivatives,1 kinds of fatty 3,5-dimethylacylpyrazole derivatives and 2 kinds of heterocyclic 3,5-bismethylacylpyrazole derivatives.Experimental results showed that using the above substrates as raw materials,the corresponding target products could be obtained with a yield of more than 90% and moderate to good enantioselectivities.