Research Of Asymmetric Domino Reaction Catalyzed By Novel Bifunctional Tertiary Amine Thiourea Catalysts

Organocatalyzed cascade reactions is consideredas a very powerful tool to buildcomplex chemical structures, secondary amine catalysts are widely used in dominoreactions due to the combination of compared with secondary amine catalysts, thefield of cascade reactions catalyzed by chiral H-bonding catalysts is relatively newand full of potential. Secondary amines is ideal for application in domino reactions.However, their scope is mainly limited to carbonyl systems and H-bond catalysts canclose this gap.Pyrazoles are considered as one of the most versatile class of organic molecules,widely used in pharmaceutical and agrochemical chemistry. In addtion,pyrano-annulated pyrazoles have been reported to possess a broad spectrum ofbiological activities. Considerable attention has been paid to the development ofmethods to generate pyrano-annulated pyrazoles. But to the best of our knowledge,there are few reports of performing domino reaction in an enantioselective fashion.Inthis paper, we dedicate to study the asymmetric domino reactions catalyzed by noveltertiary amine thiourea catalysts. And weget pyran compounds containing twostereocenters by the catalyzed asymmetricdomino SN2’/Michael reaction.The seven tertiary amine thiourea catalyststhat L-threonine scaffold and fivetertiary amine thiourea catalysts that Cyclohexanediamine scaffold or quinine scaffold was used asthe chiral scaffold of the novel bifunctional catalysts wereapplied to the asymmetricdomino reaction of3-methyl-1-substitution-2-pyrazolin-5-one1and (E)-3-substitution-2-nitroallyl acetate2. All the products werecharacterizedby melting point, optical rotation,1H NMR,13C NMR and HRMS.The factors such as catalysts and dosage, solvent,reaction temperature,molecular sieve and dosage were investigated. During the investigation, we foundthat1-phenyl-3-((2R,3R)-1-(piperidin-1-yl)-3-(triisopropylsilyloxy)butan-2-yl)thiourea(Cat.6) was optimal catalyst. Then we studied otherfactors which affected thedomino reaction, and we got the optimal reactionconditions,Cat.6was the bestcatalyst during thetwelve catalysts, the catalyst dosage was10mol%,1mLChlorobenzene was the optimalsolvent, the best reaction temperature was-10oC andwe can got the best result whenthe80mg non-actived5A molecular sieve were added.With the optimal reaction conditions in hand,we studied more substrates for thedomino reaction. In the eighteen substrates westudied, allthe domino reactions hadexcellent distereoselectivity (dr=90:10->99:1) andenantioselectivity (87%->99%ee).We put four tertiary amine thiourea catalysts that we designed andsynthesizedderived from L-threonine, two tertiary amine thiourea catalysts thatderived fromdiaminocyclohexane and two tertiary amine thiourea catalysts thatderived fromcinchona alkaloids we had into the asymmetric domino reaction of4-Hydroxycoumarin and (E)-3-phenyl-2-nitroallyl acetate2a. After thecatalyst,catalyst loading, solvent and temperature selected we can affordedthecatalytic product3a with65%yield,92:8dr and81%ee.