Organocatalyzed Construction Of New Kind Of Pyrazolone Derivatives

Pyrazoles is an important kind of five-membered heterocyclic compounds containing two adjacent nitrogen atoms,have been proved possessing diverse biological activities.The research and development of the pyrazolone and its derivatives has become one of the hot spots in the fields of pesticide,medicine,dyestuff,luminescent materials and so on.Although the pyrazolone is the core skeleton structure of many natural products and drugs,people used to research and develop pyrazolone drugs mainly concentrated in simple pyrazolone derivatives without chiral centers.But the application of optically active chiral pyrazolone compounds in medicinal chemistry is lacking in corresponding research.With the progress of medical and pharmaceutical chemistry,chiral drugs with optical activities have been widely used in clinical medicine.Therefore,it is of great significance to enantioselective synthesize of the novel pyrazole derivatives with potential bioactivity.In this dissertation,we mainly focus on the synthesis of novel pyrazole derivatives with potential bioactivity under the catalysis of chiral organocatalyst.At the same time,the organic base or tertiary phosphine was also used as the catalyst to diastereoselective synthesis of the pyrazolone derivatives.The main work is as follows:?1?Squaramide-catalyzed enantioselective Michael addition of pyrazolin-5-ones to nitroalkenesAn enantioselective Michael addition of pyrazolin-5-ones to nitroalkenes catalyzed by squaramide-based catalyst containing a piperidinyl group was developed with very low catalyst loading?0.25 mol%?.The corresponding pyrazol-3-ol derivatives could be obtained in high to excellent yields?44–>99%?and high enantioselectivities?up to 49–94%ee?under mild reaction conditions.The derivation of the product was also conducted,and the propargyloxy derivative of the pyrazole was obtained.In addition,a successful gram-scale reaction could also be performed in the presence of only 0.25 mol%of catalyst under the standard reaction conditions.Then an highly efficient enantioselective Michael addition reaction between pyrazolones and 3-nitro-2H-chromenes for the first synthesis of chiral heterocyclic compounds containing both chromans and pyrazolone derivatives under the catalysis of the same chiral squaramide was developed.The corresponding Michael adducts could be obtained in high to excellent yields?75–98%?,with high enantioselectivities?73–96%ee?and excellent diastereoselectivity?96:4–99:1 dr?in the presence of only 0.20 mol%of catalyst.A gram-scale reaction also worked well without any loss in the chemical yield and stereochemical outcome.?2?Squaramide-catalyzed enantioselective Michael addition of pyrazolin-5-ones to unsaturated estersAn efficient chiral squaramide-catalyzed enantioselective Michael addition of pyrazolin-5-ones tob,g-unsaturateda-ketoesters was also developed.The corresponding Michael adducts could be obtained in moderate to high yields?up to 99%?with high enantioselectivities?up to 96%ee?.This catalytic asymmetric reaction provides easy access to chiral pyrazolone ketoester derivatives,which possess potential pharmaceutical activity.The propargyloxy derivative of the pyrazole could also be obtained by the derivation of the product.?3?Enantioselective synthesis of dihydropyrano[2,3-c]pyrazoles catalyzed by a chiral squaramideAn enantioselective cascade Michael/Thorpe–Ziegler type reaction of?,?-unsaturated pyrazolones with malononitrile provided a direct entry to dihydropyrano[2,3-c]pyrazole derivatives catalyzed by a cinchona derived squaramide.A variety of arylidenepyrazolones reacted with malononitrile to give a series of dihydropyano[2,3-c]pyrazoles in high yields?79–99%?and moderate enantioselectivities?41–79%ee?very short reaction time.In this reaction we greatly expand the substrate scope of this kind of reaction,which is of great significance for the asymmetric synthesis of dihydropyrano[2,3-c]pyrazole derivatives.?4?Diastereoselective and enantioselective synthesis of spiro-pyrazolone- cyclopropane-oxindolesA DIPEA-catalyzed diastereoselective cascade reaction of arylidenepyrazolones with3-chlorooxindoles was successfully developed,which provided a facile and straightforward access to highly functionalized spiro-pyrazolone-cyclopropane-oxindole derivatives containing vicinal quaternary carbons constrained in a highly substituted cyclopropane ring in excellent yields?up to 99%?with high to excellent diastereoselectivities?up to>25:1 dr?.Moreover,the squaramide-catalyzed asymmetric reactions of arylidenepyrazolones with3-chlorooxindoles afforded the corresponding chiral spirocyclic heterocycles with three contiguous stereocenters,including two vicinal quaternary centers in excellent yields?up to99%?with moderate diastereoselectivities?up to 87:13 dr?and moderate to high enantioselectivities?up to 74%ee?.?5?Phosphine-catalyzed cascade reaction for the synthesis of pyrano[2,3-c]pyrazoles and spiro-cyclopentanone-pyrazolonesA triphenylphosphine-catalyzed cascade reaction of unsaturated pyrazolones with dialkyl acetylenedicarboxylates or but-3-yn-2-one to synthesize the bioactive pyrano-[2,3-c]pyrazoles in moderate to excellent yields were developed.Meanwhile,spiro-cyclopentanone-pyrazolones were also first constructed by the triphenylphosphine-catalyzed cascade reaction of unsaturated pyrazolones with 4-phenyl-but-3-yn-2-one in moderate to good yields.we also proposed the reaction mechanism for these two types of reactions.?6?Diastereo-and enantioselective construction of optically pure cyclohexanone-fused spirospyrazolones through asymmetric sequential reactionsThediastereo-andenantioselectivesynthesisofcyclohexanone-fused spirospyrazolones containing four consecutive chiral centers has been successfully developed through an asymmetric Michael/Michael/aldol cascade reaction of pyrazolone,?-nitrostyrene and cinnamaldehyde,catalyzed by the combination of the bifunctional squaramide and diphenylprolinol silyl ether,followed by a sequential oxidation with pyridinium chlorochromate.This protocol affords the highly functionalized cyclohexanone-fused spiropyrazolones with four contiguous stereocenters,including one vicinal quaternary centers in moderate to high yields?30-78%yield?,moderate to good diastereoselectivities?60:40-25:1 dr?and perfect enantioselectivities?up to>99%ee?.?7?Squaramide-catalyzed cascade aza-Michael/Michael addition for the asymmetric construction of highly functionalized spiropyrazolone tetrahydroquinolinesAn asymmetric cascade aza-Michael/Michael addition of 2-tosylaminoenones with unsaturated pyrazolones catalyzed by a chiral bifunctional tertiary amine squaramide derived from quinidine was developed.This protocol provided a facile and straightforward entry to highly functionalized chiral spiropyrazolone tetrahydroquinoline derivatives with three contiguous stereocenters,including one quaternary center,from simple starting materials.This cascade reaction proceeded well with 2 mol%chiral bifunctional tertiary amine squaramide catalyst to give the desired products in excellent yields?up to 99%?with excellent diastereoselectivity?up to>25:1 dr?and high enantioselectivity?up to 91%ee?.In addition,the reaction was easily gram-scaled and the carbonyl group of the product could be easily reduced.The possible catalytic transition state model was proposed.?8?Squaramide-catalyzed cascade aza-Michael/Michael reactions for the asymmetric synthesis of spiro-pyrrolidine-pyrazolonesA new method was developed to rapidly generate a series of 4,3'-spiro-pyrrolidine-pyrazolones with three contiguous stereocenters,including one quaternary center by using a squaramide-catalyzed cascade aza-Michael/Michael addition of either tosylaminomethyl enones or enoates with unsaturated pyrazolones.This tandem reaction sequence proceeded well by using 5 mol%of a squaramide catalyst,in CHCl₃,at room temperature.The desired products were obtained in good to excellent yields?up to 98%?with excellent diastereoselectivities?up to>20:1 dr?and high to excellent enantioselectivities?up to 98%ee?.