Synthesis Of Pyranopyrazole Derivatives Via Asymmetric Tandem Reaction With Organocatalysis

The pyran ring constitutes the core unit in the molecular framework of many natural and several pyran derivatives have been found bioactivities,such as antispasmodic,antiinflammatory,antibacterial,antihypertensive,anti-tumor,antidepressant and so on.Over the years,derivatives of pyran and its fused analogs have been and continued to be a subject of considerable importance.Among such fused heterocycles,the pyrano[2,3-c]pyrazoles provide a variety of scaffolds,the studies of have been found to display analgesic,anti-inflammatory,antibacterial properties.Owing to their potential application,many researchers explored its synthesis method.Then there are many different modes of reactions to synthesize pyrano[2,3-c]pyrazoles scaffold such as two-component,three-component and four-component.In recent years,great progress has been made in organocatalyzed asymmetric tandem reactions and it can provide an easy access to synthesize the chiral pyrano[2,3-c]pyrazole derivatives.In this paper,we developed a bifunctional tertiary amine thiourea and amide catalysts catalyzed tandem Michael-cyclization reaction to synthesis pyrano[2,3-c]pyrazoles.The specific contents and results are as follows:In this study,seven kinds of tertiary amine thiourea catalysts were designed and synthesized by using L-threonine as skeleton which were applied to the asymmetric tandem reaction of 3-methyl-1-substituted-5-pyrazolone 1 and arylidenemalononitrile 2,in this way,we can synthesis the chiral pyrano[2,3-c] pyrazole compounds.A series of reaction conditions which affected the asymmetric tandem reaction were screened,such as catalysts and dosage,reaction solvents and dosage,reaction temperature,the feed ratio,the additives and so on.During the research we found the optimum reaction conditions were obtained as follows: 25 oC,ether as solvent,the 1-phenyl-3-((2R,3R)-1-(piperidin-1-yl)-3-((triisopropylsilyl)oxy)butan-2-yl)thiourea(Cat.6)as the optimal catalyst and the dosage was 5 mol%,the ratio of 3-methyl-1-phenyl-1H-pyrazol-5-pyrazolone 1 and 2-benzylidenemalononitrile 2 was 1: 1.2,20 mg active 5? molecular sieve were added(part of the substrate with 2 mg of anhydrous sodium sulfate as additive).Under the best condition,the twenty substrates were investigated,pyrano[2,3-c]pyrazole products were obtained with good yields(up to 85%,such as:6-amino-3-methyl-1-phenyl-4-(p-tolyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbon itrile)and high enantioselectivities(up to 99% ee,such as: 6-amino-3-methyl-1,4-diphenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile).All the products were characterized by melting point,1H NMR,13 C NMR.The three L-threonine-derived tertiary amine thiourea catalysts and four novel amide catalysts were applied to catalyze the asymmetric tandem reaction with 3-methyl-1-substituted-5-pyrazolone and 2-(1-methyl-2-oxoindolin-3-ylidene)malononitrile.A series of reaction conditions which affected the asymmetric tandem reaction were also screened,such as catalysts and dosage,reaction solvents and dosage,reaction temperature,the additives and so on.The best reaction system was as follows:-78 oC,THF as solvent,5 mol% of the square amide 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((1R,2R)-2-(dimethylamino)cyclohexyl)amino)cyclobut-3-ene-1,2-dione(Cat.4).Under this condition,we obtained the target product with 98% yield and 76% ee.