Organocatalytic Asymmetric Synthesis Of Pyrazolone Derivatives

Objective:Cinchona base-derived bifunctional organocatalysts-based hydrogen bond activated are constantly emerging in the research field of asymmetric catalytic synthesis,and play an irreplaceable role in the development of novel bioactive framework compounds.This paper aims to explore the asymmetric catalytic strategies for the synthesis of bioactive skeleton compounds containing pyrazolone and 1,4-naphthoquinone core structures by designing and synthesizing the novel organocatalysts-based hydrogen bond activated,in order to obtain corresponding derivatives with excellent enantiomeric purity.Methods:（1）Using quinoline derivatives such as quinine,cinchonine and other cinchona bases,diphenylphosphinyl chloride,1,5-naphthalene diamine,1,8-naphthalene diamine,squaraine and so on as starting materials to synthesize the targeted multiple hydrogen bond organocatalysts after multi-step reactions such as chlorination and esterification.（2）The novel organocatalysts-based hydrogen bond activated were applied to the asymmetric addition reaction of 1,4-naphthoquinone and pyrazolone.The reaction solvent,temperature and other conditions were screened to obtain the target products with excellent diastereoselectivity and good enantioselectivity,and the relative configuration of product 3b was determined by single crystal X-ray diffraction structural analysis.（3）Usingα,β-unsaturated pyrazolone and 2-hydroxy-1,4-naphthoquinone as model substrates,C9 as organocatalyst and NCS as an important halogenation reagent,moderate to excellent enantioselective adducts were synthesized by a tandem Michael addition/Chlorination/Nucleophilic substitution sequence and condition optimizations.The upscaling attempt synthesis reactions also further proved the practicability of the synthetic strategy,and the absolute configuration of product 8k was determined by single crystal X-ray diffraction structural analysis.Results:（1）A total of 11 organocatalysts-based hydrogen bond activated were synthesized,of which 6 organocatalysts（C1-C6）were not reported in literatures,and their structures were characterized by ¹H-NMR,¹³C-NMR,HRMS and IR.（2）The novel organocatalyst-based hydrogen bond activated C1 was used for the asymmetric Michael addition reaction of 1,4-naphthoquinone and 1-phenyl-3-methyl-5-pyrazolone,and 4-hydroxy-substituted pyrazolone compound could be obtained with 53%isolated yield,>99:1 dr,26%ee.（3）The novel organocatalyst-based hydrogen bond activated C9 was used for the asymmetric Michael addition reaction ofα,β-unsaturated pyrazolone and 2-hydroxy-1,4-naphthoquinone,and the yield of the 4-substituted pyrazolone compound was up to 99%.In addition,a series of spiropyrazolones quinodihydrofuran heterocyclic derivatives were synthesized with moderate to excellent enantioselectivities（60%-98%ee）and good yields（67-87%）in the subsequent Chlorination/Nucleophilic substitution sequence reactions.Their chemical structures were characterized by ¹H-NMR,¹³C-NMR,HRMS,IR,and the possible reaction mechanism was inferred of Hartree-Fock calculation.Conclusion:（1）Eleven organocatalysts-based hydrogen bond activated were obtained.（2）Using C1 as the organocatalyst and 1,4-naphthoquinone and 1-phenyl-3-methyl-5-pyrazolone as model substrates,4-hydroxyl-substituted pyrazolone compounds containing three consecutive stereocenters were synthesized with excellent diastereoselectivity,but the reaction yield and enantioselectivity need to be further improved.（3）The squaramide catalyst C9 can successfully catalyze the asymmetric Michael addition ofα,β-unsaturated pyrazolones and 2-hydroxy-1,4-naphthoquinones to obtain moderate to excellent enantioselective pyrazolone derivatives with up to 99%yield.Using the halogenated reagent NCS to induce the subsequent Chlorination/Nucleophilic substitution sequence reactions,the target products containing two consecutive stereocenters can be obtained with moderate to excellent enantioselectivity under mild experimental conditions,not only explored the practicability of the reaction,but also further opened up new spiropyrazole heterocyclic derivatives.