The Application Of Phase-transfer Catalysis In The Synthesis Of Bispiro-heterocyclic Compounds

Phase transfer catalysis can effectively accelerate the rate of organic chemical reactions,which is based on the principle of using quaternary ammonium salts or quaternary phosphonium salts to transfer anions between two phases in a heterogeneous reaction.Phase transfer catalysis is characterized by mild reaction conditions,safety and environmental protection,easy operation,rapidity and high selectivity,and is one of the effective ways to achieve high efficiency and low pollution in industrial scale organic synthesis reactions.At present,phase transfer catalysis has been widely used in the production of pharmaceutical intermediates,pesticides,dyestuffs,additives and other fine chemicals.Pharmacophore is a model based on pharmacophore characteristic elements.Indole oxide,oxazolone,pyrrolidine,chromone and trifluoromethyl are the more classical pharmacophore.The C-3 position of indole oxide is more active and can be easily reacted to produce diverse spirocyclic indole oxide compounds.The five-membered ring of oxazolone contains N and O double heteroatoms,which is the core backbone of some drug molecules.As an important organic synthesis block,oxazolone has a diversity of reaction orientations.Pyrrolidine is a common core ring system for marketed small molecule drugs in the Orange Book of the U.S.Food and Drug Administration.Chromones are a class of natural oxygen-containingheterocycles widely found in plants and are of great interest to researchers for their diverse biological activities.Trifluoromethyl has a strong electron-absorbing ability,and its introduction into drug molecules can dramatically alter the metabolic stability and biological activity of the molecule.In recent years,pharmacophore hybridization has gradually become an effective way to develop drug lead compounds.Therefore,it is possible to develop highly active lead compounds if the above five pharmacophores can be hybridized into one molecule by efficient synthetic methods.In this paper,a phase transfer catalytic system was developed using a combination of inexpensive and readily available quaternary ammonium salts and potassium carbonate.The catalytic system achieved the 1,3 dipole[3+2]cycloaddition reaction of N-(2,2,2-trifluoroethyl)isatinimine with 4-tryptone methylene-oxazolone under mild conditions.The reaction can rapidly assemble the five pharmacophores of oxindole,oxazolone,pyrrolidine,chromone and trifluoromethyl into a complex bispiral heterocyclic molecule.After the optimal reaction conditions were obtained by condition screening,a larger scale substrate expansion was performed and 31bispiroheterocyclic compounds containing four chiral centers were successfully constructed in good yields(51-94%yield)and excellent diastereoselectivity(>99:1 to most cases).X-ray single crystal diffraction and ~1H NOESY NMR were used to confirm the relative conformations of the products.The investigation of the amplification reaction,reaction kinetics and reaction mechanism was carried out.The results of the scale-up reactions fully demonstrate the potential application of this reaction system in the pharmaceutical industry.The kinetic study demonstrates the unparalleled superiority of the developed phase transfer catalytic methodology,and the kinetic experimental data shows that the reaction rate of the present phase transfer catalytic system was 11 to 40times higher than that of the classical organocatalytic system.The results of the reaction mechanism study suggest that the real catalyst of this reaction may be tetrabutylammonium carbonate generated in situ from tetrabutylammonium bromide and potassium carbonate by substitution reaction.The series of pentadecamericheterocompounds synthesized in this study have the potential to become potential lead compounds,while the developed phase transfer catalytic methodology is expected to enter the synthetic toolbox of organic chemists.