Small-molecular Hydrogen-bond Donor-catalyzed Cross-dehydrogenative Coupling Reaction And Mechanism Study

Tetrahydroisoquinoline alkaloids are widely existed in nature,some of them have been used as drugs in clinical practice due to their anti-tumor,anti-virus and other biological activities.Chemical synthesis is an important means for creating structurally diverse tetrahydroisoquinolines,among these chemical transformations,cross-dehydrogenative coupling(CDC)reaction which has simple reaction,high atom utilization,environmental protection and other advantages,has made great contributions and became a research hotspot.However,CDC reactions are often dominated by the use of transition metals as catalysts,realizing the transformation through the change of the metal valence.However,there are still some problems frequently encountered with the ransition metal catalyst,such as cost,poor stability,toxicity,etc.Especially the heavy metal leaching problem hinders its application in pharmaceutical synthesis.In view that small-molecular hydrogen-bond donor catalyst has the advantages of easy preparation,low cost,mild reaction conditions,good stability,environmental friendly and other advantages,it can potentially solve the problem of transition metal-catalyzed reaction.In addition,it can activate the reaction.and stabilize the transition state anion through hydrogen bonding.Therefore,we reported for the first time that the hydrogen-bond donor catalysts(such as N,N'-bis[3,5-bis(trifluoromethyl)phenyl]thiourea(T1))can be employed as a catalyst for the CDC reaction of tetrahydroisoquinolines derivatives with a variety of nucleophiles,upon wihich tetrabutyl hydroperoxiede(TBHP)was used as a terminal oxidant.The present method not only provides a new method for the synthesis of various tetrahydroisoquinolines derivatives but also expands the application of T1 and paves a new avenue for thiourea-based organocatalysts.The main contents are listed as follows:1.T1 catalyzed C-P coupling reactiona-amino phosphonate,phosphorus analogs of biologically active natural a-amino acid,have been widely used in the fields of biology and pharmacology,due to their antiviral,antibacterial and other characteristics.In the second chapter,we developed a new catalyst system to form C-P bonds under mild reaction conditions through CDC reactions between dialkyl phosphite and various tertiary arylamines by using Tl as catalyst and TBHP as the terminal oxidant.After the optimal reaction conditions were established,various N-aryltetrahydroisoquinoline derivatives were examined for the generality of this protocol under the optimized reaction conditions,the results showed us that N-Aryltetrahydroisoquinolines bearing either electronwithdrawing or-donating groups were well tolerated with this method,the corresponding a-aminophosphonic derivatives were delivered in good yields.Morever,the possible reaction intermediates were obtained,which provided preliminary evidence of the reaction mechanism.2.T1 catalyzed C-C coupling reaction and exploration of asymmetric synthesisC-C bond is a fundamentally chemical bond in organic compounds,its construction method has been a very important research direction of the synthesis design.In the third chapter,the T1/TBHP catalytic system was successfully applied in the CDC reaction with other nucleophiles such as nitroalkanes and etc.,to synthesize the corresponding coupling products.Based on the investigation of the reaction parameters,the optimal reaction conditions are obtained.We expanded the substrate under the optimal condition,finding that a broad range of structurally and electronically diverse tetrahydroisoquinolines were well tolerated with this metal-free process,providing the corresponding a-functional amine in good yield.This metal-free catalytic system is also compatible with malononitrile.Surprisingly,a-amino nitriles were obtained as the sole products instead of the expected ?-dicyano substituted derivatives,which provided a new way for the synthesis of a-amino nitriles.3.Mechanistic studies of T1-catalyzed CDC reactionsT1 was used as catalyst in CDC reaction for the first time,the study of mechanism is still far behind.In view of this,we present detailed mechanistic studies of T1-catalyzed cross-dehydrogenative C-P and C-C coupling reactions using NMR spectroscopy,radical additives experiments,kinetic isotope effect(KIE)experiment and other experimental techniques.The results revealed that a-amino peroxide is the true intermediate within the catalytic cycle,formed via a thiourea-catalyzed rate-determining hydrogen atom transfer(HAT)process.The control experiment showed that T1 had a positive effect on the reaction of the intermediate 2.4 and the nucleophile.Finally,we put forward the mechanism in Scheme 4.9.These experimental investigations not only provide somewhat insight into the mechanism of thiourea-catalyzed CDC reactions but also promote their further applications.