Regio-and Enantioselective Allylation Of N-heteroaroaromatics To Aliphatic MBH Adduct

Optically active N-heteroaromatics containing ?-alkyl groups are prevalent in natural products and biologically active molecules.Therefore,searching for an efficient method to construct N-heteroaromatics containing ?-alkyl group is in great demand.The asymmetric N-allylation of Morita-Baylis-Hillman?MBH?adduct with nitrogen nucleophile is one of the most powerful strategies to prepare enantiomerically enriched N-allylic amines.Good to excellent results have been achieved in the enantioselective N-allylation of aromatic MBH adducts.However,the asymmetric N-allylation of aliphatic MBH adducts has been far from successfuldue to their lower reactivity and lesser stericdissimilarity compared to that of aromatic ones.Besides,the N-allylation of MBH adducts with these less nucleophilic N-heteroaromatics,including imidazole,benzimidazole,benzotriazole,and purine,remains unknown.Initially,the reaction between benzimidazole and n-hexanal derived MBH adduct was chosen as the model reaction.By employing [Pd??₃C₃H₅?Cl]2 as a Pd salt,?R,R?-DIOP as a ligand,the N-allylation reaction proceeded smoothly to give the corresponding amination product in 92% yield with a 77:23 regioselectivity for 3aa/4aa,but with poor enantioselectivity?-9% ee?.Then some privileged ligands,such as?R?-BINAP,?R,R?-Trost ligand,?R,R?-BDPP,or?R,R,R?-SKP were screened and?R,R,R?-SKP gave the higher results?92% yield,79:21 regioselectivity,and 82% ee?.Changing the SKP ligands with different aryl substituents at the P atom did not give improved results.Subsequently,several palladium salts were examined and Pd2?dba?3 afforded the superior results.Later,a few solvents were explored with Pd2?dba?3-L5 as the catalyst,but inferior results were generally obtained.To improve the enantioselectivity of the reaction,MBH adducts with different leaving groups were investigated,and MBH propionate was the better choice?92% yield,73:27 regioselectivity,and 86% ee?.Lowering the temperature resulted in enhanced enantioselectivity.When the catalyst loading was decreased from 5 mol% to 2.5 mol%,the enantioselectivity was kept,albeit with lower yield.To our delight,when the reaction was performed under ultrasonic,the reaction time could be shortened from 96 h to 6 h,along with the maintained yield and enantioselectivity.To further improve the regioselectivity and enantioselectivity of the N-allylation reaction,various ester groups in MBH propionates were screened carefully.When methyl ester derived MBH adduct 2e was used,the regioselectivity and enantioselectivity all decreased obviouslyIncreasing the steric hindrance of the ester group from tertbutyl,benzyl,or 1-adamantyl,the enantioselectivities were the same level?90-93% ee?.Surprisingly,the utilization of the MBH propionate with the 2-adamantyl further increased the ee value of the branched product 3ai to 97% ee,along with improved regioselectivity to 88:12.Thus,the optimal reaction conditions were identified as follows: 2.5 mol% of Pd2?dba?3,5 mol% SKP-L5,2-adamantyl derived MBH propionate as the reactant in DCM at-20 oC under ultrasonic for 6 h.Finally,we used the ¹H NMR,13 C NMR,HSQC,HMBC,Noesy,HRMS,HPLC and other means to characterize the chiral ?-allyl-N-heteroaryl product.due to the complexity of the N-allylation reaction of purines and benzimidazoles,the study is difficult,and the purine reaction has N7 and N9 selectivity.We determine the structure by HSQC and HMBC,The allyl amination reaction produces two products,namely the chiral branch product?B?and the achiral branched product?L?,and the linear products produced by the reaction are Z-type and E-type.The configuration is determined by the Noesy spectrum,7-methylbenzimidazole and benzotriazole and MBH adduct reaction will also have different selection sites,we want to determine the structure by HSQC,HMBC and Noesy.Due to the polyfunctionalization of the chiral ?-allyl-N-heteroaromatics products,the reaction product can be extended to synthesize the desired product.This article provides a new idea for the synthesis of optically active?-allyl-N-heteroaromatics compounds...