Pd-catalyzed Intramolecular Cyclization Of Unactivated Alkyl Iodides

The transition-metal catalyzed cross-coupling reaction has been developed into an indispensable tool for construction of chemical bond over the past half century.Palladium-catalyzed transformation is one of the most studied field,widely used in the synthesis of pharmaceuticals,pesticides,fine chemicals and natural products.Pd(?)and Pd(?)involved radical reactions have received growing attention in recent years,providing various methodologies for the construction of numerous carbocyclic and heterocyclic ring systems.These novel methodologies complement the traditional Pd-catalyzed reaction effectively,making a significant contribution to promote the palladium chemistry.The coupling reaction of unactivated alkyl halocarbons is one of the most challenging research subjects in Pd-catalyzed conversion,which is of great importance to build functionalized Csp~3.This paper is focused on Pd(0)-catalyzed cyclization of unactivated iodides,and two novel transformations are displayed:1)Pd(0)-catalyzed intramolecular 6-endo selective alkyl-Heck reactions of unactivated iodides;2)Pd(0)-catalyzed intramolecular reductive olefin hydrocarbonation.While studying and summarizing the radical involved palladium-catalyzed reactions,we got some new ideas and then designed a series of substrates for testing.Based on the reasonable experimental ideas,we firstly achieved the Pd(0)-catalyzed intramolecular6-endo selective alkyl-Heck reactions of unactivated iodides:access to5-phenyl-1,2,3,6-tetrahydropyridine derivatives,which are widely distributed in natural products and modern medicines.TEMPO testing experiment and deuterium scrambling investigation strongly suggest that a free radical process is involved in this conversion.In addition,a Pd(0)-catalyzed intramolecular hydrocarbonation of unactivated alkenes was also developed,in which toluene is used as a hydrogen donor for the first time.The radical transfer hydrogenation is designed and realized based on not only the characteristic of benzyl but also the Bond Dissociation Energy(BDE)value.It was found that xylene mixtures,mesitylene and even the ethylbenzene with lower activity acted as hydrogen source materials smoothly in this transformation.By conducting the control experiments,the possible reaction pathway and rate-determining step were proposed.The realization of this new methodology avoids employing the high-toxic tin-hydrogen and silicon-hydrogen reductants.A toluene derivative,which is cheap,readily available and easy to handle,serves as a new hydrogen donor in radical involved reactions,providing a novel and promising perspective for future reductive reactions...