Studies On Transition Metal Catalyzed Cross-Coupling Reactions Containing SP~3 C-centered Radical Process

Transition metal-catalyzed cross-coupling reactions have received a great development recent years, Compared with traditional organic synthetic methods, transition metal-catalyzed cross-coupling reaction significantly changed organic synthetic methodology. It presents an efficient method for construction of carbon-carbon, carbon-heteroatom bonds and makes it possible for construction of some new unconventional bonds. Furthermore, using sp3 carbon synthon to construct complex non-planar molecules via transition metal-catalyzed cross-coupling reaction is at the research forefront of organic chemistry. Among various sp3 carbon centered cross-coupling reactions, it has significant advantages for the construction of sp3 carbon center via radical process due to its high reactivity, less affected by steric hindrance, simple and mild reaction conditions. Recently, Gregory C. Fu and other organic chemists have achieved a series of transition-metal-catalyzed sp3 carbon centered cross-coupling reactions, but still many challenges and opportunities exist in this field. In particular, Cu, Pd and other transition metals have shown excellent properties in many cross-coupling reactions, It must lead to some new methodology of organic synthesis by combination of radical reactions with transition metal-catalyzed cross-coupling reactions. This paper briefly introduced the research background:Advances in transition metal-catalyzed decarboxylative cross-coupling reactions of alkyl carboxylic acids via a radical process and Advances in transition metal-catalyzed cross-coupling reactions of alkyl electrophiles via a radical process.By the introduction we found that the current development of transition metal-catalyzed decarboxylative cross-coupling reactions of alkyl carboxylic acids is far from perfect. The most practicable approaches in this field are Silver-catalysis and Photoredox catalysis. Only several transition metal catalysts can enable decarboxylation of alkyl carboxylic acids, furthermore, the selectivity of these reactions cannot be controlled by transition metal catalysts due to the fact that the interaction of the produced alkyl radical with the transition metal is so weak that can be ignored. To address this issue we introduced our development of Cu-catalyzed decarboxylative cross-coupling reaction of non-activated aliphatic carboxylic acid to construct intramolecular C-N bond by using a directing group in Chapter 2. We use Cu catalyst to facilitate the decarboxylation process, and the alkyl radical produced via decarboxylation can be captured by the Cu that is chelated by the directing group, followed by reductive elimination, the desired C-N bond is formed. Using a directing group makes the reaction have an excellent site-selectivity at the presence of several potential radical acceptors. This reaction provides a good idea on derivation of many common chemical skeletons in natural products.By the introduction of the Advances in transition metal-catalyzed cross-coupling reactions of alkyl electrophiles via a radical process also we found that some challenges and opportunities exist in this field. There are many examples of radical cross-coupling reactions of alkyl electrophiles catalyzed by Ni, Co and Fe. However, other transition metal catalysts especially for Pd catalyzed cross-coupling reactions of alkyl electrophiles via a radical process are rather rare. This reminds us that maybe there are some new properties of Pd catalyst that have not been discovered. Furthermore, limited cross-coupling modes aroused our interest on the reaction of electrophiles with other types of substrates. So in Chapter 3, we introduced our development on Pd catalyzed cross-coupling reaction of pyridine N-Oxides with non-activated secondary alkyl bromides. Mechanistic studies suggested that the activation of secondary alkyl bromides by Pd catalyst is a radical process.