Transition-Metal-Catalyzed Oxidative Radical/Radical Cross-coupling Reaction

Transition-metal-catalyzed direct oxidative cross-coupling of C-H/X-H provides a sustainable atom-economic powerful tool for construction of divergent compounds in organic synthesis. Based on the electron transfer in the process of C-H/X-H bonds, these reactions are classified into zero-electron process, single-electron process and two-electron process. Zero-electron process that is deprotonation mainly focuses on relatively strong acidic C(sp)-H/C(sp2)-H substrates, and two-electron process is dependent on oxidation addition of noble metals (Pd, Rh, Ru, Ir and so on). However, the research is relatively very rare for C(sp3)-H substrates. The main reasons are this kind of compounds have weak acidity and strong bond dissociation energy, and ?-H elimination is inevitable. Maybe single-electron activation of C(sp3)-H provides a way of solving these problem. Some calculated experiments have indicated that radical cation RH.+ is able to readily lose one proton and transform into the corresponding radical species due to its severely increased acidity, compared to neutral R-H. The radicals generated from C-H/X-H are very reactive. Traditional radical reaction mainly is on radical addition to unsaturated bonds. Tuning their selectivity to realize radical-radical cross-coupling is a very challenging topic. Difunctionality of alkene provides a valuable tool for construction of divergent organic molecules. Carbon cation intermediate is a necessary in traditional radical participated difunctionality of alkene, but this could bring other by-products. Developing a novel bond formation mode of alkene difunctionality will immensely promote the selectivity.This thesis elaborates the progress of radical chemistry briefly, then discusses transition metals Ni and Cu promoted radical coupling reactions and addition reactions in detail. In the following, showing the development of interaction between metal and radical species in recent years and indicating the possibility of metal tuning the reactivity of radical, which provides a documentary basis of realizing radical/radical cross-coupling. The contents of this dissertation are divided into four parts following:1. By the radical activation process, C(sp3)-H in a-position of oxygen and N-H from N-methoxybenamide are transformed into C-centered radical and N-centered radical. The both of radicals are all very reactive, easily tend to go through homo-coupling. Ni catalyst is introduced into this system, promoting their cross-coupling selectivity. (Density functional theory) DFT calculations indicate that reactivity of N-centered radical could be weakened via metal Ni complex in the formation of N-Ni bond. On the other hand, the complex could liberate the N-centered radical, which undergoes cross-coupling with C-centered radical. This work gives a novel mode of metal stabilizing radical (N-Ni bond formation) to accomplish radical/radical cross-coupling and conducting Hemiaminal ether.2. This part of work firstly discover N-centered radical from N-methoxybenamide could be stabilized by copper and this kind of N-centered radical is detected by electron paramagnetic resonance (EPR). DFT and ESI-MS show this N-Cu complex structure, which exists in the form of diradical Cu(?) complex. Subsequently, this complex is applied in coupling with allylic C-centered radical. This reaction provides another novel strategy of realizing radical/radical cross-coupling (N-centered radical species chelating metal).3. A direct intermolecular oxidative 1,2-aminoalklation of alkene has been developed highly selectively with N-methoxybenamide, alkene and inert alkane as starting materials, copper salt as catalyst, and in the way of radical activation of C-H/N-H. The primary mechanism research indicated that N-centered radical and C-centered radical coexist in the system, N-centered radical which is a key intermediate is captured by alkene via intermolecular pathway, benzylic radical from alkyl radical addition to alkene is captured by TEMPO, and C-centered radical addition to alkene is prior to N-centered radical. This protocol provides a novel mode of 1,2-aminoalkylation of alkene via radical-radical cross-coupling, and constructs a series of aliphatic amides including quaternary carbons.4. A direct intermolecular oxidative 1,2-oxyalkylation of alkene has been accomplished via single-electron activation of alkyl C-H. This reaction provides a valuable protocol for construction of ester derivatives with bulk accessible carboxylic acids and alkane as starting materials, with alkene as link, with copper as catalyst, without extra base. Another discovery is that introduction of catalytic amount of benzamide is a very key factor for this reaction.