Pd Or Cu Catalyzed Oxidative Coupling Reactions And Related Mechanism Research Towards Selectivity Control

Transition-metal catalyzed cross-coupling reaction, a reaction between anelectrophile and a nuleophile, is a powerful tool to construct C-C and C-Heteroatombonds. Due to its huge contribution to organic synthesis and wide application in manyareas, Nobel Chemistry Prize was awarded to this reaction in2010. However, it stillbears some limitations. Its reaction pathway contains both the oxidative addition andreductive elimination steps, which are contrary to each other and require distinctedconditions. The former one favors electron-rich metal center, while the latter oneprefers electron-deficient metal center. This ineluctable contradiction can be avoidedin the oxidative coupling reaction because there is no oxidative addition step in theoxidative coupling pathway, in which the low valent metal species M（n） could bereoxidized to M（n+2） by an appropriate oxidant easily. Besides, the oxidativecoupling reaction is the chemistry between two nucleophiles, which are more widelyavailable than the related electrophiles. Therefore, oxidative coupling reactions havereceived considerable attentions in recent years due to both its novelty and efficiencyfor chemical bond constructions. However, the selectivity of oxidative couplingreactions is more complicated and difficult to be well regulated.In this thesis, we mainly focus on Pd catalyzed oxidative carbonylation reactionsand Pd or Cu catalyzed C-O bond formation reactions, two challenging types ofoxidative coupling reactions. The introduction part briefly reviewed the developmentof coupling reactions and summarized the research status of the above mentioned twotypes of oxidative coupling reactions as well as corresponding classic cross-couplingreactions. The following studies concentrate on the mechanism research towardsselectivity control of oxidative coupling reactions and the development of novel Pd orCu catalyzed oxidative carbonylation reactions as well as oxidative C-O bondformation reactions. It mainly consists of the following four parts:1. The selectivity regulation of transmetallation step is a key to achieve the highreaction selectivity of oxidative coupling reaction. As a result, this studybegins with the mechanism research of transmetallation in Negishi couplingreaction. A second transmetallation step that occurs between the keyintermediate Ar¹-Pd-Ar²and the organozinc reagent Ar²-ZnX has beenobserved in Negishi coupling reactions. This critical insight provides the firstunderstanding that dehalogenated and homo-coupled by-products are formed in the Negishi reaction via oxidative coupling pathway. DFT calculations showthat a competition occurs between the second transmetallation and reductiveelimination steps, which indicates that an ortho substituent in Ar1I leads to thegeneration of by-products, while an ortho substituent in Ar²ZnCl significantlyfavors the desired cross-coupled products. It suggests a strategy to avoid thegeneration of homo-coupled and dehalogenated side products in the synthesisof biaryl compounds. This strategy has been experimentally proven to work inall the tested cases, the production of side products is almost completedinhibited.2. A novel oxidative carbonylation reaction of arylboronate esters was developed.Under a balloon pressure of CO and air gas mixture, readily availablearylboronic derivatives could be converted into their correspondingcarbonylative products using PdCl₂（PPh₃）₂as the catalyst precursor at40to50oC. It is the first example that arylboronic derivatives can be transformed intocarbonylative products using air as the sole oxidant under mild conditions. Inaddition, remarkable selectivity of oxidative carbonylation, hydroxylation andhomocoupling of arylboronic derivatives was also obtained via slightmodifications of the reaction conditions. After a preliminary mechanismexploration, a possible reaction pathway was proposed to explain theinteresting reaction selectivity.3. This study investigated a Pd-catalyzed direct and selective C3-acetoxylation ofindole derivatives. Notably, this selective acetoxylation of C-H bonds wasaccomplished without the assistance of directing groups. The kinetic studyrevealed that the reaction was zero order on the oxidant and first order onindole derivatives, which indicated that the rate determined step of thisreaction was the C-H activation process and the following oxidation of Pd（II）complex and reductive elimination of Pd（IV） species were fast steps. As aresult, the1,2migration of C3-Pd（II） intermediate leading to the generation ofC2isomer was completely avoided.4. A copper-catalyzed “oxygenase-type” oxidation of arenes and heteroarenes atroom temperature under balloon pressure of air was realized. This reactioninvolves oxygen-atom transfer from O2in the air onto the substrate. A reactionmechanism that includes a C-H activation process and sequentially facileoxidation of ArCu（I） species, has been corroborated through a series of deuteration, stoichiometric and kinetics experiments. Moreover, CuOtBu isbelieved to be the active copper species and could be generated in situ fromcatalyst precursor CuCl2and NaOtBu by a SET process. Nevertheless, thefollowing catalytic cycle follows a typical organometallic mechanism.Therefore, this copper-catalyzed aerobic oxidation reaction is believed toincorporate a novel combination of SET initiation and organometallic catalyticcycle.