Nickel/Copper-Catalyzed Coupling Reactions Involving Alkyl Radicals

Synthetic organic methodology is the research frontier of organic chemistry,among which transition metal catalyzed coupling reactions represent an enormous progress.From cross couplings between electrophiles and nucleophiles to oxidative couplings between two nucleophiles,various kinds of aryl halides or arenes could smoothly couple with different nucleophiles under transition metal catalysis to construct a series of complex organic molecules via carbon-carbon and carbon-heteroatom bond formation.While,with the flourish of radical chemistry in recent years,the activation of alkyl halides or simple alkanes which previously has been considered to be challenging becomes much more workable.Actually,the combination of radical chemistry and activation of alkyl halides or alkanes greatly enhanced the development of synthetic organic methodology,and also inspired the extensive research of transition metal catalyzed coupling reactions involving alkyl radicals.This thesis initially summarized the development of transition metal catalyzed coupling reactions,especially the coupling reactions involving alkyl radicals.Then the thesis described radical-type cross couling/cyclization of bromo amides with alkenes,radical-type intramolecular aromatic C-H alkylation of bromo amides,oxidative arylation and alkenylation of simple Csp3-H compounds based on nickel and copper catalysis via rational design.The main research findings are listed as follows:1.Nickel catalyzed cross coupling/cyclization of tertiary a-bromo alkyl amides with styrene derivatives was developed.With Ni(PPh3)4/dppp as the catalytic system and K3PO4 as the base,a series of styrene derivatives could efficiently cross couple with bromo amides to genenrate multisubstituted iminolactones in excellent yields and selectivity.Then detailed reaction mechanism was investigated through EPR analysis,radical clock,DFT calculations,kinetic isotopic effect experiments,which favored the radical addition to carbonyl oxygen to give the final cyclization product.2.Nickel catalyzed intramolecular aromatic C-H alkylation of secondary and tertiary a-bromo alkyl amides was achieved.Ni(PPh3)4/dppp was utilized as the catalytic system and K3PO4 was used as the base.Different substituted indolones could be efficiently constructed starting from various substituted secondary and tertiary a-bromo alkyl amides.Radical trapping experiment proved that the activation of bromo amide by nickel catalyst was probably a radical process.3.The first nickel catalyzed oxidative coupling between arylboronic acids and simple ethers was developed.With Ni(acac)2/PPh3 as the catalytic system and DTBP as the oxidant,differend kinds of arylboronic acids could cross couple efficiently with simple ethers such as tetrahydrofuran and 1,4-dioxane to afford a series of 2-aryl ether products in good yields.Meanwhile,nitrogen-containing substrates such as N,N-dimethyl aniline,N,N-dimcthyl acetamide,N-methyl pyrrole could also be arylated.4.Nickel catalyzed oxidative coupling of arylboronic acids?arylboronic acid glycol esters with cyclohexane was achieved.With Ni(acac)2/PPh3 as the catalytic system and DTBP as the oxidant,the reaction could tolerate different kinds of arylboronic acids and arylboronic acid glycol esters.Then DFT calculations,radical trapping experiments and kinetic isotopic effect experiments were carried out,which favored a nickel-assisted radical/radical cross coupling mechanism.5.Nickel catalyzed oxidative coupling between arylboronic acids and styrene derivatives was developed.Ni(acac)2/PPh3 was employed as the catalytic system and TEMPO was utilized as the oxidant.A bunch of substituted traps-1,2-stilbenes could be selectively synthesized from diverse arylboronic acids and styrenes.At last,a plausible radical reaction mechanism was proposed according to the experimental results.6.The first copper catalyzed oxidative coupling of simple ethers with alkenes was achieved.With Cul as the catalyst precursor,KI as the efficient additive and DTBP as the oxidant,a series of simple ethers such as tetrahydrofuran,1,4-dioxane,diethyl ether could cross couple smoothly with substituted 1,1-diaryl ethene,constructing different allylic ether derivatives with good yields.Radical trapping experiment proved the probable radical process of this reaction.