Highly Efficient Suzuki Cross-Coupling Of Aryl Chlorides

Suzuki cross-coupling reaction is a more popular tool over the other transition-metal-catalyzed cross-coupling reactions for constructing biaryls because of the advantages of arylboronic acids such as nontoxicity, air/moisture stability, tolerance of a variety of functional groups. Since its discovery, innumerable improvements on the original protocol have been reported with respect to catalyst/ligand systems as well as scope of electrophiles, which have led to its explosive application in synthesis of fine chemicals. Comparably, arylboronic acids and their derivatives have still overwhelmingly dominated the nucleophiles in Suzuki coupling. In fact, few advances have been made on utility of high-order arylborons, diarylborinic acids and tetraarylborates, in Suzuki coupling although they have higher atom economy and could be more economically prepared. This thesis deals with highly efficient Suzuki cross-coupling of cost-effective aryl chlorides with high-order arylborons of diarylborinic acids and tetraarylborates, mainly including three parts: cross-oupling of high-order arylborons with aryl clorides catalyzed by a phosphite/N-heterocyclic carbene co-supported palladium catalyst system, triarylphosphine/nickel catalyzed cross-coupling of high-order arylborons with aryl chlorides and design and synthesis of sterically unsymmetric N-heterocyclic carbene supported palladium complexes and their catalysis performance in Suzuki coupling of aryl chlorides.In the first part, a process was developed at first for synthesis of diarylborinic acids by one-pot procedure from arylhalides, boronates and magnesium under non-cryogenic conditions. Purification of diarylborinic acids was effected by treatment of the crude products with2-aminoethanol affording crystalline solid materials of2-aminoethoxy diarylborates. A highly efficient palladium catalyst system co-supported by a strong σ-donor N-heterocyclic carbene (NHC), N,N’-bis(2,6-diisopropylphenyl)imidazol-2-ylidene and a strong π-acceptor phosphite, triphenylphosphite, has been developed for cross-coupling of diarylborinic acids with aryl chlorides and bromides in tBuOH in the presence of K3PO43H2O. Unsymmetrical biaryls with a variety of functional groups could be obtained in good to excellent yields (98%) using as low as0.01mol%and0.5-1mol%palladium loading for aryl bromides, activated and deactivated aryl chlorides, respectively, under mild conditions. A ligand synergy between a-donor NHC and n-acceptor phosphite in the Pd/NHC/P(OPh)3catalytic system has been proposed to be responsible for the high efficacy to arylchlorides in the cross-coupling. A scalable (0.2mol) and economical process has therefore been developed for synthesis of Sartan biphenyl from the Pd/NHC/P(OPh)3catalyzed cross-coupling of di(4-methylphenyl)borinic acid with2-chlorobenzonitrile. The cross-coupling of aryl chlorides with tetraarylborates was also explored by using coupling of Ph4BNa with4-AeC6H4Cl catalyzed by Pd/IPr/P(OPh)3as model reaction. It was found that the presence of10mol%MgCl2·bH2O could promote the coupling. Under the optimized condition,4-acetylbiphenyl could be obtained in45%and79%yields, respectively, using equivalent and excess of4-ACC6H4Cl. Further work along this line is still in progess in our laboratory.In the second part, A highly efficient triarylphosphine/nickel catalyst system, Ni[P(4-MeOPh)3]2Cl2/2P(4-MeOPh)3, has been developed for cross-coupling of diarylborinic acids with a wide range of aryl chlorides. A variety of unsymmetrical biaryl and heterobiaryl compounds with various functional groups and steric hindrance could be obtained in good to excellent yields (98%) by using0.5-2mol%catalyst loadings in the presence of K3PO4·3H2O in toluene. The high atom economy of diarylborinic acids and cost-effectiveness of the phosphine/nickel catalyst system make the cross-coupling truly practical in production of biaryl fine chemicals. Usefulness of the phosphine/nickel catalyzed cross-coupling of diarylborinic acids with aryl chlorides has been demonstrated in development of a scalable and economical process for synthesis of4’-methyl-2-cyanobiphenyl (95-97%), Sartan biphenyl, in which the catalyst cost is about only10%of the corresponding palladium system. Suzuki coupling of aryl chlorides with tetraarylborates was also preliminary explored by using Ni(PPh3)2Cl2/2PPh3catalyzed coupling of Ph4BNa with4-AcC6H4Cl as model reaction. Under the optimized condition,4-acetylbiphenyl could be obtained in55%and77%yields, respectively, using equivalent and excess of4-AcC6H4Cl, promising a potential for development of efficient Suzuki coupling of aryl chlorides with tetraarylborates.In the third part, a series of sterically unsymmetric N-heterocyclic carbene supported palladium complexes were designed, synthesized and structurally characterized by X-Ray. Their catalysis performance in Suzuki coupling of aryl chlorides with aryl borinic acids was also preminarily invsitigated. At first, three sorts of sterically unsymmetric NHC precursors were synthesized, including imidazolium,1,2,4-triazolium and benzimidazolium salts. Eight palladium complexes were obtained by transmetallation between the palladium source and the corresponding NHC silver complexes generated by reaction of the NHC precursors with silver oxide. X-Ray crystal structures of six representative complexes were determined. A large difference between activated and unactivated aryl chlorides in the Suzuki coupling catalyzed by these sterically unsymmetric N-heterocyclic carbene supported palladium complexes was observed. High catalytic activity in Suzuki coupling of PhB(OH)2with activated arylchlorides was obtained by using palladium supported by N-methyl-N-(2.6-diisopropylphenyl) benzimidazole-2-ylidene as catalyst either generated in situ or isolated previously. With the optimal conditions. Suzuki coupling of2-nitrophenyl chloride with phenylboronic acid or 4-chlorophenyl boronic acid to afford the corresponding biphenyls in93%and76-82%yields, respectively. The later is a key intermediate of new fungicide Boscalid, which is hardly accessible by traditional cross-coupling reactions because of the sensitivity of nitro group and chloride. An efficient and green process for synthesis of Boscalid is under developed using this selective catalyst system.During synthesis of1,2,4-triazoles from1,3,4-oxadiazoles, it was found that more than a green alternative to traditional volatile molecular organic solvents, protic ionic liquids as dual solvent-catalysts could significantly promote reaction of organoamines with oxadiazoles to afford sterically hindered1,2,4-triazoles. Among the tested protic ionic liquids, pyridinium trifluoroacetate and acetate showed the highest efficiency for the reactions of arylamines and alkylamines, respectively, indicating that tunable catalysis could be readily effected with protic ionic liquid solvent-catalysts by simply tuning their cation and anion counterparts. A general and efficient approach has been developed for synthesis of multiply substituted1,2,4-triazoles based on the tunable protic ionic liquid solvent-catalyst systems.