Studies On Palladium Catalyzed Aminocarbonylation And Reductive Coupling Reactions

The carbonylation reaction plays an important role in the synthesis of carbonyl compounds,and the transition metal-catalyzed aminocarbonylation reaction is an efficient method for amides synthesis.The palladium-catalyzed hydroaminocarbonylation reaction can directly generate amides from alkenes or alkynes with 100%atomic economy.However,due to the basicity of the amines,the catalytically active species palladium-hydride complexes are difficult to produce effectively.Moreover,the strong coordination abilities of amine would lead to palladium catalyst poisoning by forming "Werner complex".Therefore,it is of great difficult to develop an efficient strategy through the design of the substrate and the adjustment of the catalytic system to overcome the "basic barrier" in the palladium-catalyzed hydroaminocarbonylation reaction and the catalyst poisoning caused by the strong coordination ability in the development of carbonylation reactions.On this basis,we use simple amides and pyridine,quinoline,oxazoline,imine,etc.containing sp2-N with weak basicity and coordination abilities as the source of amine groups.A series of novel and efficient aminocarbonylation reactions have been developed via regulation of the catalytic system.These reactions provide efficient synthetic methods for the synthesis of amides and nitrogen-containing heterocycles with physiological activity.Based on the understanding of the mechanism of the above carbonylation reactions,and the accidental discovery that CO can be served as the reducing agent for the reductive coupling reaction,the reductive coupling reaction using H2 as the sole reductant was further developed,which overcome the problem of using stoichiometric metal reducing agents in traditional reductive coupling,and laid the foundation for the development of green reductive coupling reactions.1.Based on the acyl-metathesis reaction between acyl-palladium species and simple amide compounds,a novel and efficient palladium catalyzed hydroaminocarbonylation reaction by using simple amides as nitrogen sources has been developed.Under the optimal conditions,when 2 mol%of Pd(t-Bu3P)2 is used as a catalyst under a 30 atm of CO atmosphere,the branched amides could be obtained from aryl olefins in a yield of up to 89%and a regioselectivity of up to 98:2.When using 2 mol%of Pd(MeCN)2Cl2/XantPhos as a catalyst under a 10 atm of CO atmosphere,the linear amides could be obtained from alkenes in a yield of up to 89%and a regioselectivity of up to>99:1.The catalyst loading for gram-scale reaction could be reduced to 0.02 mol%(TON=3500),which shows the practicability of this reaction.Control experiments proved the occurrence of acyl metathesis in the catalytic cycle.On this basis,we have developed intramolecular hydrocarbonylative transacylation reaction utilizing 5 mol%of PdI2/XantPhos as a catalyst,which could obtain five to eight-membered lactam compounds.In addition,with inexpensive NMP·DCl or d7-DMF as the stoichiometric proton source,the deuterium could be incorporated into the amides.2.We have developed a catalytic protocol for the formal aromatic C=N bond insertion into the acyl-palladium could be furnished via the sequential reductive elimination and oxidative addition of the C=N bond-coordinated ?-complexes,which enabled a highly efficient palladium-catalyzed hydrocarbonylative cyclization by utilizing azaarenes as sp2 nitrogen sources.Under the optimal conditions,when 1 mol%of Pd(t-Bu3P)2 is used as a catalyst under a 30 atm of CO atmosphere,the quinolizinones could be obtained in a yield of up to 98%with 100%atom economy.For gram-scale reactions,the catalyst loading could be reduced to 0.1 mol%.The kinetic isotope effect experiment and control experiment shown that the insertion of acyl palladium species to C=N bond took place in the reaction catalytic cycle,followed by a unique long-range proton coupled electron transfer to furnish the expected product and furnish the catalytic cycle.Furthermore,this transformation leads to the formation of a family of fluorophores.These compounds can also be used as synthetic precursors for some nitrogen-containing heterocyclic compounds.3.On the basis of demonstration that the acyl-palladium species can be captured by the C=N bond species to generate highly active N-acylimine cationic species,we have successfully developed a new and efficient C=N bond difunctionalization protocol,which activates C=N bond via intercepting acyl-palladium species with C=N bond.Therefore,a novel and efficient palladium-catalyzed carbonylative cyclization reaction for the direct synthesis of quinazolinones by using inactive azaarenes or imines as nitrogen sources was developed,which provided a greener and more economical method for the synthesis of quinazolinones.Under the optimal conditions,when 5 mol%of Pd(t-Bu3P)2 is used as a catalyst under al atm of CO atmosphere,the quinazolinones could be obtained in a yield of up to 97%.The reaction could be employed in the one-step synthesis of evodiamine and its analogues with inexpensive starting materials.4.A novel and highly efficient palladium-catalyzed hydroaminocarbonylation[2+2]cyclization reaction is developed via the ?-hydrogen elimination of the acyl-palladium intermediate.Under the optimal conditions,when 5 mol%of Pd(t-Bu3P)2 is used as a catalyst and 20 mol%of TMSCl as additive under a 40 atm of CO atmosphere,the ?-lactam could be obtained in a yield of up to 94%with partial diastereoselectivity by using imines as nitrogen sources.The optimized reaction conditions proved to be effective for treatment of imines derived from arylaldehydes containing various substituents and imines derived from alkyl aldehydes with a series of the aryl-1,3-butadiene containing various substituents,styrene,cyclohexadiene,1,3-butadiene.Importantly,the atom economy could reach to 100%.5.In order to overcome the problem of using stoichiometric metal reducing agents in traditional reductive coupling,by using hydrogen as a green and economic reductant,under the optimal conditions,when allylamines were used as the substrates,with 2 mol%of PdCl2/DPPB as the catalyst under al atm of CO atmosphere,the 1,5-dienes could be obtained in a total yield of up to 94%.For gram-scale reactions,the catalyst loading could be reduced to 0.1 mol%.When allyl alcohol is used as the substrate,with 2 mol%PdCl2/DPPB as the catalyst and 20 mol%NEt3 as an additive under 1 atm of CO atmosphere,the reaction could be furnished with 1,5-dienes in a total yield of up to 93%.In addition,we have overcome the side reactions of hydrogenolysis and hydrogenation in the presence of hydrogen and palladium catalyst.High chemoselectivity has been achieved for green synthesis of 1,5-diene,and the E/Z selectivity of carbon-carbon double bond was controlled in a good manner.Kinetic experiments show that the reaction exhibits second-order dependence for palladium catalyst and zero-order dependence for the substrate,indicating that an intermediate with two palladium centers might be involved in rate-determining step.