Palladium-catalyzed Multicomponent Reactions By Trapping Of Active Intermediates

Metal-stabilized carbenes generated from metal-catalyzed transformation of precursors, diazo compounds mostly, have more controllable reactivity compared to free carbenes, and are now solidly established as reactive intermediates in organic chemistry. These highly reactive carbene species are capable of a breadth of new, unusual, and surprising reactions, and some of these have become standard methods in organic synthesis. Cycloadditions and insertions, typical types of carbene-mediated reactions, have achieved excellent control in regio-and stereoselectivity with the development of chiral catalysts. The reactive carbenes have also inspired wide range of reactions far beyond classical cycloaddition and insertion reactions. The rather wide scope of carbene-mediated reactions results from high reactivity of their own, as well as the fact that many of the initial products/intermediates are often highly reactive, and thus, they are capable of undergoing a broad range of elaborate cascade reactions. Carbene chemistry is among the hottest areas in organic chemistry.Metal carbene-based multicomponent reactions (MCRs) combine the high reactivity of metal carbenes and high efficiency of MCRs, and thus are very suitable for the synthesis of complicated and functional group-enriched molecules. Divalent carbon chemistry of carbene allows the polarity reversal of carbene carbon; that is, the electrophilic carbene carbon would turn to a nucleophile when accepts a nucleophilic attack and can further undergo reactions with electrophiles. Diverse reactivities of carbene are the base of new reaction discovery, but also challenge the reaction controls. Given to the complexity of these MCRs, chemo-, regio-, and stereoselectivity will be the first thing to consider.The electrophilic carbene carbon center can accept the nucleophilic attack from alcohols, amines, or electron-rich nitrogen-containing aromatic heterocycles (indoles etc.) to generate protic onium ylides or zwitterionic intermediates, which can be trapped by a number of electrophiles to establish MCRs. These new MCRs provide efficient synthetic approaches for the rapid synthesis of polyfunctional complicated molecules and solid experimental evidence for the existence of the protic onium ylides and zwitterionic intermediates. Attracted by this fascinating and productive research area. we further developed this kind of MCRs.This dissertation discovered and developed palladium-catalyzed MCRs based on the trapping of active oxonium/ammonium ylides and zwitterionic intermediates. [PdCl(η3-C3H5)]2 was found efficient in catalyzing this kind of reactions. We reported the first highly enantioselective palladium carbene transfer reaction in three-component reaction of diazoesters, pyrroles, and imines. In the palladium-catalyzed three-component reaction of diazoesters, enamines, and imines, we described a new mode of chemical bond formation; that is, chemical bond cleavage, fragment modification and specific reassembly of the modified fragment. This strategy was extended in a palladium-catalyzed reaction of diazoesters and chromene acetals/hemiaminal ethers. The palladium complex also show high efficiency in the reaction between N-aryl diazoamides and N-acyl pyridinium salts.In chapter 2, we discovered an effective catalytic system, palladium(II) with chiral Br(?)nsted acids (chiral BINOL derived phosphoric acids), to catalyze an enantioselective three-component reaction of unprotected pyrroles, diazoesters, and imines. In this reaction, asymmetric C-H functionalization of unprotected pyrroles is realized, through palladium carbenoid activation, to produce pyrrole derivatives bearing two stereogenic centers. The reaction was stereodivergent and selectively produced all four possible stereoisomers of chiral pyrrole derivatives in moderate yield with high control of diastereo-and enantioselectivity by simply altering the substituents of the chiral phosphoric acids.A palladium/phosphate complex was detected by high-resolution mass spectrometry (HRMS) analysis, thus indicating that ligand exchange occurred during the reaction. When the premade palladium phosphate complex was employed to the reaction, comparable yield with essentially the same selectivity was obtained. The in situ generated palladium phosphate complex was supposed as the real catalytic species, which is different from the cocatalytic mode with dirhodium/chiral phosphoric acid. The palladium/chiral PPA catalytic system was first used in the zwitterionic intermediate trapping process. This is also the first highly enantioselective reaction in palladium carbene transfer process.In chapter 3, we described a multi-component process that involves chemical bond cleavage, fragment modification, and specific reassembly of the modified fragment to afford functional group enriched molecules. In the palladium-catalyzed three-component reaction of diazoesters, enamines, and imines, we have not realized the initially designed zwitterionic intermediates trapping process with imines, but discovered a novel process that involves cleavage of a C-N bond, modification of the resulting amino fragment by forming an ammonium ylide, and then regio-and stereoselective reassembly of the modified fragment back to another iminium fragment to produce a chiral a-amino-δ-oxo pentanoic acid derivative.Mechanistic study reveals that a keto-iminium fragment is the key intermediate and a chiral palladium/phosphate complex is the real catalyst. Also, the proposed process was supported by a series of reactions as well as density functional theory (DFT) calculations. This unique mode of bond formation provides an atom-efficient and step-economic way to build functional group-enriched molecules that existing methods cannot easily accomplish, and could inspire more discoveries in the efficient construction of unique molecules.In chapter 4. the strategy of bond cleavage, fragment modification and reassembly is also extended to a palladium-catalyzed reaction of diazoesters with chromene acetals/hemiaminal ethers. Under the activation of Brensted acid, Chromene acetals or chromene hemiaminal ethers would decompose to form reactive 1-benzopyrylium intermediates with the leaving of alcohols or amines. In the meantime, the palladium catalyzed decomposition of diazo compounds generates palladium carbenes by extrusion of dinitrogen. The carbenes can modify the released alcohols or amines to afford protic onium ylides, which underwent nucleophilic addition to another fragment 1-benzopyrylium ion to provide 2-substituted 2H-chromene derivatives. High enantioselectivity was not achieved although careful optimizations were carried out. As a result, the reaction provided 2-substituted 2H-chromene derivatives with good to excellent yields and diastereoselectivities. This innovative multi-component process represents a highly efficient way to build structurally diversified and functional group-enriched 2H-chromene derivatives in an atom and step economic fashion.In chapter 5, the palladium complex [PdCl(η3-C3H5)]2 was employed to modify the N-acyl pyridinium salts with N-aryl diazoamides.N-aryl diazoamides can be transformed to active zwitterionic intermediates under the catalysis of palladium complex, and then the resulting active intermediates can ungergo nucleophilic addition to C4 position of the the pre-formed N-acyl pyridinium salts. Initially, the products bearing 3,3-disubstituted oxindole and 1,4-dihydropyridine motifs were obtained in high yields but with low diastereoselectivities. However the dr value was promoted to be excellent when using a pyridine with a diethyl amide functionality [C(O)NEt2] at C3 position. This palladium-catalyzed reaction of N-aryl diazoamides and N-acyl pyridinium salts gave an efficient approach to construct structurally novel nitrogen-containing heterocycles, which were thought to be of high importance for medicinal chemistry and new drug discovery.