Development of Nickel- and Palladium-Mediated Decarbonylative Coupling of Carboxylic Acid Derivatives: From Organometallic Reactivity to Catalysis
Creators: name: Brigham, Conor
Publisher: name: My University
Year: 2022
Subjects: subject: Nickel and palladium decarbonylative cross coupling
subject: Chemistry
subject: Science

description: Transition metal catalyzed cross coupling reactions are among the most widely used transformations in organic chemistry. While there has been tremendous work regarding aryl halide cross coupling, there has been growing interest in using carboxylic acid derived electrophiles in catalysis. Carboxylic acids can be derivatized into highly tunable, modular electrophiles. A weak C(acyl)-X bond (X = OR, Cl, F, SR, NR2) allows for addition into nucleophilic low valent transition metals. Our interest is utilizing these carboxylic acid derivatives in a decarbonylative manner, that is where carbonyl deinsertion on the metal removes CO. This can then introduce aryl or alkyl organic groups in an analogous fashion to aryl halides. A persisting challenge decarbonylative cross coupling is balancing selectivity for acyl-retaining products. Ultimately, gaining better insights into reaction mechanisms may help with further development of these types of transformations. Chapter 1 describes the current state of decarbonylative cross coupling chemistry. Here we will go through recent history of relevant palladium and nickel catalyzed decarbonylation methodologies of carboxylic acid derivatives. Key features of these reactions include the choice of metal, choice of phosphine ligand/ligand-type (i.e. mono- vs. bi-dentate ligands), temperature, coupling partner and necessary additives. Chapter 2 begins with our work on decarbonylation of aryl carboxylic acid derivatives. Initial experiments demonstrate the feasibility of oxidative addition and decarbonylation for acid fluoride electrophiles. While C-F reductive elimination is not observed, we found that Ni-F intermediates could undergo base-free transmetallation with boronic acids. This leads to the discovery of two cross-coupling methodologies, a Suzuki-Miyaura C-C coupling and aryl amination C-N coupling. ((Diphenyl)methyl)phosphine (PPh2Me) demonstrated high selectivity of the decarbonylated product due to rapid carbonyl deinsertion under the Suzuki-Miyaura conditions. Blocking background amidation was main challenge for C-N coupling, which was solved by utilizing alternative aryl acid derivatives, aryl phenyl esters, with silyl-protected amines. Chapter 3 describes out detailed studies of the decarbonylation of fluoroalkyl thioesters to their corresponding fluoroalkyl thioether. Development of a nickel catalyst was optimized with difluoromethyl thioesters, and the scope was broad for aryl and alkyl thiols. Importantly, we demonstrate that we can successfully decarbonylate several fluoroalkyl acid thioesters. This was our first demonstration of decarbonylative coupling of several fluoroalkyl substituents. Chapter 4 follows our work on intramolueclar fluoroalkylation as we persue a general intermolecular coupling. With the information learned in Chapters 2 and 3, we applied our understandings of decarbonylative cross coupling to highly electrophilic fluoroalkul acid derivatives. This chapter will describe several possible acid-derivatives, and discuss the pros and cons to each. Ultimately, this has so far led to two decarbonylative couplings (RF = CF2H and CF2Ph).