Faculty of Science School of Chemistry 0100505x jzeevaart@csir.co.za / The application of homogenous transition metal catalysis to the arylation of enolates to develop new synthetic procedures which are more environmentally benign, atomefficient and economically viable than current methods was the motivation behind the current work. The specific choice of molecules with an aromatic group in the a- position of a ketone, carboxylic acid, amide or other electron-withdrawing group arose from the fact that many natural products, pharmaceutical actives and synthetic intermediates contain such a substructure while the syntheses of these substructures are often cumbersome. The application of homogenous catalysis to various types of enolates was explored and in the process several developments were achieved and discoveries made. These included the use of inorganic bases under phase transfer conditions for the Heck reaction of acrylic acid as well as the synthesis and application of phosphine and phosphite ligands in the Heck reaction of acrylic acid esters. The successful use of low palladium loadings (as low as 0.01mol%) in the arylation of diethyl malonate using aryl chlorides and the application to the synthesis of ketoprofen and phenobarbital was demonstrated. The novel application of palladium catalysis to the arylation of methanesulfonamides and the first example of a bromoindole derivative as the aryl halide partner in an enolate arylation reaction was demonstrated. Ligand-free palladium catalysed phenylation of pinacolone followed by Baeyer Villiger oxidation led to a proposed novel synthetic route to tert-butyl esters of 2-arylacetic acids. The palladium and copper catalysed arylation of acetoacetate esters, with in situ decarbonylation, provided a different route to 2-arylacetic acid esters which are useful in the preparation of non-steroidal anti-inflammatory compounds.

Formation of the diaryl ether moiety remains a challenging target for organic synthesis despite modern technologies, however, better understanding of older techniques often leads to improvements. The copper-catalysed Ullmann ether synthesis, whilst attractive in many ways, is frequently problematic due to the inherent irreproducibility of the reaction on scale up. Little is yet known about the mechanism of the reaction and conflicting views are rife within the scientific community. In a well-studied example, we show that the potassium iodide formed during the reaction slows catalysis. Additionally, the deprotonation of phenol is complicated by the insolubility of the inorganic base. This results in a beneficial outcome, providing a rate enhancement and reduction of by-products, which can be further exploited to provide lower stoichiometries, improved selectivity and greater functional group tolerance. The development of an improved, more reproducible procedure in combination with reaction calorimetry has allowed the mechanism to be studied in intricate detail. Excellent agreement with a mechanistic model has led to further insight into the enigmatic aryl halide activation and provides good evidence for a single electron transfer mechanism. In addition, evidence for a dynamic catalyst resting state has been observed which adds to the complexity of the mechanism. This, in turn, leads to a fine balance of concentration and electronic effects that prove vital to the rate of reaction.

Durant ma thèse, j'ai recherché les conditions pour l'activation / fonctionnalisation de liaisons C-H pour la construction de bi(hétéro)aryles tolérant des groupement fonctionnels réactifs tels que des silyles, des alcènes, des esters ou encore des amides. Par rapport aux protocoles de couplage classiques tels que les réactions de Suzuki, Stille ou Negishi, la fonctionalisation de liaisons C-H fournit des procédures moins coûteuses et plus écologiques si elle tolère des groupements utiles en synthèse. D'abord, nous avons observé que les thiophènes substitués par des silyles en C2 peuvent être arylés avec des bromures d'aryle sans désilylation en présence du précatalyseur Pd(OAc)2/dppb. Les produits de couplage sont obtenus avec de bons rendements et avec inhibition de la réaction de désilylation. Ensuite, nous avons démontré que le système Pd(OAc)2/KOAc sans ligand phosphine, favorise l'arylation directe des hétéroaromatiques et inhibe la réaction de type Heck avec des thiophenes substitués par des alcènes substituées sur les carbones 2 ou 3. Ensuite, nous avons démontré que les fonctions esters sur les hétéroaromatiques peuvent être avantageusement utilisées comme groupements protecteurs, permettant l'arylation directe d'hétéroaromatiques sur le carbone C5. Enfin, l'heteroarylation directe de 2- ou 4-bromobenzamides avec des hétéroarènes catalysée au palladium a été étudiée. En présence de KOAc comme base, aucune formation de liaisons C-C ou C-N par couplage de deux bromobenzamides n'a été observée. / During my thesis, I focused on condition for the activation / functionalisation of C-H bonds for the construction of biaryl derivatives tolerant to the reactive functional groups such as silyl, alkenes, esters or amides. Compared to classic cross-coupling protocols (Suzuki, Stille or Negishi), C-H bond functionalisation provides a costly effective and environmentally attractive procedures. At first, we observed that the silyl-substituted thiophenes can be directly arylated with aryl bromides without desilylation, using the simple Pd(OAc)2/dppb precatalyst for both conversion and desilylation inhibition. Then, we have demonstrated that the Pd(OAc)2/KOAc catalyst system without phosphine ligand, even using as few as 0.1 mol% of Pd catalyst, promotes the direct arylation of heteroaromatics and inhibits the Heck type reaction with 1,2-disubstituted alkenes. In addition, we demonstrated that easily accessible esters on heteroaromatics can be advantageously employed as blocking groups in the course of the direct arylation of several heteroaromatic derivatives. Finally, the palladium-catalyzed direct heteroarylation of 2- or 4-bromobenzamide with heteroarenes was studied. In the presence of KOAc as the base, no formation of C-N or C-C bonds by coupling of two bromobenzamide was observed.

Durant ma thèse, j’ai recherché des conditions pour l'activation / fonctionnalisation de liaisons C-H pour l’arylation d’hétérocycles viables pour l’industrie. Par rapport aux protocoles de couplage classiques tels que les réactions de Suzuki, Stille ou Negishi, la fonctionalisation de liaisons C-H fournit des procédures moins coûteuses et plus écologiques si elle tolère des groupements utiles en synthèse et si elle utilise des solvants peu ou non toxiques. Nous avons observé que le thiophène peut être arylé en C2 avec de nombreux bromures d'aryle en présence de seulement 0.2 mol% de Pd(OAc)2. Ensuite, nous avons démontré que des solvants de type alcool tels que le pentan-1-ol permet le couplage de thiazoles ou d’imidazoles avec des bromures d’aryle. Ce type de solvant est certainement plus viable pour l’industrie que les solvants usuellement utilisés pour ces couplages tels que le DMF ou le DMAc. Nous avons ensuite montré que certains de ces couplages peuvent même être effectués sans aucun solvant. Finalement, nous avons démontré que de nombreuses fonctions sur des bromopyridines sont tolérées lors de ces couplages, permettant l’accès à des pyridines arylées fonctionnelles utiles pour l’industrie pharmaceutique en une étape. / During my PhD, I searched for industrially viable conditions for activation / functionalization of CH bonds for the arylation of heterocycles. Compared to conventional coupling protocols such as Suzuki, Stille or Negishi reactions, the functionalization of CH bonds provides less costly and more environmentally friendly procedures if it tolerates synthetically useful functional groups and if it uses solvents with little or no toxicity. We observed that thiophene can be arylated at C2 with a wide scope of aryl bromides in the presence of only 0.2 mol% of Pd(OAc)2. Then, we demonstrated that alcoholic solvents such as pentan-1-ol allow the coupling of thiazoles or imidazoles with aryl bromides. This type of solvent is certainly more viable for the industry as the solvents commonly used for these couplings such as DMF or DMAc. We then showed that some of these couplings can even be performed without any solvent. Finally, we have shown that many functions on bromopyridines are tolerated in these couplings, enabling access to arylated functionalized pyridines useful for the pharmaceutical industry in one step.