Academic literature on the topic 'Catalytic C-H'

Harnessing site selectivity in C-H functionalisation remains one of the greatest challenges in modern catalysis. In order to differentiate electronically and sterically similar C-H bonds, a variety of pioneering methods have been developed in recent years. One of the key developments is the use of Lewis basic directing groups to selectively direct a metal centre. The results herein report the manipulation of directing group chemistry to allow selective ortho, meta and para C-H functionalisation of arenes. Chapter 1 reports the developments in moving beyond ortho-selectivity in transition metal catalysed C-H functionalisation chemistry. Chapter 2 reports the use of the biologically relevant oxazolidinone and hydantoin heterocycles as weakly coordinating directing groups in ruthenium catalysed ortho-C-H alkenylation methodology. Chapter 3 reports the application of ruthenium catalysed σ-activation to the remote C-H functionalisation of indoles at the C6 position and carbazoles at the C4 position. Chapter 4 reports the manipulation of site selective cyclometalation and its application in the para-C-H alkylation of aniline derivatives.

The work described herein involves the exploration of sequential reaction processes involving catalytic C-H functionalisations and Pd-catalysed cross-couplings in both batch and continuous-flow operation, in an effort to improve overall reaction efficiencies.

This thesis details the current methods for meta-selective C-H functionalisation and contains three chapters relating to the area of ruthenium catalysed meta selective functionalisation by σ-activation. The first of which contains a published manuscript entitled “Catalytic meta-selective C-H functionalization to construct quaternary carbon centres” and describes a meta selective tertiary alkylation procedure on 2-phenylpyridine substrates. Key findings from this work provide good evidence for a radical based mechanism and proposes a catalytic cycle involving two distinct roles for the ruthenium catalyst; both in the activation of the substrate molecule and in the formation of a tertiary radical coupling partner. The second chapter contains another published manuscript entitled “Mechanistic insight into ruthenium catalysed meta-sulfonation of 2-phenylpyridine” and provides mechanistic analysis for the meta selective sulfonation of 2-phenylpyridine. Key findings from this work show through stoichiometric experiments that sulfonation occurs at the position para to the C-Ru bond formed following cyclometalation with a radical addition being implied. The work also shows that the catalytic species involved do not require an arene ligand and deuterium labelling studies identified a likely rate limiting radical sulfonation step. The final chapter contains additional work relating to the use of α-halo carbonyl coupling reagents to enable meta selective primary, secondary and tertiary alkylations. The use of a triphenylphosphine ligand source was necessary for the coupling of primary α-halo carbonyl coupling partners at the meta position. Crucially, this transformation was not possible with simple, straight-chain alkyl halides, highlighting the privileged reactivity of α-halo carbonyl coupling reagents. This work also contains experimental and computational mechanistic analysis which reveals additional support for a dual activation pathway.

El objetivo principal de esta tesis doctoral ha sido la activación de enlaces inertes C-H de forma catalítica para la construcción de enlaces C-O. El primer proyecto desarrollado ha consistido en la funcionalización de enlaces C(sp3)-H para la síntesis directa de phthalides catalizado por Pd, utilizando simples ácidos benzoicos como materiales de partida. Continuando con la misma línea de investigación, el segundo proyecto realizado se ha basado en la utilización de catalizadores simples y de bajo coste de Cu para la funcionalización de enlaces C(sp2)-H/formación de enlaces C-O para la síntesis de benzolactonas. Finalmente, se ha desarrollado una metodología libre de metales para la síntesis de benzolactonas generando reactivos hipervalentes de I(III) de forma catalítica.<br>The main objective of this Thesis has been the activation of inert C-H bonds catalytically for the construction of C-O bonds. The fist project developed consisted on the activation of C(sp3)-H bonds for the direct synthesis of phthalides catalyzed by Pd, employing simple benzoic acids as starting materials. Continuing in the same research line, the second project described deals with the utilization of cheaper and easy to handle Cu salts as catalyst for the functionalization of C(sp2)-H bonds towards the formation of C-O bonds for the synthesis of benzolactones. Finally, the last project discovered handles a metal-free C-H functionalization approach for the synthesis of benzolactones by using simple iodoarenes as catalyst, thus

Dans la thèse de doctorat, nous avons développé une approche efficace pour la modification rapide d'oxydes d'arylphosphines via la fonctionnalisation de liaisons C-H en position ortho du groupement P=O catalysée par le ruthénium (II) en présence des alcènes. Intéressement, l'ajustement du pH du milieu réactionnel permet de contrôler la sélectivité de la réaction à savoir alkylation or oléfination. La réduction des oxydes de phosphines fonctionnalisées permet la formation d'arylphosphines portant un carboxylate flexible. Dans le second objectif, un couplage C(sp3)–H /N-H oxydatif catalysé par le cuivre a permis l'alkylation d'hétérocycles à partir de (cyclo alcanes abordables. Ce protocole implique la formation de liaisons C (sp3)–N via une voie radicalaire générée par un clivage homolytique du peroxyde de di-tert-butyle et le piégeage du ou des radicaux par des catalyseurs au cuivre. Dans une troisième partie, nous avons utilisé ces processus radicalaires pour la fonctionnalisation le liassions C(sp3)–H benzylique d'oxyde de 2-alkylpyridines. Ces transformations impliquent un processus en cascade : estérification oxydative catalysée par le cuivre suivie d'un transfert d'atome d'oxygène. Enfin, des dérivés tosylés de pyridin-2-ylméthyl ont été obtenus avec des rendements élevés à partir des oxide de 2-alkylpyridines grâce à un réarrangement sigmatropic [3,3] du produit d'addition entre les oxides de 2-alkylpridine avec des chlorures de chlorure de benzènesulfonyles. De plus, les alkylnitrones subissent également ce réarrangement sigmatropique [3,3] pour donner des cétones α-tosylées après hydrolyse<br>In the first chapter, we have developed an efficient approach for the fast modification of arylphosphine oxides using ruthenium(II)-catalyzed C–H bond functionalization with alkenes. Interestingly, we have found that the selectivity of the reaction, namely alkylation versus alkenylation, is depending on the reaction pH. The reduction of the phosphine oxide allows the formation of aryl phosphines bearing a flexible pendent carboxylate. In the second objective, a copper-catalyzed oxidative C(sp3)–H/N–H coupling of NH-heterocycles with affordable (cyclo)alkanes was developed. This protocol involved C(sp3)–N bond formation via a radical pathway generated by a homolytic cleavage of di-tert-butyl peroxide and trapping of the radical(s) by copper catalyst.In a third part, benzylic C(sp3)–H acyloxylation of 2-alkylpyridine, 2-alkylpyrazine and 2-alkylthiazole compounds was achieved using simple aldehydes via a copper-catalyzed tandem reaction, involving oxidative esterification followed by O-atom transfer. Finally, pyridin-2-ylmethyl tosylate derivatives are obtained in high yields from 2-alkylpyridine N-oxides via a [3,3]-sigmatropic rearrangement of the adduct between 2-alkylpridine N-oxides with benzenesolfonyl chlorides. Moreover, alkylnitrones also underwant [3,3]-sigmatropic rearrangement to give α-tosylated ketones after hydrolysis

The continuous drive for efficient bond forming reactions has led to the emergence of C-H activation methodologies. More specifically, direct arylation reactions are commonly employed in the synthesis of a range of heteroaromatic products. The latter make up a considerable proportion of medicinally important compounds and therefore their rapid and efficient synthesis is paramount. The preparation of carbazoles has been extensively developed within the Bedford group. The expansion of this palladium-catalysed intramolecular direct arylation methodology has been explored with the aim of producing interesting heterocycles, namely acridans and acridines. Interestingly, instead of the expected C-H activation reaction, an unprecedented catalytic dearomatisation reaction took place. This was developed into a more general methodology to produce a range of novel heterocycles, including 4a-alkyl-4aH- carbazoles and dihydroindolo[2,3-b]indoles. Due to their instability these heterocycles undergo a range of interesting transformations, including dimerisation, dealkylation and hydro lysis reactions. Furthermore, it was proposed that typical direct arylation reactions could be occurring via a catalytic dearomatisation mechanism rather than one of the more generally accepted C-H activation mechanisms. A detailed kinetic study has been carried out. Although evidence to support a dearomatisation mechanism could not be obtained, the turnover-limiting step for two substrates could be proposed and a number of interesting observations made.

I) Synthesis of Spiroindenes by Enolate-Directed Ruthenium-Catalyzed Oxidative Annulation of Alkynes with 2-Aryl-1,3-dicarbonyl Compounds The synthesis of carbocycles by the ruthenium-catalyzed oxidative annulation of alkynes with 2-aryl cyclic 1,3-dicarbonyl substrates is described. Proceeding by the functionalization of C(sp3)–H and C(sp2)–H bonds, and the formation of all-carbon quaternary centers, the reactions provide a diverse range of spiroindenes in good yields and high levels of regioselectivity. II) Synthesis of Benzopyrans by Pd(II)- or Ru(II)-Catalyzed C–H Alkenylation of 2-Aryl-3-hydroxy-2-cyclohexenones We have explored the 2-aryl-3-hydroxy-2-cyclohexenones as competent substrates for palladium- and ruthenium-catalyzed C–H alkenylation reactions with terminal alkenes. This process affords benzopyrans, in most cases, with good functional group tolerance. III) Synthesis of Spiroindanes by Palladium-Catalyzed Oxidative Annulations of 1,3-Dienes Involving C–H Functionalization 1,3-Dienes have been an underexplored class of substrates in catalytic oxidative annulation reactions involving C‒H functionalization. The synthesis of spiroindanes by the palladium-catalyzed oxidative annulation of 1,3-dienes with 2-aryl cyclic 1,3-dicarbonyl compounds is described. Several examples of the dearomatizing oxidative annulation of 1,3-dienes with 1-aryl-2-naphthols are also presented. IV) Enantioselective Spiroindene Formation via C‒H Functionalization Using Chiral Cyclopentadienyl Rhodium Catalysts A chiral cyclopentadienyl rhodium ligand with an atropchiral biaryl backbone enables an asymmetric synthesis of spiroindenes from 2-aryl-1,3-dicarbonyl compounds and alkynes. The process affords a range of products with all-carbon quaternary center in high yields and excellent enantiselectivities. The good functional group tolerance and broad substrate generality are the advantages of this reaction.