10 research outputs found
Carbon-carbon bond formation : from transition metal catalysis to base-promoted homolytic aromatic substitution
Cette thĂšse de doctorat porte sur la catalyse Ă partir de mĂ©taux de transition et sur la substitution homolytique aromatique favorisĂ©e par une base visant Ă former de nouvelles liaisons CâC, et Ă ainsi concevoir de nouvelles structures chimiques. Au cours des vingt derniĂšres annĂ©es, des nombreux efforts ont Ă©tĂ© rĂ©alisĂ©s afin de dĂ©velopper des mĂ©thodologies pour la fonctionnalisation de liens CâH, qui soient efficaces et sĂ©lectives, et ce Ă faible coĂ»t et en produisant le minimum de dĂ©chets. Le chapitre d'introduction donnera un aperçu de la fonctionnalisation directe de liens CâH sur des centres sp2 et sp3. Il sera Ă©galement discutĂ© dans cette partie de certains aspects de la chimie radicalaire reliĂ©s a ce sujet. Les travaux sur la fonctionnalisation dâimidazo[1,5-a]pyridines catalysĂ©e par des compleces de ruthĂ©nium seront prĂ©sentĂ©s dans le chapitre 2. MalgrĂ© l'intĂ©rĂȘt des imidazo[1,5-a]azines en chimie mĂ©dicinale, ces composĂ©s nâont reçu que peu d'attention dans le domaine de la fonctionnalisation de liens CâH. L'Ă©tendue de la rĂ©action et l'influence des effets stĂ©riques et Ă©lectroniques seront dĂ©taillĂ©s.
Les cyclopropanes reprĂ©sentent les 10Ăšme cycles carbonĂ©s les plus rencontrĂ©s dans les petites molĂ©cules dâintĂ©rĂȘt pharmacologique. Ce sont aussi des intermĂ©diaires de synthĂšse de choix pour la crĂ©ation de complexitĂ© chimique. MalgrĂ© de grands progrĂšs dans le domaine de la fonctionnalisation de liens C(sp3)âH, l'Ă©tude des cyclopropanes comme substrats dans les transformations directes est relativement nouvelle. Le chapitre trois prĂ©sentera l'arylation intramolĂ©culaire directe de cyclopropanes. Cette rĂ©action est rĂ©alisĂ©e en prĂ©sence de palladium, en quantitĂ© catalytique, en combinaison avec des sels dâargent. Des Ă©tudes mĂ©canistiques ont rĂ©futĂ© la formation d'un Ă©nolate de palladium et suggĂ©reraient plutĂŽt une Ă©tape de mĂ©tallation - dĂ©protonation concertĂ©e. En outre, les cycles de type benzoazepinone Ă sept chaĂźnons ont Ă©tĂ© synthĂ©tisĂ©s par l'intermĂ©diaire d'une sĂ©quence d'activation de cyclopropane/ouverture/cyclisation. Une arylation directe intermolĂ©culaire des cyclopropanes a Ă©tĂ© rĂ©alisĂ©e en prĂ©sence d'un auxiliaire de type picolinamide (Chapitre 4).
Les deux derniers chapitres de ce mĂ©moire de thĂšse dĂ©criront nos Ă©tudes sur la substitution homolytique aromatique favorisĂ©e par une base. Le mĂ©canisme de la rĂ©action de cyclisation intramolĂ©culaire d'halogĂ©nures d'aryle, rĂ©alisĂ©e en prĂ©sence de tert-butylate de potassium, a Ă©tĂ© Ă©lucidĂ© et se produit via une voie radicalaire (Chapitre 5). La transformation, exempte de mĂ©taux de transition, ne nĂ©cessite que la prĂ©sence dâune base et de pyridine comme solvant. Cette rĂ©action radicalaire a Ă©tĂ© Ă©tendue Ă la cyclisation d'iodures d'alkyle non activĂ©s en prĂ©sence d'un catalyseur Ă base de nickel et de bis(trimethylsilyl)amidure de sodium comme base (Chapitre 6). Des Ă©tudes de RMN DOSY ont dĂ©montrĂ© une association entre le catalyseur, la base et le matĂ©riel de dĂ©part.The dissertation will focus on transition metal catalysis and base-promoted homolytic aromatic substitution as a means of forming new CâC bonds, and thus designing new chemical scaffolds. During the last twenty years, tremenduous efforts have been expended to achieve low-cost, waste-free, efficient and selective CâH bond functionalization methodologies. The introductory chapter will provide an overview of direct functionalization of CâH sp2 and sp3 centers, as well as discuss relevant topics in radical chemistry. Work on the ruthenium-catalyzed functionalization of imidazo[1,5-a]pyridines will be presented in Chapter 2. Despite interest from the medicinal chemistry field, imidazo[1,5-a]azines have received little attention in the CâH functionalization field. The scope of the reaction and, in particular, the influence of sterics and electronics will be detailed.
Cyclopropanes represent the 10th most encountered rings in small drug synthesis. They are also valuable synthetic intermediates en route to more chemical complexity. Despite great advances in the field of C(sp3)âH functionalizations, the exploration of cyclopropanes as substrates in direct transformations is relatively novel. Chapter three will present the intramolecular direct arylation of cyclopropanes. A combination of palladium catalysis in presence of a silver salt was found to mediate the reaction. Mechanistic studies disproved the formation of a palladium-enolate and pointed towards a concerted metalation-deprotonation pathway. Furthermore, seven-membered benzoazepinone rings were synthesized via a cyclopropane activation/opening/cyclization sequence. An intermolecular direct arylation of cyclopropanes was achieved in presence of a picolinamide auxiliary (Chapter 4).
The last two chapters of the thesis will describe our studies on base-promoted homolytic aromatic substitution. A potassium tert-butoxide-promoted intramolecular cyclization of aryl halides was shown to occur through a radical pathway (Chapter 5). The transition metal-free transformation occurred in the sole presence of the base and pyridine as the solvent. The radical process was extended to the cyclization of unactivated alkyl iodides in presence of a nickel catalyst and sodium hexamethyldisilzide as the base (Chapter 6). DOSY NMR studies demonstrated an association between the catalyst, base and starting material
CâH Functionalization of Cyclopropanes: A Practical Approach Employing a Picolinamide Auxiliary
A Pd-catalyzed, picolinamide-enabled, and efficient CâH arylation of cyclopropanes is described. The reaction can be promoted by either a silver additive or catalytic pivalic acid in the presence of a carbonate base. Various aryl iodides can be employed as coupling partners, providing exclusively <i>cis</i>-substituted cyclopropylpicolinamides
Silver-Promoted, Palladium-Catalyzed Direct Arylation of Cyclopropanes: Facile Access to Spiro 3,3âČ-Cyclopropyl Oxindoles
The Pd-catalyzed, Ag(I)-mediated intramolecular direct arylation of cyclopropane CâH bonds is described. Various spiro 3,3âČ-cyclopropyl oxindoles can be obtained in good to excellent yields from easily accessible 2-bromoanilides. The kinetic isotope effect was determined and epimerization studies were conducted, suggesting that the formation of a putative Pd-enolate is not operative and that the reaction proceeds via a CâH arylation pathway
TMPâMagnesium and TMPâZinc Bases for the Regioselective Metalation of the Cinnoline Scaffold
A regioselective
functionalization of cinnolines in positions 3
and 8 using metalations has been developed. This involves either the
use of a frustrated Lewis pair consisting of BF<sub>3</sub>·Et<sub>2</sub>O and TMP<sub>2</sub>Mg·2LiCl or the in situ generated
base TMP<sub>2</sub>Zn·2MgCl<sub>2</sub>·2LiCl. Successive
metalations allow the preparation of 3,8-disubstituted cinnolines.
Various functionalizations by acylation, allylation, and cross-coupling
reactions with aryl halides or alkenyl iodides were carried out successfully
Directed Zincation with TMPZnCl·LiCl and Further Functionalization of the Tropolone Scaffold
The directed zincation of tropolone
derivatives was achieved using
TMPZnCl·LiCl. Various functionalizations of the zincated intermediates
by halogenation, acylation, allylation, and Negishi cross-coupling
were successfully performed. Additionally, 1,8-conjugate additionâelimination
reactions with a variety of arylmagnesium and secondary alkylzinc
reagents were carried out to further elaborate the tropolone core
Transition-Metal-Free Amination of Pyridine-2-sulfonyl Chloride and Related <i>N</i>âHeterocycles Using Magnesium Amides
A new transition-metal-free
amination of pyridine-2-sulfonyl chloride
and related <i>N</i>-heterocycles using magnesium amides
of type R<sub>2</sub>NMgCl·LiCl is reported. Additionally, the
directed <i>ortho</i>-magnesiation of pyridine-2-sulfonamides
using TMPMgCl·LiCl was investigated. Reaction of the magnesium
intermediates with various electrophiles and subsequent amination
using magnesium amides led to a range of 2,3-functionalized pyridines.
Also, cyclization reactions providing an aza-indole and an aza-carbazole
were carried out
Transition-Metal-Free Cross-Coupling of Aryl and <i>N</i>âHeteroaryl Cyanides with Benzylic Zinc Reagents
Functionalized 4-benzylated
pyridines can be efficiently prepared
by a transition-metal-free cross-coupling between various benzylic
zinc chlorides and substituted 4-cyanopyridines in THF/DMPU under
microwave irradiation (40 °C, 0.5â1.5 h). Selective benzylations
on polycyano-aromatics have also been achieved under these mild conditions.
We also report a novel oxidative nucleophilic substitution of a hydrogen
on 1,3-dicyanobenzene using benzylic zinc reagents