Despite the great abundance of C–H bonds in readily available starting materials, their use in synthesis of functionalized molecules has been hampered by the high bond strengths, rendering them inert to common organic reagents. However, recent progress in the field has addressed this issue, enabling selective C–H bond functionalizations to be performed using catalytic transition metal mediated processes. Herein, the use of sulfonyl chlorides as versatile reagents for C–H bond functionalizations is reported. Using chelation assistance, the regioselective conversion of C–H bonds to either C–S, C–Cl or C–C bonds was achieved. The methodology development, substrate scope determination and mechanistic investigations will be discussed.

Despite the great abundance of C–H bonds in readily available starting materials, their use in synthesis of functionalized molecules has been hampered by the high bond strengths, rendering them inert to common organic reagents. However, recent progress in the field has addressed this issue, enabling selective C–H bond functionalizations to be performed using catalytic transition metal mediated processes. Herein, the use of sulfonyl chlorides as versatile reagents for C–H bond functionalizations is reported. Using chelation assistance, the regioselective conversion of C–H bonds to either C–S, C–Cl or C–C bonds was achieved. The methodology development, substrate scope determination and mechanistic investigations will be discussed.

No description available.

La grande variété de propriétés biologiques associées au noyau purine en fait une structure privilégiée pour la conception et la synthèse de nouvelles molécules à visée thérapeutique. Cette spécificité est étroitement liée à la grande diversité de substituants pouvant être introduits sur les différentes positions du noyau purine et en particulier sur C2, C6, C8 et N9. Par conséquent, le développement de méthodes de fonctionnalisation rapides de cette famille de composés est d’un grand intérêt synthétique. Nous nous sommes focalisés sur la formation de liaisons C-C et C-N sur les positions 6 et 8 du noyau purine pour pouvoir présenter de nouveaux outils de synthèse permettant d’introduire une plus grande diversité fonctionnelle. D’une part, nous avons étudié la fonctionnalisation directe de liaisons C-H de purines, sujet encore peu exploré. En effet, de nos jours, le traditionnel couplage croisé (Negishi, Suzuki-Miyaura), utilisé pour la création de liaisons C-C, se voit de plus en plus concurrencé par ces réactions puisqu’elles ne nécessitent pas la préparation d’un partenaire organométallique. Ce sont des réactions dites à économie d’atomes. En nous basant sur l’expérience du laboratoire dans le domaine de la fonctionnalisation directe de liaisons C-H, nous avons envisagé l’alcénylation et l’alcynylation directes en position 8 de la purine, les motifs alcényle et alcynyle étant présents dans certaines purines d’intérêt biologique. D’autre part, nous nous sommes intéressés à deux méthodes de couplage croisé pallado-catalysé permettant la formation de liaisons C-N et C-C : le couplage de Buchwald – Hartwig entre une 8-iodopurine et des amides ou des amines aromatiques, et le couplage de Liebeskind – Srogl entre une 6-thioétherpurine et divers acides boroniques. / Purine is the most widely distributed N-heterocycle scaffold in the nature and its derivatives are well known for their biological and fluorescent properties. These characteristics are linked to the diversity of substituents that can be introduced, especially on the C-2, C-6, C-8 and N-9 positions. Therefore, the development of methods for rapid functionalization of this family of compounds represent a valuable asset. We focused on the formation of C-C and C-N bonds at positions 6 and 8 of the purine ring in order to provide new synthesis tools allowing the introduction of functional diversity. On the one hand, we studied the direct functionalization of C-H bonds of purines, subject still little explored. Indeed, nowadays, traditional cross-coupling reactions (Negishi, Suzuki-Miyaura), used for the creation of C-C bonds, are increasingly challenged by these reactions since they do not require the preparation of an organometallic partner. Their advantage lies in step and atom economy. Based on previous experience in our laboratory in the field of direct functionalization of C-H bonds, we envisioned direct alkenylation and alkynylation at position 8 of the purine, knowing that alkenyl and alkynyl patterns are found in purines of biological interest. On the other hand, we were interested in two pallado-catalyzed cross-coupling methods for the formation of C-N and C-C bonds : Buchwald – Hartwig coupling between 8-iodopurine and aromatic amines or amides, and Liebeskind – Srogl coupling between 6-thioétherpurine and a range of boronic acids.

No description available.

The selective transformation of carbon-carbon and carbon-hydrogen bonds represents an attractive approach and rapidly developing frontier in synthesis. Benefits include step and atom economy, as well as the ubiquitous presence in organic molecules. Advances to this exciting realm of synthesis are described in this thesis with an emphasis on the development of catalytic, selective reactions under mild conditions. Additionally some applications of the methodologies are demonstrated. In Chapter 1, the first examples of inter-and intramolecular enantioselective conjugate alkenylations employing organostannanes are reported. A chiral, cationic Rh(I)-diene complex catalyzed the enantioselective conjugate addition of alkenylstannanes to benzylidene Meldrum’s acids in moderate enantiomeric ratios and yields. Notably, the cationic and anhydrous conditions required for the asymmetric alkenylation are complementary to existing protocols employing other alkenylmetals. In Chapter 2, a domino, one-pot formation of tetracyclic ketones from benzylidene Meldrum’s acids using Sc(OTf)3 via a [1,5]-hydride shift/cyclization/Friedel-Crafts acylation sequence is described. Respectable yields were obtained in accord with the ability to convert to the spiro-intermediate, and considering the formation of three new bonds: one C-H and two C-C bonds. An intriguing carbon-carbon bond cleavage was also serendipitously discovered as part of a competing reaction pathway. In Chapter 3, the pursuit of novel C-H bond transformations led to the development of non-carbonyl-stabilized rhodium carbenoid Csp3-H insertions. This methodology enabled the rapid synthesis of N-fused indolines and related complex heterocycles from N-aziridinylimines. By using a rhodium carboxamidate catalyst, competing processes were minimized and C-H insertions were found to proceed in moderate to high yields. Also disclosed is an expedient total synthesis of (±)-cryptaustoline, a dibenzopyrrocoline alkaloid, which highlights the methodology. In Chapter 4, the Lewis acid promoted substitution of Meldrum’s acid discovered during the course of the domino reaction was explored in detail. The protocol transforms unstrained quaternary and tertiary benzylic Csp3-Csp3 bonds into Csp3-X bonds (X = C, N, H) and has even shown to be advantageous with regards to synthetic utility over the use of alternative leaving groups for substitutions at quaternary benzylic centers. This reaction has a broad scope both in terms of suitable substrates and nucleophiles with good to excellent yields obtained (typically >90%).

The selective transformation of carbon-carbon and carbon-hydrogen bonds represents an attractive approach and rapidly developing frontier in synthesis. Benefits include step and atom economy, as well as the ubiquitous presence in organic molecules. Advances to this exciting realm of synthesis are described in this thesis with an emphasis on the development of catalytic, selective reactions under mild conditions. Additionally some applications of the methodologies are demonstrated. In Chapter 1, the first examples of inter-and intramolecular enantioselective conjugate alkenylations employing organostannanes are reported. A chiral, cationic Rh(I)-diene complex catalyzed the enantioselective conjugate addition of alkenylstannanes to benzylidene Meldrum’s acids in moderate enantiomeric ratios and yields. Notably, the cationic and anhydrous conditions required for the asymmetric alkenylation are complementary to existing protocols employing other alkenylmetals. In Chapter 2, a domino, one-pot formation of tetracyclic ketones from benzylidene Meldrum’s acids using Sc(OTf)3 via a [1,5]-hydride shift/cyclization/Friedel-Crafts acylation sequence is described. Respectable yields were obtained in accord with the ability to convert to the spiro-intermediate, and considering the formation of three new bonds: one C-H and two C-C bonds. An intriguing carbon-carbon bond cleavage was also serendipitously discovered as part of a competing reaction pathway. In Chapter 3, the pursuit of novel C-H bond transformations led to the development of non-carbonyl-stabilized rhodium carbenoid Csp3-H insertions. This methodology enabled the rapid synthesis of N-fused indolines and related complex heterocycles from N-aziridinylimines. By using a rhodium carboxamidate catalyst, competing processes were minimized and C-H insertions were found to proceed in moderate to high yields. Also disclosed is an expedient total synthesis of (±)-cryptaustoline, a dibenzopyrrocoline alkaloid, which highlights the methodology. In Chapter 4, the Lewis acid promoted substitution of Meldrum’s acid discovered during the course of the domino reaction was explored in detail. The protocol transforms unstrained quaternary and tertiary benzylic Csp3-Csp3 bonds into Csp3-X bonds (X = C, N, H) and has even shown to be advantageous with regards to synthetic utility over the use of alternative leaving groups for substitutions at quaternary benzylic centers. This reaction has a broad scope both in terms of suitable substrates and nucleophiles with good to excellent yields obtained (typically >90%).

Le domaine de recherche de la chimie du fluor a connu un essor considérable. En particulier, le motif SCF3 et plus récemment les groupements SCF2R (R = H, SO2Ph, SAr, COAr, Rf) ont fait l'objet d'une attention particulière de la part de la communauté scientifique du fait de leurs propriétés remarquables. Dans ce contexte, le développement de nouvelles méthodologies et de réactifs originaux pour l'introduction de ces groupements fluorés a suscité un fort intérêt. En conséquence, les objectifs de cette thèse ont été 1) de développer de nouvelles méthodologies pour la fonctionnalisation de liaisons C(sp3)-H par l'introduction directe d'un motif SCF3 catalysée par des métaux de transition, et son extension à d'autres groupements fonctionnels ainsi que 2) de concevoir et étudier de nouveaux réactifs fluorés électrophiles. La première partie de cette thèse a été dédiée au développement d'une réaction de trifluorométhylthiolation d'amides aliphatiques catalysée au palladium, une transformation inédite (Chapitre 2). Puis, la chloration d'amides aliphatiques catalysée au palladium, dans des conditions douces, a été étudiée (Chapitre 3). Enfin, une nouvelle voie de synthèse pour accéder aux sulfénamides trifluorométhylés a été développée (Chapitre 4). Cette approche a été étendue à la préparation d'un nouveau réactif électrophile pour l'introduction du groupement SCN. De plus, un réactif électrophile original, source du motif SCF2PO(OEt)2, a été synthétisé et appliqué à la construction de liaisons C-SCF2PO(OEt)2, N-SCF2PO(OEt)2 et S-SCF2PO(OEt)2 ainsi qu'à la synthèse d'un composé d'intérêt biologique (Chapitre 4). / The organofluorine chemistry field has witnessed a very fast expansion. In particular, the SCF3 moiety and more recently the SCF2R groups (R = H, SO2Ph, SAr, COAr, Rf) have attracted a special interest from the scientific community because of their remarkable properties. In this context, the development of new methodologies and original reagents for the introduction of such fluorinated groups is particularly appealing. Therefore, the goals of this thesis were 1) to develop a new methodology for the direct introduction of the SCF3 group by transition metal-catalyzed C(sp3)-H bond functionalization and its extension to other functional groups as well as 2) to design and study new electrophilic fluorinated reagents.The first part of this Ph.D. thesis was dedicated to the development of an unprecedented Pd-catalyzed trifluoromethylthiolation of aliphatic amides by C-H bond functionalization (Chapter 2). Then, the Pd-catalyzed chlorination of aliphatic amides by C-H bond functionalization under mild conditions was investigated (Chapter 3). Finally, a newly designed strategy for the synthesis of trifluoromethanesulfenamides was elaborated (Chapter 4). This approach was extended to the preparation of a new electrophilic reagent for the thiocyanation reaction. In addition, an original electrophilic SCF2PO(OEt)2 reagent was designed and applied to the construction of C-SCF2PO(OEt)2, N-SCF2PO(OEt)2 and S-SCF2PO(OEt)2 bonds as well as to the synthesis of a biorelevant compound (Chapter 4).

Dans ce mémoire sont décrites deux méthodologies impliquant la synthèse de biaryles via l’arylation directe d’espèces aromatiques non activées, catalysée par différents éléments de transition. La première partie présente les résultats obtenus dans le cadre du développement d’une méthode simple d’arylation directe du benzène catalysée au palladium. Cette méthodologie a l’avantage de procéder sans l’ajout de ligand phosphine généralement utilisé dans les systèmes catalytiques avec le palladium et par conséquent cette réaction peut évoluer à l’air libre sans nul besoin d’une atmosphère inerte. Il est proposé que le mécanisme de formation de ces motifs biarylés pourrait passer par la mise en place d’un palladium d’espèce cationique. Ces composés pourraient éventuellement s’avérer intéressants dans la synthèse de produits pharmaceutiques comportant un motif biphényle de ce type. La deuxième partie est consacrée à une méthodologie très attrayante utilisée pour la synthèse des biphényles impliquant le fer comme catalyseur. Plusieurs catalyseurs à base de rhodium, palladium et ruthénium ont démontré leur grande efficacité dans les processus de couplage direct (insertion C-H). Cette méthodologie consiste en la première méthode efficace d’utilisation d’un catalyseur de fer dans les couplages directs sp2-sp2 avec les iodures d’aryles et iodures d’hétéroaryles. Les avantages du fer, impliquent sans contredit, des coûts moindres et des impacts environnementaux bénins. Les conditions réactionnelles sont douces, la réaction peut tolérer la présence de plusieurs groupements fonctionnels et cette dernière peut même se produire à température ambiante. La transformation s’effectue généralement avec de très bons rendements et des études mécanistiques ont démontré que le processus réactionnel était radicalaire. / This thesis describes the development of two methodologies involved in the biaryls synthesis. The first part is directed towards the use of a directing group or stabilizing group for the palladium catalyzed direct arylation. In all the examples found in the literature, the moiety bearing the directing group has the proton subject to abstraction in the ortho-position leaving the halide to the other coupling partner. We thought that by designing a compound having both a directing group and a halide, at the ortho position, the direct arylation of unactivated molecule species would be possible. This reaction is performed under air and without the use of any phosphine ligand providing a low cost and practical access to the pharmaceutically useful biaryl moieties containing a versatile ester functionality for further transformations. Owing to the ubiquity of C-H bonds in organic compounds, the possibility of directly introducing a new C-C bond (or other functionalities) via a direct C-H bond transformation is a highly attractive strategy in synthesis. Several rhodium, palladium, and ruthenium catalysts have proven to be highly effective in such direct coupling processes. Herein the first general and efficient iron-catalyzed direct arylation of iodo-aryls and iodo-hetereoaryl derivatives using a cost effective and environmentally benign catalyst is described. The reaction is performed under neat conditions and can even proceed at room temperature providing 22 examples of biaryls and heteroaryls construction with moderate to excellent yield. Mechanistic studies showed that the transformation was going through an aryl radical transfer pathway.

No description available.