Loïc R. E. Pantaine

Hydroarylation of cinnamylanilines under cobalt and photoredox catalysis provides diverse C4-functionalised tetrahydroquinolines in batch and flow. Mechanistic studies are consistent with a radical-polar crossover event before cyclisation.

Les travaux exposés dans ce manuscrit ont pour objectif d’étudier des séquences réactionnelles organocatalysées permettant la formation stéréosélective de liaisons carbone-carbone ou carbone-hétéroatome. Plusieurs stratégies ont été développées pour la préparation d’architectures cycliques chirales dont la synthèse représente un enjeu important en raison de leur présence dans un grand nombre de molécules d’intérêt biologique. Le manuscrit débute par une introduction sur le principe de l’organocatalyse en se focalisant sur les différents modes d’activation en aminocatalyse.Le premier chapitre traite de la synthèse, sans solvant, régio- et diastéréosélective de bicycles comportant une hydrazine cyclique. Le deuxième chapitre combine la désaromatisation ou la désymétrisation à une séquence aminocatalysée, pour former des polycycles tridimensionnels énantio-enrichis à partir d’aldéhydes insaturés. Enfin, le troisième chapitre se concentre sur la synthèse de sulfamides non symétriques et leur utilisation comme substrats en aminocatalyse.

Synthetic transformations that advance through excited states proceed by unconventional mechanistic pathways and deliver products not accessible using ground-state chemistry. The breadth of these synthetically valuable transformations is constrained by the range of molecules—and particularly the functional groups—that can deliver productive excited states, with most methods using the same functional groups that were defined more than 100 years ago. In this work, we show that N -silyl sulfinylamines can undergo synthetically useful excited-state reactivity accessed using energy transfer catalysts and visible light. We exploit these intermediates in reactions with alkenes to form four-membered cyclic sulfinamide products. The reactions are efficient and broad in scope, and the products are advanced to sulfonamides as well as four-membered cyclic sulfonimidamides.

Motifs related to 1,2-diols and 1,2-amino alcohols are found widely in bioactive natural products, drugs and agrochemicals. These highly sought-after substructures would ideally be constructed by the direct addition of alcohols to the C=C bond of alkenes, both common substrate classes in chemical synthesis. However, their direct union is only possible if one of the pair can be rendered electron-deficient through derivatization; such approaches typically require stoichiometric amounts of strong oxidants and often lack generality. Here we describe a straightforward process in which both simple and complex alcohols can be converted under photocatalytic conditions to the corresponding alkoxy radicals—via the formation of alkoxy sulfonium salts—that react with alkenes en route to 1,2-diol and 1,2-amino-alcohol derivatives. The method can be easily adapted from laboratory to industrial, kilogram scale using a photoflow system. Spectroscopic analysis and control experiments have been used to probe the underpinning mechanism.

An intramolecular cyclization strategy to synthesize nitrogen-rich and biologically important 2-heteroaryl-indolin-3-ones has been developed in both batch and flow. Using high-throughput screening, citric acid in a dimethylformamide/water mixture was found to facilitate the reaction under batch conditions, which can tolerate substituted phenyl rings, quinolines, and naphthalenes with a variety of electronic and steric properties. The reaction was reoptimized for flow conditions using design of experiments, complementing the batch conditions for some substrates with greatly reduced reaction times.

Heteroaromatic sulfinates are effective nucleophilic reagents in Pd ⁰ ‐catalyzed cross‐coupling reactions with aryl halides. However, metal sulfinate salts can be challenging to purify, solubilize in reaction media, and are not tolerant to multi‐step transformations. Here we introduce base‐activated, latent sulfinate reagents: β‐nitrile and β‐ester sulfones. We show that under the cross‐coupling conditions, these species generate the sulfinate salt in situ, which then undergo efficient palladium‐catalyzed desulfinative cross‐coupling with (hetero)aryl bromides to deliver a broad range of biaryls. These latent sulfinate reagents have proven to be stable through multi‐step substrate elaboration, and amenable to scale‐up.

Heteroaromatic sulfinates are effective nucleophilic reagents in Pd⁰‐catalyzed cross‐coupling reactions with aryl halides. However, metal sulfinate salts can be challenging to purify, solubilize in reaction media, and are not tolerant to multi‐step transformations. Here we introduce base‐activated, latent sulfinate reagents: β‐nitrile and β‐ester sulfones. We show that under the cross‐coupling conditions, these species generate the sulfinate salt in situ, which then undergo efficient palladium‐catalyzed desulfinative cross‐coupling with (hetero)aryl bromides to deliver a broad range of biaryls. These latent sulfinate reagents have proven to be stable through multi‐step substrate elaboration, and amenable to scale‐up.

Azine‐containing biaryls are ubiquitous scaffolds in many areas of chemistry, and efficient methods for their synthesis are continually desired. Pyridine rings are prominent amongst these motifs. Transition‐metal‐catalysed cross‐coupling reactions have been widely used for their synthesis and functionalisation as they often provide a swift and tuneable route to related biaryl scaffolds. However, 2‐pyridine organometallics are capricious coupling partners and 2‐pyridyl boron reagents in particular are notorious for their instability and poor reactivity in Suzuki–Miyaura cross‐coupling reactions. The synthesis of pyridine‐containing biaryls is therefore limited, and methods for the formation of unsymmetrical 2,2′‐bis‐pyridines are scarce. This Review focuses on the methods developed for the challenging coupling of 2‐pyridine nucleophiles with (hetero)aryl electrophiles, and ranges from traditional cross‐coupling processes to alternative nucleophilic reagents and novel main group approaches.

Azine‐containing biaryls are ubiquitous scaffolds in many areas of chemistry, and efficient methods for their synthesis are continually desired. Pyridine rings are prominent amongst these motifs. Transition‐metal‐catalysed cross‐coupling reactions have been widely used for their synthesis and functionalisation as they often provide a swift and tuneable route to related biaryl scaffolds. However, 2‐pyridine organometallics are capricious coupling partners and 2‐pyridyl boron reagents in particular are notorious for their instability and poor reactivity in Suzuki–Miyaura cross‐coupling reactions. The synthesis of pyridine‐containing biaryls is therefore limited, and methods for the formation of unsymmetrical 2,2′‐bis‐pyridines are scarce. This Review focuses on the methods developed for the challenging coupling of 2‐pyridine nucleophiles with (hetero)aryl electrophiles, and ranges from traditional cross‐coupling processes to alternative nucleophilic reagents and novel main group approaches.