Substitution nucléophile | EPFL Graph Search

En chimie organique, une réaction de substitution nucléophile est une réaction de substitution au cours de laquelle un groupe nucléophile riche en électrons, noté Nu−, attaque une molécule électrophile ayant un site pauvre en électrons, et remplace un atome ou un groupe d'atomes, appelé groupe partant (noté GP), ou groupe nucléofuge. Équation générale de ce type de réaction Les électrons libres (:) du nucléophile Nu− attaquent le substrat R-GP en formant une nouvelle liaison, et entraînant ainsi le départ du groupe partant GP. Parfois, le solvant à lui seul peut provoquer la rupture et laisser le nucléophile réagir. Le nucléophile peut être aussi bien électroniquement neutre, que chargé négativement, tandis que le substrat peut être neutre ou chargé positivement. Substitution nucléophile d'halogénoalcane Un exemple de substitution nucléophile est la transformation d'un composé halogéné en alcool (hydrolyse d'un halogénure d'alkyle en milieu basique). :\

Fluorine in an heteroaromatic context

Thierry Rausis

The organometallic approach to the functionalization of arenes and heteroarenes has recently been investigated by our group introducing modifications of the standard methods. This includes, in particular, the basicity-driven heavy halogen migration, which allows the introduction of a functional group at a not directly accessible position. Then, some attentions were reported toward nucleophilic aromatic substitution and especially to a regio-controlled attack at heteroarenes. Bulky trialkylsilyl groups were used to shield a given position by steric congestion against both electrophilic and nucleophilic attack. Using different electrophiles, commercially available 2,6-difluoropyridine was selected as substrate for a large proliferation of derivatives through organolithium intermediates. To allow for more regioflexibility, one can either rely on protective groups or introduce iodine which will be subsequently submitted to a basicity gradient-driven relocation and eventually a halogen/metal exchange. A systematic investigation was undertaken to explore the scope and the limitations of this latter option. Di-, tri- and tetrahalopyridines are used to explore the substituent effect in nucleophilic substitutions with the pyridine ring. An activating substituent as chlorine directed the nucleophilic substitution at the vicinal fluorine atom. Unprecedented was the finding that bulky 3-trialkylsilyl group effectively shielded the fluorine at the adjacent 2- and 4-positions, reorienting the nucleophilic substitution to the 6-position. To exploit the regioselectivity established by the "silyl trick", some halopyridines, such as 2,4,5-trifluoropyridine or 2,4-dichloro-6-hydrazinopyridine, were prepared for the fist time. Highly substituted derivatives isolated during nucleophilic substitutions were the starting point for the development of more complex structures such 2-amino-5-bromo-4-chloro-6-fluoro-3-nitropyridine obtained by using some of the developed techniques.

EPFL2005

Rh-catalyzed C-H Bond Heteroarylation with Hypervalent Iodine Reagents and Pd-Catalyzed Tethered Functionalizations of Carbon-Carbon Multiple Bonds.

Ashis Kumar Das

Transition metal-catalyzed C-H activation is a powerful tool for the synthesis of organic building blocks, materials, and natural products. Over the last decade, directing-group-assisted metal-catalyzed C-H functionalization has attracted increasing interest as a means to target specific C-H bonds. Moreover, a large variety of electrophiles has been employed in this kind of processes. In this thesis, we describe a novel C-6 selective C-H heteroarylation of pyridine-2-ones using indoleBX reagents as coupling partners under Rh(I)-catalysis. The reaction worked efficiently also with other analogous heterocyclic substrates and with a quinoline-N-oxide. We were able to obtain 6-(indol-3-yl)pyridinone and 8-(indol-3-yl)quinolone after cleavage of the directing group or rearrangement of the N-oxide moiety. 1,2-Amino alcohols are important structural motifs in organic chemistry that can be observed in natural products, pharmaceutically and biologically active molecules. The palladium-catalyzed difunctionalization of C-C multiple bonds has been broadly investigated as an efficient strategy to access such substructures. This transformation has been reported using either Pd(0)/Pd(II) or Pd(II)/Pd(IV) catalytic cycles, in which the nucleophilic functionalization of a putative Pd(II)-alkyl intermediate is achieved prior to beta-hydride elimination. As a further topic of this thesis, we developed new methods for the synthesis of amino alcohols whereby the Pd-catalyzed difunctionalization of alkynes and alkenes was combined with the tethering approach previously established in our laboratories. We first investigated the Pd-catalyzed enantioselective hydroalkoxylation of propargylic amines. The latter were tethered in situ with a trifluoroacetaldehyde hemiacetal. Best results were obtained with commercially available DACH-Phenyl Trost ligand. Aryl iodides were required as an additive in catalytic amount for successful outcome. A large variety of chiral oxazolidines were obtained in good to excellent yields and ee, followed by a diastereoselective reduction to give protected enantioenriched amino alcohols. A possible mechanism for this transformation relies on a Pd(0)/Pd(II) catalytic cycle involving oxidative addition of aryl iodide with a subsequent oxypalladation/protodemetallation (or reductive elimination) reaction. This is necessary to generate the active complex, not as the start of a cross-coupling event. The use of a commercially available DACH-Ph Trost ligand to produce high enantioselectivity in an unprecedented DYKAT process was critical to success.The Pd-catalyzed amino acetoxylation of cinnamyl alcohols was next taken into consideration towards the synthesis of valuable amino diol derivatives. In this case, preformed substrates were used, where the alcohol moiety was tethered to N-nucleophilic groups. Conditions involving Pd(II)/Pd(IV) catalysis and employing PIDA as a strong oxidant were employed. The use of this hypervalent iodine reagent was key to the success of the transformation. Amino acetoxylated products were obtained in moderate to good yields and dr. The scope of this reaction remains mostly limited to cinnamyl derived substrates. The reaction conditions did not tolerate substituents on the alpha, beta, and gamma positions of the allylic chains. Alkyl chain containing unsaturated alcohols delivered Aza-Wacker-type products.

EPFL2022

Rh-catalyzed C-H Bond Heteroarylation with Hypervalent Iodine Reagents and Pd-Catalyzed Tethered Functionalizations of Carbon-Carbon Multiple Bonds.

Ashis Kumar Das

EPFL2022

Fluorine in an heteroaromatic context

Thierry Rausis

EPFL2005