ABSTRACT: In recent years, the synthesis of amines and other nitrogen-containing motifs has been a major area of research in organic chemistry because they are widely represented in biologically active molecules. Current strategies rely on a multistep approach and require one reactant to be activated prior to the carbon-nitrogen bond formation. This leads to a reaction inefficiency and functional group intolerance. As such, a general approach to the synthesis of nitrogen-containing compounds from readily available and benign starting materials is highly desirable. Here we present a palladium-catalysed oxidative amination reaction in which the addition of the nitrogen occurs at the less-substituted carbon of a double bond, in what is known as anti-Markovnikov selectivity. Alkenes are shown to react with imides in the presence of a palladate catalyst to generate the terminal imide through trans-aminopalladation. Subsequently, olefin isomerization occurs to afford the thermodynamically favoured products. Both the scope of the transformation and mechanistic investigations are reported.
Project description:A one-pot anti-Markovnikov hydroamination of alkenes is reported. The synthesis of primary and secondary amines from unactivated olefins was accomplished in the presence of a variety of functional groups. Hydrozirconation, followed by amination with nitrogen electrophiles, provides exclusive anti-Markovnikov selectivity. Most products are isolated in high yields without the use of column chromatography.
Project description:Palladium-catalyzed hydroalkylation of allylic amine derivatives by alkylzinc reagents is reported. This reductive cross-coupling reaction yields anti-Markovnikov products using a variety of allylic amine protecting groups. Preliminary mechanistic studies suggest that a reversible ?-hydride elimination/hydride insertion process furnishes the primary Pd-alkyl intermediate, which then undergoes transmetalation followed by reductive elimination to form a new sp(3)-sp(3) carbon-carbon bond.
Project description:Alkene hydrodifluoroalkylation is a fruitful strategy for synthesizing difluoromethylated compounds that are interesting for developing new medicinal agents, agrochemicals, and advanced materials. Whereas the anti-Markovnikov hydrodifluoroalkylation to linear-type products is developed, employing radical-based processes, the Markovnikov synthesis of branched adducts remains unexplored. Herein, we describe acid-catalyzed processes involving carbocation intermediates as a promising strategy to secure the Markovnikov regioselectivity. Accordingly, the Markovnikov hydrodifluoroalkylation of mono-, di-, tri-, and tetrasubstituted alkenes using difluoroenoxysilanes, catalyzed by Mg(ClO4)2·6H2O, is achieved. This allows the diversity-oriented synthesis of ?,?-difluoroketones with a quaternary or tertiary carbon at the ?-position that are otherwise difficult to access. The method is applied to the modification of natural products and drug derivatives. The resulting ?,?-difluorinated ketones could be converted to the corresponding ?,?-difluorinated esters or alcohols, or organofluorine compounds featuring a CF2H or CF2CF2Ph moiety. Mechanistic studies support that Mg(ClO4)2·6H2O functions as a hidden Brønsted acid catalyst.
Project description:Herein we report a metal-free method for the direct anti-Markovnikov hydroamination of unsaturated amines. Irradiation of the amine substrates with visible light in the presence of catalytic quantities of easily synthesized 9-mesityl-10-methylacridinium tetrafluoroborate and thiophenol as a hydrogen-atom donor furnished the nitrogen-containing heterocycles with complete regiocontrol. Two examples of intermolecular anti-Markovnikov alkene hydroamination are also disclosed.
Project description:[reaction: see text] Olefinic pyrazines are found to react with benzene in CF3SO3H and give anti-Markovnikov-type addition products. We propose that this is caused by two effects: destabilization of the carbocationic intermediates that would lead to Markovnikov-type products and the generation of a considerable amount of positive charge at the terminal carbon of the olefinic groups. This suggests that acid-catalyzed addition reactions can give anti-Markovnikov-type products when a multiply charged (i.e., superelectrophilic) group is adjacent to the olefinic site.
Project description:Disclosed herein is a general catalytic system for the intermolecular anti-Markovnikov hydroamination of alkenes. By using an organocatalytic photoredox system, ?- and ?-substituted styrenes as well as aliphatic alkenes undergo anti-Markovnikov hydroamination. Heterocyclic amines were also successfully employed as nitrogen nucleophiles, thus providing a direct route to heterocyclic motifs common in medicinal agents.
Project description:Herein we describe the development of a Pd-catalyzed enantioselective Markovnikov addition of carbamates to allylic alcohols for the construction of ?-tertiary and ?-secondary amines. The reaction affords a range of ?-amino alcohols, after reduction of the aldehyde in situ, which contain a variety of functional groups in moderate yields and moderate to good enantioselectivities. These products can be readily oxidized to ?-amino acids, valuable building blocks for the synthesis of biologically active compounds. Mechanistic studies indicate that the C-N bond formation occurs via a syn amino-palladation mechanism, an insight which may guide future reaction development given the limited number of enantioselective syntheses of ?-tertiary amines.
Project description:We have developed a nickel-catalyzed hydroarylation of alkenes using aryl halides as coupling partners. Excellent anti-Markovnikov selectivity is achieved with aryl-substituted alkenes and enol ethers. We also show that hydroarylation occurs with alkyl substituted alkenes to yield linear products. Preliminary examination of the reaction mechanism suggests irreversible hydrometallation as the selectivity determining step of the hydroarylation.
Project description:We report a highly enantioselective CuH-catalyzed Markovnikov hydrosilylation of vinylarenes and vinyl heterocycles. This method has a broad scope and enables both the synthesis of isolable silanes and the conversion of crude products to chiral alcohols. Density functional theory calculations support a mechanism proceeding by hydrocupration followed by ?-bond metathesis with a hydrosilane.
Project description:A direct intramolecular anti-Markovnikov hydroetherification reaction of alkenols is described. By employing catalytic quantities of commercially available 9-mesityl-10-methylacridinium perchlorate and 2-phenylmalononitrile as a redox-cycling source of a H-atom, we report the anti-Markovnikov hydroetherification of alkenes with complete regioselectivity. In addition, we present results demonstrating that this novel catalytic system can be applied to the anti-Markovnikov hydrolactonization of alkenoic acids.