Palladium-Catalyzed trans-Hydroalkoxylation: Counterintuitive Use of an Aryl Iodide Additive to Promote C-H Bond Formation.

We report an enantioselective palladium-catalyzed trans-hydroalkoxylation of propargylic amines with a trifluoroacetaldehyde-derived tether to build chiral oxazolidines. Diastereoselective hydrogenation using a heterogeneous palladium catalyst then gave access to protected benzylic amino alcohols in 45-87% yields and 84-94% ee values. Hydroalkoxylation of the alkynes required a catalytic amount of aryl iodide, highlighting the counterintuitive key role played by a putative Pd(II)/ArI oxidative addition complex to promote oxypalladation/protodemetalation.

Enantioselective Carboetherification/Hydrogenation for the Synthesis of Amino Alcohols via a Catalytically Formed Chiral Auxiliary.

Chiral auxiliaries and asymmetric catalysis are the workhorses of enantioselective transformations, but they still remain limited in terms of either efficiency or generality. Herein, we present an alternative strategy for controlling the stereoselectivity of chemical reactions. Asymmetric catalysis is used to install a transient chiral auxiliary starting from achiral precursors, which then directs diastereoselective reactions. We apply this strategy to a palladium-catalyzed carboetherification/hydrogenation sequence on propargylic amines, providing fast access to enantioenriched chiral amino alcohols, important building blocks for medicinal chemistry and drug discovery. All stereoisomers of the product could be accessed by the choice of ligand and substituent on the propargylic amine, leading to a stereodivergent process.

Photocatalysis with organic dyes: facile access to reactive intermediates for synthesis.

Organic dyes have emerged as a reliable class of photoredox catalysts. Their great structural variety combined with the easy fine-tuning of their electronic properties has unlocked new possibilities for the generation of reactive intermediates. In this review, we provide an overview of the available approaches to access reactive intermediates that employ organophotocatalysis. Our contribution is not a comprehensive description of the work in the area but rather focuses on key concepts, accompanied by a few selected illustrative examples. The review is organized along the type of reactive intermediates formed in the reaction, including C(sp3) and C(sp 2 ) carbon-, nitrogen-, oxygen-, and sulfur-centered radicals, open-shell charged species, and sensitized organic compounds.

Amide Synthesis by Nickel/Photoredox-Catalyzed Direct Carbamoylation of (Hetero)Aryl Bromides.

Herein, we report a one-electron strategy for catalytic amide synthesis that enables the direct carbamoylation of (hetero)aryl bromides. This radical cross-coupling approach, which is based on the combination of nickel and photoredox catalysis, proceeds at ambient temperature and uses readily available dihydropyridines as precursors of carbamoyl radicals. The method's mild reaction conditions make it tolerant of sensitive-functional-group-containing substrates and allow the installation of an amide scaffold within biologically relevant heterocycles. In addition, we installed amide functionalities bearing electron-poor and sterically hindered amine moieties, which would be difficult to prepare with classical dehydrative condensation methods.

A Redox-Active Nickel Complex that Acts as an Electron Mediator in Photochemical Giese Reactions.

We report a simple protocol for the photochemical Giese addition of C(sp3 )-centered radicals to a variety of electron-poor olefins. The chemistry does not require external photoredox catalysts. Instead, it harnesses the excited-state reactivity of 4-alkyl-1,4-dihydropyridines (4-alkyl-DHPs) to generate alkyl radicals. Crucial for reactivity is the use of a catalytic amount of Ni(bpy)3 2+ (bpy=2,2'-bipyridyl), which acts as an electron mediator to facilitate the redox processes involving fleeting and highly reactive intermediates.

Mechanistic Studies in Photocatalysis.

The fast-moving fields of photoredox and photocatalysis have recently provided fresh opportunities to expand the potential of synthetic organic chemistry. Advances in light-mediated processes have mainly been guided so far by empirical findings and the quest for reaction invention. The general perception, however, is that photocatalysis is entering a more mature phase where the combination of experimental and mechanistic studies will play a dominant role in sustaining further innovation. This Review outlines the key mechanistic studies to consider when developing a photochemical process, and the best techniques available for acquiring relevant information. The discussion will use selected case studies to highlight how mechanistic investigations can be instrumental in guiding the invention and development of synthetically useful photocatalytic transformations.

Radical-Based C-C Bond-Forming Processes Enabled by the Photoexcitation of 4-Alkyl-1,4-dihydropyridines.

We report herein that 4-alkyl-1,4-dihydropyridines (alkyl-DHPs) can directly reach an electronically excited state upon light absorption and trigger the generation of C(sp3 )-centered radicals without the need for an external photocatalyst. Selective excitation with a violet-light-emitting diode turns alkyl-DHPs into strong reducing agents that can activate reagents through single-electron transfer manifolds while undergoing homolytic cleavage to generate radicals. We used this photochemical dual-reactivity profile to trigger radical-based carbon-carbon bond-forming processes, including nickel-catalyzed cross-coupling reactions.

Visible-light excitation of iminium ions enables the enantioselective catalytic ß-alkylation of enals.

Chiral iminium ions-generated upon condensation of α,ß-unsaturated aldehydes and amine catalysts-are used extensively by chemists to make chiral molecules in enantioenriched form. In contrast, their potential to absorb light and promote stereocontrolled photochemical processes remains unexplored. This is despite the fact that visible-light absorption by iminium ions is a naturally occurring event that triggers the mechanism of vision in higher organisms. Herein we demonstrate that the direct excitation of chiral iminium ions can unlock unconventional reaction pathways, enabling enantioselective catalytic photochemical ß-alkylations of enals that cannot be realized via thermal activation. The chemistry uses readily available alkyl silanes, which are recalcitrant to classical conjugate additions, and occurs under illumination by visible-light-emitting diodes. Crucial to success was the design of a chiral amine catalyst with well-tailored electronic properties that can generate a photo-active iminium ion while providing the source of stereochemical induction. This strategy is expected to offer new opportunities for reaction design in the field of enantioselective catalytic photochemistry.

Smooth Photocatalyzed Benzylation of Electrophilic Olefins via Decarboxylation of Arylacetic Acids.

Arylacetic acids were used as sources of benzyl radicals under tetrabutylammonium decatungstate photocatalyzed conditions for the benzylation of electron-poor olefins. The reaction proceeds smoothly in a mixed aqueous medium (MeCN/H2O 2/1) in the presence of NaHCO3, NaClO4, and an electron transfer agent (biphenyl). The reaction tolerates a wide variety of functional groups on the aromatic ring (whether electron donating or electron withdrawing) and can be extended to heteroaromatic analogues. The olefins have the double role of radical trap and electron acceptor. The present approach can also be extended to arylpropionic acids (including the nonsteroidal anti-inflammatory drugs ibuprofen and flurbiprofen), as well as mandelic acid derivatives.

Hydrogenations without hydrogen: titania photocatalyzed reductions of maleimides and aldehydes.

A mild procedure for the reduction of electron-deficient alkenes and carbonyl compounds is described. UVA irradiations of substituted maleimides with dispersions of titania (Aeroxide P25) in methanol/acetonitrile (1:9) solvent under dry anoxic conditions led to hydrogenation and production of the corresponding succinimides. Aromatic and heteroaromatic aldehydes were reduced to primary alcohols in similar titania photocatalyzed reactions. A mechanism is proposed which involves two proton-coupled electron transfers to the substrates at the titania surface.