C-H deuteration has been intricately developed to satisfy the urgent need for site-selectively deuterated organic frameworks. Deuteration has been primarily used to study kinetic isotope effects of reactions but recently its significance in pharmaceutical chemistry has been discovered. Deuterium labelled compounds have stolen the limelight since the inception of the first FDA-approved deuterated drug, for the treatment of chorea-associated Huntington's disease, and their pharmacological importance was realised by chemists, although surprisingly very late. Various approaches were developed to carry out site-selective deuteration. However, the most common and efficient method is hydrogen isotope exchange (HIE). This review summarises deuteration methods of various organic motifs containing C(sp2)-H and C(sp3)-H bonds utilizing C-H bond functionalisation as a key step along with a variety of catalysts, and exemplifies their biological relevance.

C-H deuteration of organic compounds and potential drug candidates.

Agro-waste to sustainable energy: A green strategy of converting agricultural waste to nano-enabled energy applications.

Herein, a facile and general electroreductive deuteration of unactivated alkyl halides (X = Cl, Br, I) or pseudo-halides (X = OMs) using D2O as the economical deuterium source was reported. In addition to primary and secondary alkyl halides, sterically hindered tertiary chlorides also work very well, affording the target deuterodehalogenated products with excellent efficiency and deuterium incorporation. More than 60 examples are provided, including late-stage dehalogenative deuteration of natural products, pharmaceuticals, and their derivatives, all with excellent deuterium incorporation (up to 99% D), demonstrating the potential utility of the developed method in organic synthesis. Furthermore, the method does not require external catalysts and tolerates high current, showing possible use in industrial applications. 

/pdf/facile-and-general-electrochemical-deuteration-of-2zx3yc34.pdf

Facile and general electrochemical deuteration of unactivated alkyl halides

Aliphatic allylic amines are found in a great variety of complex and biorelevant molecules. The direct allylic C–H amination of alkenes serves as the most straightforward method toward these motifs. However, use of widely available internal alkenes with aliphatic amines in this transformation remains a synthetic challenge. In particular, palladium catalysis faces the twin challenges of inefficient coordination of Pd(II) to internal alkenes but excessively tight and therefore inhibitory coordination of Pd(II) by basic aliphatic amines. We report a general solution to these problems. The developed protocol, in contrast to a classical Pd(II/0) scenario, operates through a blue light–induced Pd(0/I/II) manifold with mild aryl bromide oxidant. This open-shell approach also enables enantio- and diastereoselective allylic C–H amination. Description Illuminating C–N bond formation Forming carbon–nitrogen (C–N) bonds is integral to pharmaceutical synthesis. Palladium (Pd) catalysis is an especially efficient means to this end, but alkyl amines can deactivate the catalyst by tight binding. Several recent approaches to circumventing this problem in allylic amination have focused on modifying either the amines or the Pd coordination environment. Cheung et al. report a distinct protocol that operates through photoinduced electron transfer to form versatile Pd(I) intermediates. This method is also compatible with more densely substituted carbon frameworks and can selectively produce just one of two mirror image products. —JSY Photoexcitation promotes palladium-catalyzed C–N bond formation between internal alkenes and aliphatic amines.

Asymmetric intermolecular allylic C–H amination of alkenes with aliphatic amines

The development of efficient and sustainable methods for decarboxylative transformations is of great importance due to the ease of availability and nontoxicity of carboxylic acids. Despite tremendous efforts in this area, it remains challenging to develop enantioselective transformations direct from carboxylic acids. Herein we disclose a photoelectrocatalytic method for the direct and enantioselective decarboxylative cyanation. The photoelectrochemical reactions convert carboxylic acids to enantioenriched nitriles by employing cerium/copper relay catalysis with a cerium salt for catalytic decarboxylation and a chiral copper complex for stereoselective C-CN formation.

Photoelectrochemical Asymmetric Catalysis Enables Direct and Enantioselective Decarboxylative Cyanation.

Isotope labelling, particularly deuteration, is an important tool for the development of new drugs, specifically for identification and quantification of metabolites. For this purpose, many efficient methodologies have been developed that allow for the small-scale synthesis of selectively deuterated compounds. Due to the development of deuterated compounds as active drug ingredients, there is a growing interest in scalable methods for deuteration. The development of methodologies for large-scale deuterium labelling in industrial settings requires technologies that are reliable, robust and scalable. Here we show that a nanostructured iron catalyst, prepared by combining cellulose with abundant iron salts, permits the selective deuteration of (hetero)arenes including anilines, phenols, indoles and other heterocycles, using inexpensive D2O under hydrogen pressure. This methodology represents an easily scalable deuteration (demonstrated by the synthesis of deuterium-containing products on the kilogram scale) and the air- and water-stable catalyst enables efficient labelling in a straightforward manner with high quality control. 

/pdf/scalable-and-selective-deuteration-of-hetero-arenes-3fgocdpy.pdf

Scalable and selective deuteration of (hetero)arenes

Selective cleavage and functionalization of C-C bonds in alcohols is gaining increasing interest in organic synthesis and biomass conversion. In particular, the development of redox-neutral catalytic methods with cheap catalysts and clean energy is of utmost interest. In this work, we report a versatile redox-neutral method for the ring-opening functionalization of cycloalkanols by electrophotochemical (EPC) cerium (Ce) catalysis. The EPC-Ce-enabled catalysis allows for cycloalkanols with different ring sizes to be cleaved while tolerating a broad range of functional groups. Notably, in the presence of chloride as a counteranion and electrolyte, this protocol selectively leads to the formation of C-CN, C-C, C-S, or C-oxime bonds instead of a C-halide bond after β-scission. A preliminary mechanistic investigation indicates that the redox-active Ce catalyst can be tuned by electro-oxidation and photo-reduction, thus avoiding the use of an external oxidant. Spectroscopic characterizations (cyclic voltammetry, UV-vis, electron paramagnetic resonance, and X-ray absorption fine structure) suggest a Ce(III)/Ce(IV) catalytic pathway for this transformation, in which a Ce(IV)-alkoxide is involved.

Electrophotochemical Ce-Catalyzed Ring-Opening Functionalization of Cycloalkanols under Redox-Neutral Conditions: Scope and Mechanism.

Oxidation-induced strategy for inert chemical bond activation through highly active radical cation intermediate has exhibited unique reactivity. Understanding the structure and reactivity patterns of radical cation intermediates is crucial in the mechanistic study and will be beneficial for developing new reactions. In this work, the structure and properties of indole radical cations have been revealed using time-resolved transient absorption spectroscopy, in situ electrochemical UV-vis, and in situ electrochemical electron paramagnetic resonance (EPR) technique. Density functional theory (DFT) calculations were used to explain and predict the regioselectivity of several electrochemical oxidative indole annulations. Based on the understanding of the inherent properties of several indole radical cations, two different regioselective annulations of indoles have been successfully developed under electrochemical oxidation conditions. Varieties of furo[2,3-b]indolines and furo[3,2-b]indolines were synthesized in good yields with high regioselectivities. Our mechanistic insights into indole radical cations will promote the further development of oxidation-induced indole functionalizations.

Unraveling the Structure and Reactivity Patterns of the Indole Radical Cation in Regioselective Electrochemical Oxidative Annulations.

Aliphatic allylamines are widely used for the synthesis of diverse building blocks for agrochemicals and pharmaceuticals; there is therefore considerable interest in developing versatile and direct routes to aliphatic allylamines using common chemical feedstocks—olefins and amines. However, examples of such coupling reactions remain limited. It is even more challenging to achieve this goal with precise site control. Here we report that the combination of a photocatalyst and cobaloxime enables site-selective amination of olefins with secondary alkyl amines to afford allylic amines, eliminating the need for oxidants. This method is compatible with a broad scope of olefins and can be extended to achieve a site- and diastereoselective amination of terpenes. Mechanistic studies disclose that the reaction proceeds via a cobaloxime-promoted hydrogen atom transfer pathway to afford the product that results from cleavage of the stronger, primary allylic C–H bonds over other weaker allylic C–H bond options. Allylic amination of unactivated alkenes with aliphatic amines is a long-standing synthetic challenge in organic chemistry. This is now accomplished in an oxidant-free, site-selective process by using a combination of a photocatalyst and cobalt complex for the coupling of olefins and alkyl amines with hydrogen evolution. 

/pdf/site-selective-amination-towards-tertiary-aliphatic-2t3cb9o1.pdf

Site-selective amination towards tertiary aliphatic allylamines

A multicomponent sulfonylarylation reaction via cobalt-catalyzed alkene difunctionalizations with sulfonyl chlorides and OPiv-supported organozinc reagents was reported. Herein, anion-coordination played a critical role in the chemical property modification of organozinc reagents. Changing the anions of organozincs from halides (Cl, Br, and I) to pivalate (OPiv) resulted in a very different reactivity. OPiv-supported organozinc reagents steered the success of cobalt-catalyzed carbosulfonylation of alkenes, while halide-supported organozincs preferred to direct sulfonylation. Detailed mechanistic studies demonstrated that the OPiv-coordination results in lower reducibility of arylzinc pivalates, thereby enabling the in situ formation of catalytically relevant Co(I) species as the active catalyst. Density functional theory calculations suggested that the carbosulfonylation of alkenes involves a Co(I/II/I) manifold. Hence, ubiquitous sulfonyl chlorides, readily accessible alkenes, 1,3-dienes, and polyfunctionalized organozinc pivalates successfully underwent a regio- and stereoselective carbosulfonylation process through a radical relay pathway, thus realizing sequential functional group installation on both sides of the double bond. 

Anion-Tuning of Organozincs Steering Cobalt-Catalyzed Radical Relay Couplings

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