The electrochemical hydrogenation of enones and alkenes using commercial nickel foam and an aqueous acidic solution is presented. The reaction shows excellent selectivity in CC vs. CO reduction, with enhanced activity when using 7% of nBuOH as cosolvent. The method presents good applicability and recyclability properties, with more than 30 different substrates explored, and it can be recycled at least 15 times. Toxicological and screening life cycle assessments were used to identify potential “hotspots” of environmental and human health impact during the development phase of the method, as well as to evaluate the performance of the electrochemical nickel method against the conventional use of Pd/C and H₂ gas.

The synthesis of strained carbocyclic building blocks is relevant for Medicinal Chemistry, and methylenecyclobutanes are particularly challenging with current synthetic technology. Careful inspection of the reactivity of [1.1.1]propellane and diboron reagents has revealed that bis(catecholato)diboron (B2cat2) can produce a bis(borylated) methylenecyclobutane in a few minutes at room temperature. This reaction constitutes the first example of B−B bond activation by a special apolar hydrocarbon and also the first time that propellane is electrophilically activated by boron. Mechanistic studies including in situ NMR kinetics and DFT calculations demonstrate that the diboron moiety can be directly activated through coordination with the inverted sigma bond of propellane, and reveal that DMF is involved in the stabilization of diboronate ylide intermediates rather than the activation of the B−B bond. These results enable new possibilities for both diboron and propellane chemistry, and for further developments in the synthesis of methylenecyclobutanes based on propellane strain release.

Electrochemistry has emerged as an increasingly viable tool in molecular synthesis. Here the authors realize electrocatalyzed C-H activations, with the aid of data science and artificial intelligence, towards selective alkenylations for late-stage drug diversifications. Electrooxidation has emerged as an increasingly viable platform in molecular syntheses that can avoid stoichiometric chemical redox agents. Despite major progress in electrochemical C-H activations, these arene functionalizations generally require directing groups to enable the C-H activation. The installation and removal of these directing groups call for additional synthesis steps, which jeopardizes the inherent efficacy of the electrochemical C-H activation approach, leading to undesired waste with reduced step and atom economy. In sharp contrast, herein we present palladium-electrochemical C-H olefinations of simple arenes devoid of exogenous directing groups. The robust electrocatalysis protocol proved amenable to a wide range of both electron-rich and electron-deficient arenes under exceedingly mild reaction conditions, avoiding chemical oxidants. This study points to an interesting approach of two electrochemical transformations for the success of outstanding levels of position-selectivities in direct olefinations of electron-rich anisoles. A physical organic parameter-based machine learning model was developed to predict position-selectivity in electrochemical C-H olefinations. Furthermore, late-stage functionalizations set the stage for the direct C-H olefinations of structurally complex pharmaceutically relevant compounds, thereby avoiding protection and directing group manipulations.

The borylation of aryl and heteroaryl C–H bonds is valuable for the site-selective functionalization of C–H bonds in complex molecules. Iridium catalysts ligated by bipyridine ligands catalyze the borylation of the C–H bond that is most acidic and least sterically hindered in an arene, but predicting the site of borylation in molecules containing multiple arenes is difficult. To address this challenge, we report a hybrid computational model that predicts the Site of Borylation (SoBo) in complex molecules. The SoBo model combines density functional theory, semiempirical quantum mechanics, cheminformatics, linear regression, and machine learning to predict site selectivity and to extrapolate these predictions to new chemical space. Experimental validation of SoBo showed that the model predicts the major site of borylation of pharmaceutical intermediates with higher accuracy than prior machine-learning models or human experts, demonstrating that SoBo will be useful to guide experiments for the borylation of specific C(sp²)–H bonds during pharmaceutical development.

Introducing amide functional groups under mild conditions has growing importance owing to the prevalence of such moiety in biologically active molecules. Herein, we disclose a mild protocol for the directed ruthenium-catalyzed C−H aminocarbonylation with isocyanates as the amidating agents developed through high-throughput experimentation (HTE). The redox-neutral and base-free reaction is guided by weakly Lewis basic functional groups, including anilides, lactams and carbamates to access anthranilamide derivatives. The synthetic utility of this transformation is reflected by large-scale synthesis and late-stage functionalization.

Selective reduction strategies based on abundant-metal catalysts are very important in the production of chemicals. In this paper, a method for the electrochemical semihydrogenation and semideuteration of alkynes to form Z-alkenes was developed, using a simple nickel foam as catalyst and H₃O⁺ or D₃O⁺ as sources of hydrogen or deuterium. Good yields and excellent stereoselectivities (Z/E up to 20 : 1) were obtained under very mild reaction conditions. The reaction proceeded with terminal and nonterminal alkynes, and also with alkynes containing easily reducible functional groups, such as carbonyl groups, as well as aryl chlorides, bromides, and even iodides. The nickel-foam electrocatalyst could be recycled up to 14 times without any change in its catalytic properties. 

H₂O₂-driven enzymes are of great interest for industrial biotransformations. Herein, we show for the first time that oxalate oxidase (OXO) is an efficient in situ source of H₂O₂ for one of these biocatalysts, which is known as unspecific peroxygenase (UPO). OXO is reasonably robust, produces only CO₂ as a by-product and uses oxalate as a cheap sacrificial electron donor. UPO has significant potential as an industrial catalyst for selective C−H oxyfunctionalisations, as we confirm herein by testing a diverse drug panel using miniaturised high-throughput assays and mass spectrometry. 33 out of 64 drugs were converted in 5 μL-scale reactions by the UPO with OXO (conversion >70 % for 11 drugs). Furthermore, oxidation of the drug tolmetin was achieved on a 50 mg scale (TON_UPO 25 664) with 84 % yield, which was further improved via enzyme immobilization. This one-pot approach ensures adequate H₂O₂ levels, enabling rapid access to industrially relevant molecules that are difficult to obtain by other routes. 

Over the past decade, the landscape of molecular synthesis has gained major impetus by the introduction of late-stage functionalization (LSF) methodologies. C-H functionalization approaches, particularly, set the stage for new retrosynthetic disconnections, while leading to improvements in resource economy. A variety of innovative techniques have been successfully applied to the C-H diversification of pharmaceuticals, and these key developments have enabled medicinal chemists to integrate LSF strategies in their drug discovery programmes. This Review highlights the significant advances achieved in the late-stage C-H functionalization of drugs and drug-like compounds, and showcases how the implementation of these modern strategies allows increased efficiency in the drug discovery process. Representative examples are examined and classified by mechanistic patterns involving directed or innate C-H functionalization, as well as emerging reaction manifolds, such as electrosynthesis and biocatalysis, among others. Structurally complex bioactive entities beyond small molecules are also covered, including diversification in the new modalities sphere. The challenges and limitations of current LSF methods are critically assessed, and avenues for future improvements of this rapidly expanding field are discussed. We, hereby, aim to provide a toolbox for chemists in academia as well as industrial practitioners, and introduce guiding principles for the application of LSF strategies to access new molecules of interest.