As an alternative to iridium catalysts, a procedure to access and employ a more earth-adundant Mn2(CO)10-derived pincer complex was successfully demonstrated in the synthesis of a complex pharmaceutically relevant ketone from milligram to 500g scales. Mechanistic studies revealed that the dissociation of CO driven by light is a critical step in forming the active catalyst. This robust and mechanistically informed method reliably promotes hydrogen autotransfer of alcohols, catalyzing a diverse array of C-C and C-N bond formations. This emphasizes the importance of precatalyst selection and understanding catalyst activation to enable rapid and successful uptake of novel methods in sustainable catalysis.

Organic electrosynthesis opens novel routes for pharmaceutical production; however, limited knowledge and experience with the scale up of this technique have hindered its industrial implementation. In this work, we report a kilogram-scale flow electrochemical Ni-catalyzed cross-electrophile coupling (XEC) to prepare a key intermediate in the synthesis of the toll-like receptor (TLR) 7/8 inhibitor afimetoran. We successfully demonstrate scalability across 2 orders of magnitude while maintaining reaction performance. We also conduct a continuous 120 h reaction, highlighting compatibility with industrially relevant time scales. Key design aspects of our custom parallel-plate reactor are discussed that enabled kilogram-scale synthesis with a single electrode stack. This report showcases that with proper reaction engineering, electrochemical Ni-catalyzed XEC is a viable alternative to existing Pd-catalyzed cross-coupling methods.

N,N,N′,N′ -Tetramethylchloroformamidinium hexafluorophosphate and N-methylimidazole (TCFH-NMI), a reagent combination for acylation reactions first described in 2018, is gaining recognition and finding applications from research laboratories through to large-scale manufacturing. In this review, we will detail the unique properties of this method for amide bond formation before discussing its extension into the synthesis of esters, ketones, and other functional group transformations. The high reactivity of the N-acyl imidazolium ion, the unique activated ester intermediate accessible by this method, provides for a broad substrate scope under mild conditions. In combination with the favorable safety characteristics of these reagents and ease of isolation provided by the simple water-soluble byproducts, TCFH-NMI should prove an impactful addition to the organic chemists’ toolbox alongside more commonly used amide bond-forming reagents.

The two-proton/two-electron electrochemical reduction of a phosphine oxide with elimination of water as the sole byproduct (P(V)=O + 2H+ + 2e- → P(III) + H2O) is reported. Under electrochemical (constant current electrolysis) conditions, reduction of 5-phenylphospholo[3,2-c:4,5-c']dipyridine P-oxide (1 O ) in the presence of a proton donor gives the corresponding phosphine (1) in up to 90% yield and 95% conversion. Electrokinetic data and simulations are consistent with an E r C i E r C i mechanism, in which an initial one-electron reduction brings about rate-limiting protonation of the phosphoryl bond. A regioisomeric phosphine oxide (9-phenylphospholo[2,3-c:5,4-c']dipyridine P-oxide, 2 O ) shows reversible electron transfer (ET) behavior but does not lead to proton-coupled electron transfer (PCET) P=O reduction. These results introduce the electronic design of π-substituents as a tunable mode by which to access previously challenging proton-coupled reduction of the strong P=O bond.

The application of chemical transformations to substrates that surpass the scope of the original method for either steric or electronic reasons can often lead to failure. The chances of succeeding in reoptimizing that method can vary and are increased when the existing method is well-defined in terms of critical parameters and mechanism. As part of efforts to develop a sustainable and scalable synthesis of a functionalized indole intermediate en route to the TLR7/8 antagonist afimetoran, reoptimization of a previously developed (phenoxyimine)nickel-catalyzed C(sp2)-C(sp3) Suzuki-Miyaura coupling led to conditions which presented significant advantages over the alternatives in terms of purity and yield. When combined with a nickel-catalyzed borylation, a streamlined two-step telescope was demonstrated which shows the potential for successful and rapid extension of existing methodologies to challenging substrates when starting reoptimization from a mechanistically well-defined starting point.

Organic electrosynthesis opens new avenues of reactivity and promises more sustainable practices in the preparation of fine chemicals and pharmaceuticals. The full value of this approach will be realized by taking these processes to the production scale; however, achieving this goal will require a better understanding of the influence of mass transport on reaction behavior and the interactions between reactive species and electrodes inherent to organic electrosynthesis. The limited options for cell geometries used on small scale limit elucidation of these features. Here, we show how advanced cell geometries allow us to control the interplay between reaction mechanism and mass transport, leading to improved performance of three modern organic electrosynthetic reactions. Each reaction shows a unique relationship with mass transport, highlighting the importance of understanding this relationship further to maximize the utility of organic electrosynthesis at scale.

Sacrificial anodes composed of inexpensive metals such as Zn, Fe, and Mg are widely used to support electrochemical nickel-catalyzed cross-electrophile coupling (XEC) reactions, in addition to other reductive electrochemical transformations. Such anodes are appealing because they provide a stable counter-electrode potential and typically avoid interference with the reductive chemistry. The present study outlines the development of an electrochemical Ni-catalyzed XEC reaction that streamlines access to a key pharmaceutical intermediate. Metal ions derived from sacrificial anode oxidation, however, directly contribute to homocoupling and proto-dehalogenation side products that are commonly formed in chemical and electrochemical Ni-catalyzed XEC reactions. Use of a divided cell limits interference by the anode-derived metal ions and supports a high product yield with negligible side product formation, introducing a strategy to overcome one of the main limitations of Ni-catalyzed XEC.

Over the last fifty years, the use of nickel catalysts for facilitating organic transformations has skyrocketed. Ni(0) sources act as useful precatalysts because they can enter a catalytic cycle through ligand exchange, without needing to undergo additional elementary steps. However, most Ni(0) precatalysts are synthesized with stoichiometric aluminum–hydride reductants, pyrophoric reagents that are not atom-economical and must be used at cryogenic temperatures. Here, we demonstrate that Ni(II) salts can be reduced on preparative scale using electrolysis to yield a variety of Ni(0) and Ni(II) complexes that are widely used as precatalysts in organic synthesis, including bis(1,5-cyclooctadiene)nickel(0) [Ni(COD)2]. This method overcomes the reproducibility issues of previously reported methods by standardizing the procedure, such that it can be performed anywhere in a robust manner. It can be easily transitioned to large scale through an electrochemical recirculating flow process. We anticipate that this work will accelerate adoption of preparative electrochemistry for the synthesis of low-valent organometallic complexes in academia and industry.

N,N,N',N'-Tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI) enable the facile and practical reaction of carboxylic acids with amines, alcohols, and thiols to form amides, esters, and thioesters. To develop a mild synthesis of ketones with TCFH-NMI directly from carboxylic acids at room temperature, the Mayr nucleophilicity scale was used to compare the N values of competent nucleophiles to potential carbon-centered nucleophiles, identifying pyrroles and indoles as successful substrates when N ≥ 10.

BMS-986020 was developed as an antagonist of the LPA1 receptor for the treatment of lung fibrosis (Idiopathic Pulmonary Fibrosis (IPF)). During the development of BMS-986020, a high percentage byproduct was observed in the mother liquor of a Curtius rearrangement reaction. The structure identification and formation mechanism of this unknown byproduct was deemed necessary to understand for further the reaction optimization and knowledge generation for the project. The characterization process required a multifaceted approach utilizing LC-HRMS, VT-NMR, and HPLC isolation. The investigation’s final result implicated the reaction base as the root cause of the byproduct formation and indicated a nitrene-iminium reaction pathway to form the byproduct.

Cyclopropanes are a common motif in many pharmaceutically relevant compounds, and methods for the synthesis of these strained rings have relevance throughout the pharmaceutical development process. Among the many options, the Corey- Chaykovsky cyclopropanation stands out due to its broad substrate scope, high functional group tolerance, and mild conditions. Despite these benefits, its application to the synthesis of cyclopropanes, specifically in the context of large-scale syntheses, has been limited. In this review, the scope and limitations of the Bronsted-base-promoted Corey-Chaykovsky cyclopropanation with sulfur ylides will be examined. Through this discussion, gaps in the scope and understanding of the transformation will be highlighted to promote further application and advancement of this powerful and useful methodology.

In response to an increased awareness of sensitization issues with amide bond forming agents, a detailed toxicological analysis of this broad family of reagents was undertaken which led to a quantitative ranking of the sensitization potential of these commonly used compounds. This data enables occupational toxicologists to guide the safer use of these reagents in the laboratory, but it also provides an opportunity for chemists working on reaction development, optimization and scale-up. To illustrate this, one of the strongest sensitizers, EDAC, is compared with the performance of one of the weakest, TCFH, showing the potential of this data for minimizing risks for researchers when using this family of reagents. image

A method for deoxyfluorination of aliphatic primary, secondary, and tertiary alcohols is reported, employing a nontrigonal phosphorus triamide for base-free alcohol activation in conjunction with an organic soluble fluoride donor and a triarylborane fluoride shuttling catalyst. Mechanistic experiments are consistent with a reaction that proceeds by the collapse of an oxyphosphonium fluoroborate ion pair with fluoride transfer. The substrate scope complements existing deoxyfluorination methods and enables the preparation of homochiral secondary and tertiary alkylfluorides by stereoinversion of the substrate alcohol.

In this Communication, an investigation of the combination of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI) for the synthesis of esters and thioesters is described. This work revealed the unique challenges of the reactions of less nucleophilic alcohols and more reactive thiols with the N-acyl imidazolium intermediate and led to the identification of general enabling conditions that provide high yields and selectivity for a range of alcohols and thiols.

ADVERTISEMENT RETURN TO ISSUEEditor's PageNEXTAdvances and Applications in Catalysis with Earth-Abundant MetalsKatherine M. P. Wheelhouse*Katherine M. P. WheelhouseDrug Substance Development, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.Chemical Process Development, Bristol Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States*Email for K.W.: [email protected]More by Katherine M. P. Wheelhousehttps://orcid.org/0000-0002-1963-1465, Ruth L. Webster*Ruth L. WebsterDrug Substance Development, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.Chemical Process Development, Bristol Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States*Email for R.W.: [email protected]More by Ruth L. Websterhttps://orcid.org/0000-0001-9199-7579, and Gregory L. Beutner*Gregory L. BeutnerDrug Substance Development, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.Chemical Process Development, Bristol Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States*Email for G.L.B.: [email protected]More by Gregory L. Beutnerhttps://orcid.org/0000-0001-8779-1404Cite this: Organometallics 2023, 42, 14, 1677–1679Publication Date (Web):July 24, 2023Publication History Received28 June 2023Published online24 July 2023Published inissue 24 July 2023https://pubs.acs.org/doi/10.1021/acs.organomet.3c00292https://doi.org/10.1021/acs.organomet.3c00292editorialACS PublicationsCopyright © Published 2023 by American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1493Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (1 MB) Get e-AlertscloseSUBJECTS:Catalysis,Catalysts,Chemical structure,Elements,Metals Get e-Alerts

Having robust and reliable methods for monitoring catalyst activation processes is an important part of ensuring the reproducibility of a catalytic reaction. For asymmetric Diels–Alder reactions, chiral oxazaborolidine or oxazaborolidinium catalysts are powerful reagents that promote these reactions in high yield and selectivity. Supported by mechanistic findings, several modern analytical methods are compared for quantitating the oxazaborolidine catalyst formation from amino alcohol and boroxine to arrive at useful monitoring methods for this important transformation.

A new undergraduate organic laboratory experiment has been developed for amide bond formation between biorenewable 2-furoic acid and either of two substituted piperazines to prepare medicinally relevant amide products using a procedure with industrial significance. The reactions proceeded smoothly under ambient conditions using the combination of N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) and N-methylimidazole (NMI) in a minimal volume of acetonitrile with a direct crystallization upon addition of water. Students successfully collected their product by filtration and then characterized it by NMR (1H, 13C, COSY, DEPT-135, HSQC), IR, MS, and melting point. Students also explored the reaction mechanism and compared green chemistry aspects of their procedure with literature routes. A virtual version of the experiment was adapted for remote instruction.

Peptide couplers (also known as amide bond-forming reagents or coupling reagents) are broadly used in organic chemical syntheses, especially in the pharmaceutical industry. Yet, occupational health hazards associated with this chemical class are largely unexplored, which is disconcerting given the intrinsic reactivity of these compounds. Several case studies involving occupational exposures reported adverse respiratory and dermal health effects, providing initial evidence of chemical sensitization. To address the paucity of toxicological data, a pharmaceutical cross-industry task force was formed to evaluate and assess the potential of these compounds to cause eye and dermal irritation as well as corrosivity and dermal sensitization. The goal of our work was to inform health and safety professionals as well as pharmaceutical and organic chemists of the occupational health hazards associated with this chemical class. To that end, 25 of the most commonly used peptide couplers and five hydrolysis products were selected for in vivo, in vitro, and in silico testing. Our findings confirmed that dermal sensitization is a concern for this chemical class with 21/25 peptide couplers testing positive for dermal sensitization and 15 of these being strong/extreme sensitizers. We also found that dermal corrosion and irritation (8/25) as well as eye irritation (9/25) were health hazards associated with peptide couplers and their hydrolysis products (4/5 were dermal irritants or corrosive and 4/5 were eye irritants). Resulting outcomes were synthesized to inform decision making in peptide coupler selection and enable data-driven hazard communication to workers. The latter includes harmonized hazard classifications, appropriate handling recommendations, and accurate safety data sheets, which support the industrial hygiene hierarchy of control strategies and risk assessment. Our study demonstrates the merits of an integrated, in vivo -in silico analysis, applied here to the skin sensitization endpoint using the Computer-Aided Discovery and REdesign (CADRE) and Derek Nexus programs. We show that experimental data can improve predictive models by filling existing data gaps while, concurrently, providing computational insights into key initiating events and elucidating the chemical structural features contributing to adverse health effects. This interactive, interdisciplinary approach is consistent with Green Chemistry principles that seek to improve the selection and design of less hazardous reagents in industrial processes and applications.

As sp2-sp3 disconnections gain acceptance in the medicinal chemist's toolbox, an increasing number of potential drug candidates containing this motif are moving into the pharmaceutical development pipeline. This raises a new set of questions and challenges around the novel, direct methodologies available for forging these bonds. These questions gain further importance in the context of process chemistry, where the focus is the development of scalable processes that enable the large-scale delivery of clinical supplies. In this paper, we describe our efforts to apply a wide variety of standard, photo-, and electrochemical sp2-sp3 cross-coupling methods to a pharmaceutically relevant intermediate and optimize each through a combination of high throughput and mechanistically guided experimentation. With data regarding the performance, benefits, and limitations of these novel methods, we evaluate them against a more traditional two-step palladium-catalyzed process. This work reveals trends and similarities between these sp2-sp3 bond-forming methods and suggests a path forward for further refinements.