Showing papers on "Nucleophile published in 2022"

Decarboxylative cross-nucleophile coupling via ligand-to-metal charge transfer photoexcitation of Cu(ii) carboxylates

Abstract: Reactions that enable carbon-nitrogen, carbon-oxygen and carbon-carbon bond formation lie at the heart of synthetic chemistry. However, substrate prefunctionalization is often needed to effect such transformations without forcing reaction conditions. The development of direct coupling methods for abundant feedstock chemicals is therefore highly desirable for the rapid construction of complex molecular scaffolds. Here we report a copper-mediated, net-oxidative decarboxylative coupling of carboxylic acids with diverse nucleophiles under visible-light irradiation. Preliminary mechanistic studies suggest that the relevant chromophore in this reaction is a Cu(II) carboxylate species assembled in situ. We propose that visible-light excitation to a ligand-to-metal charge transfer (LMCT) state results in a radical decarboxylation process that initiates the oxidative cross-coupling. The reaction is applicable to a wide variety of coupling partners, including complex drug molecules, suggesting that this strategy for cross-nucleophile coupling would facilitate rapid compound library synthesis for the discovery of new pharmaceutical agents.

Asymmetric Catalytic Rearrangements with α-Diazocarbonyl Compounds.

Abstract: Conspectusα-Diazocarbonyl compounds serve as nucleophiles, dipoles, carbene precursors, and rare electrophiles, enabling a vast array of organic transformations under the influence of metal catalysts. Among them, rearrangement processes are attractive and provide straightforward and efficient accesses to one-carbon extension adducts or heteroatom-containing molecules. The reactions occur upon the release of dinitrogen after nucleophilic addition or before ylide formation. Although significant progress has been made for these two types of rearrangement reactions, the issue of enantiocontrol is challenging because the final optically enriched products are generated via multistep transformations and the inherent spacial arrangement of the intermediates has more or less influence on the regio- and enantioselectivity.In this Account, we collected several rearrangements of α-diazocarbonyl compounds, showcasing the efficient catalysts and tailored strategies for tackling enantioselective varieties of these two types of rearrangement reactions. Our research group initiated the catalytic asymmetric reactions of α-diazocarbonyl compounds during the development of chiral Feng N,N'-dioxide-metal complex catalysts and others. As a kind of useful chiral Lewis acid catalyst chiral N,N'-dioxide-metal complexes are favorable for the activation of various carbonyl compounds, accelerating the diastereo- and enantioselective nucleophilic addition of α-diazoesters and the sequential rearrangements in either an intermolecular or intramolecular manner. Aldehydes, acyclic and cyclic ketone derivatives, and α,β-unsaturated ketones could participate in efficient asymmetric homologation reactions, and an obvious ligand-acceleration effect is observed in these processes. For example, the Roskamp-Feng reaction of aldehydes gives optically active β-ketoesters through a H-shift, overwhelming the aryl group shift or oxygen attack. The shift preference and enantiocontrol in the homologation of acyclic and cyclic ketone derivatives could be under excellent control of the chiral catalysts. An unusual electrophilic α-amination of aryl/alkyl ketones and even a complicated homologation/dyotropic rearrangement/interconversion/[3 + 2] cycloaddition cascade used to construct dimeric polycyclic compounds were discovered as a result of the selection of chiral ligands and additives. On the basis of the understanding of the interaction of the functional group with N,N'-dioxide-metal complexes in catalysis and the key enantio-determining issues in ylide-based rearrangements, we designed new α-diazocarbonyl compounds by introducing a pyrazole-1-carboxyl group as the acceptor unit, which could benefit the formation of both carbenoid species and the chiral catalyst-bound ylides to deliver stereoselectivity. Taking advantage of Ni(II) or Co(II) complexes of Feng N,N'-dioxide ligands, we realized several kinds of enantioselective [2,3]-sigmatropic rearrangements, such as the Doyle-Kirmse reaction with allylic sulfides or selenides, [2,3]-Stevens rearrangements of vinyl-substituted α-diazo pyrazoleamides with thioacetates, Sommelet-Hauser rearrangements of aryl-substituted α-diazo pyrazoleamides with thioamides, and thio-Claisen rearrangements of 2-thio-indoles as well. Moreover, this strategy was shown to be applicable to highly γ-selective and enantioselective insertion into N-H bonds of secondary amines with vinyl-substituted α-diazo pyrazoleamides.

Electrochemically driven cross-electrophile coupling of alkyl halides

Abstract: Recent research in medicinal chemistry has suggested that there is a correlation between an increase in the fraction of sp3 carbons-those bonded to four other atoms-in drug candidates and their improved success rate in clinical trials1. As such, the development of robust and selective methods for the construction of carbon(sp3)-carbon(sp3) bonds remains a critical problem in modern organic chemistry2. Owing to the broad availability of alkyl halides, their direct cross-coupling-commonly known as cross-electrophile coupling-provides a promising route towards this objective3-5. Such transformations circumvent the preparation of carbon nucleophiles used in traditional cross-coupling reactions, as well as stability and functional-group-tolerance issues that are usually associated with these reagents. However, achieving high selectivity in carbon(sp3)-carbon(sp3) cross-electrophile coupling remains a largely unmet challenge. Here we use electrochemistry to achieve the differential activation of alkyl halides by exploiting their disparate electronic and steric properties. Specifically, the selective cathodic reduction of a more substituted alkyl halide gives rise to a carbanion, which undergoes preferential coupling with a less substituted alkyl halide via bimolecular nucleophilic substitution to forge a new carbon-carbon bond. This protocol enables efficient cross-electrophile coupling of a variety of functionalized and unactivated alkyl electrophiles in the absence of a transition metal catalyst, and shows improved chemoselectivity compared with existing methods.

Designing Electrophilic and Nucleophilic Dual Centers in the ReS2 Plane toward Efficient Bifunctional Catalysts for Li-CO2 Batteries.

Abstract: Two-dimensional transition metal dichalcogenides (TMDCs) show great potential as efficient catalysts for Li-CO2 batteries. However, the basal plane engineering on TMDCs toward bifunctional catalysts for Li-CO2 batteries is still poorly understood. In this work, density functional theory calculations reveal that nucleophilic N dopants and electrophilic S vacancies in the ReS2 plane tailor the interactions with Li atoms and C/O atoms in intermediates, respectively. The electrophilic and nucleophilic dual centers show suitable adsorption with all intermediates during discharge and charge, resulting in a small energy barrier for the rate-determining step. Thus, an efficient bifunctional catalyst is produced toward Li-CO2 batteries. As a result, the optimal catalyst achieves an ultrasmall voltage gap of 0.66 V and an ultrahigh energy efficiency of 81.1% at 20 μA cm-2, which is superior to those of previous catalysts under similar conditions. The introduction of electrophilic and nucleophilic dual centers provides new avenues for designing excellent bifunctional catalysts for Li-CO2 batteries.

Direct decarboxylative Giese reactions.

Abstract: The quest to find milder and more sustainable methods to generate highly reactive, carbon-centred intermediates has led to a resurgence of interest in radical chemistry. In particular, carboxylic acids are seen as attractive radical precursors due their availability, low cost, diversity, and sustainability. Moreover, the corresponding nucleophilic carbon-radical can be easily accessed through a favourable radical decarboxylation process, extruding CO2 as a traceless by-product. This review summarizes the recent progress on using carboxylic acids directly as convenient radical precursors for the formation of carbon-carbon bonds via the 1,4-radical conjugate addition (Giese) reaction.

Intramolecular hydroxyl nucleophilic attack pathway by a polymeric water oxidation catalyst with single cobalt sites

Abstract: Abstract Exploration of efficient water oxidation catalysts (WOCs) is the primary challenge in conversion of renewable energy into fuels. Here we report a molecularly well-defined heterogeneous WOC with Aza-fused, π-conjugated, microporous polymer (Aza-CMP) coordinated single cobalt sites (Aza-CMP-Co). The single cobalt sites in Aza-CMP-Co exhibited superior activity under alkaline and near-neutral conditions. Moreover, the molecular nature of the isolated catalytic sites makes Aza-CMP-Co a reliable model for studying the heterogeneous water oxidation mechanism. By a combination of experimental and theoretical results, a pH-dependent nucleophilic attack pathway for O-O bond formation was proposed. Under alkaline conditions, the intramolecular hydroxyl nucleophilic attack (IHNA) process with which the adjacent -OH group nucleophilically attacks Co 4+ =O was identified as the rate-determining step. This process leads to lower activation energy and accelerated kinetics than those of the intermolecular water nucleophilic attack (WNA) pathway. This study provides significant insights into the crucial function of electrolyte pH in water oxidation catalysis and enhancement of water oxidation activity by regulation of the IHNA pathway.

Streamlined Alkylation via Nickel-Hydride-Catalyzed Hydrocarbonation of Alkenes.

Abstract: Compounds rich in sp3-hybridized carbons are desirable in drug discovery. Nickel-catalyzed hydrocarbonation of alkenes is a potentially efficient method to synthesize these compounds. By using abundant, readily available, and stable alkenes as pro-nucleophiles, these reactions can have broad scope and high functional group tolerance. However, this methodology is still in an early stage of development, as the first efficient examples were reported only in 2016. Herein, we summarize the progress of this emerging field, with an emphasis on enantioselective reactions. We highlight major developments, critically discuss a wide range of possible mechanisms, and offer our perspective of the state and challenges of the field. We hope this Perspective will stimulate future works in this area, making the methodology widely applicable in organic synthesis.

Dispersion and Steric Effects on Enantio-/Diastereoselectivities in Synergistic Dual Transition-Metal Catalysis.

Abstract: Comprehensive computational studies were carried out to explore the mechanisms of enantioselective Cu/Pd and stereodivergent Cu/Ir dual-catalytic syntheses of α,α-disubstituted α-amino acids (α-AAs). A chiral copper azomethine ylide undergoes facile α-allylation with racemic π-allylpalladium species or stereopure π-allyliridium complex to stereoconvergently or stereodivergently furnish single/double stereocenters, respectively. Stereoselectivity at the α-center is controlled by the facial selectivity of α-allylation with respect to the prochiral nucleophile. Despite apparently similar transition-state assemblies, computational models and distortion/interaction analyses disclose versatile modes of stereoinduction wherein the copper azomethine ylide species can face-selectively intercept metal-π-allyl intermediates utilizing attractive dispersion interactions and/or sterically caused distortions. Generation of the β-stereocenter in the Cu/Ir system relies on a stereospecifically generated allyliridium complex and electronically controlled branched-to-linear selectivity, while the dual Cu/Pd system yields a linear monochiral product due to steric factors and π-π stacking interactions. The studies demonstrate on a molecular level how ligand-encoded chiral information is transferred to the α-/β-sites of the resulting α-AAs and how the mode of regio-/stereoselection is altered by differences in transition-metal-stabilized coupling partners. To facilitate studies of stereoselective catalysis, a suite of analytical tools to extract controlling factors for asymmetric induction is demonstrated.

Organocatalytic Enantioselective Synthesis of Axially Chiral Molecules: Development of Strategies and Skeletons.

Abstract: ConspectusThe growing importance of axially chiral architectures in different scientific domains has unveiled shortcomings in terms of efficient synthetic access and skeletal variety. This account describes our strategies in answering these challenges within the organocatalytic context where the emergence of bifunctional catalysts such as chiral phosphoric acids (CPAs) has proven invaluable in controlling the sense of axial chirality. The wide occurrence of bi(hetero)aryl skeletons in privileged structures constitutes a strong motivation to devise more effective arylation methods. Our design revolves around modulating the intrinsic nucleophilicity of aromatic amines and alcohols. The first approach involves the design of an electron-withdrawing activating group which could associate with the catalyst for reactivity enhancement and selectivity control. The resonance of arenes offers the unique mechanistic possibility to select between activating sites. C2-Azo- and nitroso-substituted naphthalenes undergo atroposelective ortho C- or N-arylation with (hetero)aromatic nucleophiles. For monocyclic benzenes, programmable charge localization leads to regioselective activation by catalytic control alone or aided by substrate design. For instance, selective addition to nitroso nitrogen enables successive annulation initiated by the amine to yield axially chiral N-arylbenzimidazoles. In a biomimetic manner, a finely tuned catalyst could direct a para-selective nucleophilic approach in the atroposelective arylation of azobenzenes. The second strategy employs electrophilic arene precursors for arylation which occurs via rearomatization with central-to-axial chirality transfer. This enabled the arylation of (imino)quinones with indoles to access phenylindole atropisomers. By adapting this chemistry with an additional oxidation event to liberate the carbonyl functionalities, aryl-o-naphthoquinone and aryl-p-quinone atropisomers were attained. Along with the development of new arylation strategies, deriving new axially chiral structures has been another consistent theme of our research program. The atroposelective functionalization of alkynes provides broad entry to atropisomeric alkenes. The monofunctionalization of alkynes through the interception of an electrophilic vinylidene-quinone-methide (VQM) intermediate with 2-naphthols yielded the new EBINOL scaffolds. By designing an internal directing group, the atroposelective dihalogenation of alkynes was realized using abundant alkali halides despite their weak nucleophilicities and poor solubilities. The atroposelective N-alkylation of alkenes was pursued to prepare multifunctionalized alkene atropisomers that could be converted into 2-arylpyrroles with chirality transfer. The synthesis of B-aryl-1,2-azaborines containing a C-B chiral axis was accomplished where the CPA catalyst effects the desymmetrization and defines the configuration of the distal C-B bond. Inspired by the axially chiral scaffold of allenes, we leveraged the developed arene activation strategy to achieve para-addition and dearomatization of judiciously designed azobenzenes, which led to structurally novel cyclohexadienylidene-based hydrazones. To complement these structures, axially chiral cyclohexadienyl oxime ethers were also attained through CPA-catalyzed condensation between hydroxylamines and spiro[4.5]trienones.

Photoinduced, Copper-Catalyzed Enantioconvergent Alkylations of Anilines by Racemic Tertiary Electrophiles: Synthesis and Mechanism.

Abstract: Transition-metal catalysis of substitution reactions of alkyl electrophiles by nitrogen nucleophiles is beginning to emerge as a powerful strategy for synthesizing higher-order amines, as well as controlling their stereochemistry. Herein, we report that a readily accessible chiral copper catalyst (commercially available components) can achieve the photoinduced, enantioconvergent coupling of a variety of racemic tertiary alkyl electrophiles with aniline nucleophiles to generate a new C-N bond with good ee at the fully substituted stereocenter of the product; whereas this photoinduced, copper-catalyzed coupling proceeds at -78 °C, in the absence of light and catalyst, virtually no C-N bond formation is observed even upon heating to 80 °C. The mechanism of this new catalytic enantioconvergent substitution process has been interrogated with the aid of a wide array of tools, including the independent synthesis of proposed intermediates and reactivity studies, spectroscopic investigations featuring photophysical and EPR data, and DFT calculations. These studies led to the identification of three copper-based intermediates in the proposed catalytic cycle, including a chiral three-coordinate formally copper(II)-anilido (DFT analysis points to its formulation as a copper(I)-anilidyl radical) complex that serves as a persistent radical that couples with a tertiary organic radical to generate the desired C-N bond with good enantioselectivity.

Triazoles and Their Derivatives: Chemistry, Synthesis, and Therapeutic Applications

Abstract: Among the nitrogen-containing heterocyclic compounds, triazoles emerge with superior pharmacological applications. Structurally, there are two types of five-membered triazoles: 1,2,3-triazole and 1,2,4-triazole. Due to the structural characteristics, both 1,2,3- and 1,2,4-triazoles are able to accommodate a broad range of substituents (electrophiles and nucleophiles) around the core structures and pave the way for the construction of diverse novel bioactive molecules. Both the triazoles and their derivatives have significant biological properties including antimicrobial, antiviral, antitubercular, anticancer, anticonvulsant, analgesic, antioxidant, anti-inflammatory, and antidepressant activities. These are also important in organocatalysis, agrochemicals, and materials science. Thus, they have a broad range of therapeutic applications with ever-widening future scope across scientific disciplines. However, adverse events such as hepatotoxicity and hormonal problems lead to a careful revision of the azole family to obtain higher efficacy with minimum side effects. This review focuses on the structural features, synthesis, and notable therapeutic applications of triazoles and related compounds.

Photoassisted Cobalt-Catalyzed Asymmetric Reductive Grignard-Type Addition of Aryl Iodides.

Abstract: Grignard addition is one of the most important methods used for syntheses of alcohol compounds and has been known for over a hundred years. However, research on asymmetric catalysis relies on the use of organometallic nucleophiles. Here, we report the first visible-light-induced cobalt-catalyzed asymmetric reductive Grignard-type addition for synthesizing chiral benzyl alcohols (>50 examples, up to 99% yield, and 99% ee). This methodology has the advantages of mild reaction conditions, good functionality tolerance, excellent enantiocontrol, the avoidance of mass metal wastes, and the use of precious metal catalysts. Kinetic realization studies suggested that migratory insertion of an aryl cobalt species into the aldehyde was the rate-determining step of the reductive addition reaction.

Palladium-Catalyzed Regioselective B(9)-Amination of o-Carboranes and m-Carboranes in HFIP with Broad Nitrogen Sources.

Abstract: Amination of carboranes has a good application prospect in organic and pharmaceutical synthesis. However, the current methods used for this transformation suffer from limitations. Herein, we report a practical method for a highly regioselective formation of a B-N bond by Pd(II)-catalyzed B(9)-H amination of o- and m-carboranes in hexafluoroisopropanol (HFIP) with different nitrogen sources under air atmosphere. The silver salt and HFIP solvent play critical roles in the present protocol. The mechanistic study reveals that the silver salt acts as a Lewis acid to promote the electrophilic palladation step by forming a heterobimetallic active catalyst PdAg(OAc)3; the strong hydrogen-bond-donating ability and low nucleophilicity of HFIP enhance the electrophilic ability of Pd(II). It is believed that these N-containing carboranes are potentially of great importance in the synthesis of new pharmaceuticals.

Dicarbofunctionalization of [1.1.1]Propellane Enabled by Nickel/Photoredox Dual Catalysis: One-Step Multicomponent Strategy for the Synthesis of BCP-Aryl Derivatives.

Abstract: Bicyclo[1.1.1]pentane (BCP) motifs as para-disubstituted aryl bioisosteres are playing an emerging role in pharmaceutical, agrochemical, and materials chemistry. The vast majority of these structures is obtained from a BCP electrophile or nucleophile, which are themselves derived from [1.1.1]propellane via cleavage of the internal C-C bond through the addition of either radicals or metal-based nucleophiles. Compared with the current stepwise approaches, a multicomponent reaction that provides direct access to complex and diverse disubstituted BCP products would be more attractive. Herein, we report a single-step, multicomponent approach to synthetically versatile arylated BCP products via nickel/photoredox catalysis. Importantly, this three-component process allows two C-C bonds to be formed in a single step and sets three quaternary centers, unprecedented in any previously reported methods. The method has been demonstrated to allow access to complex BCP architectures from aryl halide and radical precursor substrates.

Selective Difunctionalization of Unactivated Aliphatic Alkenes Enabled by a Metal-Metallaaromatic Catalytic System.

Abstract: The design of organometallic catalysts is crucial in the development of catalytic reactions. Herein, we describe a heterometallic [Os-Cu] complex with the characteristics of bimetallics, metallaaromatics, and pincer complexes. This complex serves as a highly effective catalyst for selective amino- and oxyselenation of unactivated alkenes. More than 80 examples including challenging substrates of unsymmetric aliphatic alkenes and amine-based nucleophiles in such reactions are provided. These reactions produce 1,2-difunctionalized products with good yields and high levels of chemo-, regio-, and stereoselectivity. Our studies revealed the following: (i) The usually inert osmium center activates the N- or O-centered nucleophiles. (ii) The copper-osmium bonding and its cooperative effects play essential roles in control the selectivity by bringing the reaction components into close proximity. (iii) The metallaaromatic moiety helps to stabilize the intermediate. These findings provide a versatile platform for catalyst design based on metal-metallaaromatic cooperative effects that have not been attained previously with bimetallic complexes.

Hydropersulfides Inhibit Lipid Peroxidation and Protect Cells from Ferroptosis.

Abstract: Hydropersulfides (RSSH) are believed to serve important roles in vivo, including as scavengers of damaging oxidants and electrophiles. The α-effect makes RSSH not only much better nucleophiles than thiols (RSH), but also much more potent H-atom transfer agents. Since HAT is the mechanism of action of the most potent small-molecule inhibitors of phospholipid peroxidation and associated ferroptotic cell death, we have investigated their reactivity in this context. Using the fluorescence-enabled inhibited autoxidation (FENIX) approach, we have found RSSH to be highly reactive toward phospholipid-derived peroxyl radicals (kinh = 2 × 105 M-1 s-1), equaling the most potent ferroptosis inhibitors identified to date. Related (poly)sulfide products resulting from the rapid self-reaction of RSSH under physiological conditions (e.g., disulfide, trisulfide, H2S) are essentially unreactive, but combinations from which RSSH can be produced in situ (i.e., polysulfides with H2S or thiols with H2S2) are effective. In situ generation of RSSH from designed precursors which release RSSH via intramolecular substitution or hydrolysis improve the radical-trapping efficiency of RSSH by minimizing deleterious self-reactions. A brief survey of structure-reactivity relationships enabled the design of new precursors that are more efficient. The reactivity of RSSH and their precursors translates from (phospho)lipid bilayers to cell culture (mouse embryonic fibroblasts), where they were found to inhibit ferroptosis induced by inactivation of glutathione peroxidase-4 (GPX4) or deletion of the gene encoding it. These results suggest that RSSH and the pathways responsible for their biosynthesis may act as a ferroptosis suppression system alongside the recently discovered FSP1/ubiquinone and GCH1/BH4/DHFR systems.

NiH-catalysed proximal-selective hydroalkylation of unactivated alkenes and the ligand effects on regioselectivity

Abstract: Abstract Alkene hydrocarbonation reactions have been developed to supplement traditional electrophile-nucleophile cross-coupling reactions. The branch-selective hydroalkylation method applied to a broad range of unactivated alkenes remains challenging. Herein, we report a NiH-catalysed proximal-selective hydroalkylation of unactivated alkenes to access β- or γ-branched alkyl carboxylic acids and β-, γ- or δ-branched alkyl amines. A broad range of alkyl iodides and bromides with different functional groups can be installed with excellent regiocontrol and availability for site-selective late-stage functionalization of biorelevant molecules. Under modified reaction conditions with NiCl 2 (PPh 3 ) 2 as the catalyst, migratory hydroalkylation takes place to provide β- (rather than γ-) branched products. The keys to success are the use of aminoquinoline and picolinamide as suitable directing groups and combined experimental and computational studies of ligand effects on the regioselectivity and detailed reaction mechanisms.

Borane-Catalyzed C3-Alkylation of Pyridines with Imines, Aldehydes, or Ketones as Electrophiles.

Abstract: Achieving C3-selective pyridine functionalization is a longstanding challenge in organic chemistry. The existing methods, including electrophilic aromatic substitution and C-H activation, often require harsh reaction conditions and excess pyridine and generate multiple regioisomers. Herein, we report a method for borane-catalyzed tandem reactions that result in exclusively C3-selective alkylation of pyridines. These tandem reactions consist of pyridine hydroboration, nucleophilic addition of the resulting dihydropyridine to an imine, an aldehyde, or a ketone, and subsequent oxidative aromatization. Because the pyridine is the limiting reactant and the reaction conditions are mild, this method constitutes a practical tool for late-stage functionalization of structurally complex pharmaceuticals bearing a pyridine moiety.

Functional group divergence and the structural basis of acridine photocatalysis revealed by direct decarboxysulfonylation

Abstract: The reactivity of the sulfonyl group varies dramatically from nucleophilic sulfinates through chemically robust sulfones to electrophilic sulfonyl halides—a feature that has been used extensively in medicinal chemistry, synthesis, and materials science, especially as bioisosteric replacements and structural analogs of carboxylic acids and other carbonyls. Despite the great synthetic potential of the carboxylic to sulfonyl functional group interconversions, a method that can convert carboxylic acids directly to sulfones, sulfinates and sulfonyl halides has remained out of reach. We report herein the development of a photocatalytic system that for the first time enables direct decarboxylative conversion of carboxylic acids to sulfones and sulfinates, as well as sulfonyl chlorides and fluorides in one step and in a multicomponent fashion. A mechanistic study prompted by the development of the new method revealed the key structural features of the acridine photocatalysts that facilitate the decarboxylative transformations and provided an informative and predictive multivariate linear regression model that quantitatively relates the structural features with the photocatalytic activity.

Allylic C–H amination cross-coupling furnishes tertiary amines by electrophilic metal catalysis

Abstract: Intermolecular cross-coupling of terminal olefins with secondary amines to form complex tertiary amines—a common motif in pharmaceuticals—remains a major challenge in chemical synthesis. Basic amine nucleophiles in nondirected, electrophilic metal–catalyzed aminations tend to bind to and thereby inhibit metal catalysts. We reasoned that an autoregulatory mechanism coupling the release of amine nucleophiles with catalyst turnover could enable functionalization without inhibiting metal-mediated heterolytic carbon-hydrogen cleavage. Here, we report a palladium(II)-catalyzed allylic carbon-hydrogen amination cross-coupling using this strategy, featuring 48 cyclic and acyclic secondary amines (10 pharmaceutically relevant cores) and 34 terminal olefins (bearing electrophilic functionality) to furnish 81 tertiary allylic amines, including 12 drug compounds and 10 complex drug derivatives, with excellent regio- and stereoselectivity (>20:1 linear:branched, >20:1 E:Z). Description Controlled release of amine reactants The formation of carbon–nitrogen bonds is a key step in the synthesis of numerous pharmaceuticals and related compounds. However, it is often not feasible to use the most direct nitrogen-bearing precursors because they inhibit metal catalysts at high concentration through strong coordination. Ali et al. report a creative way around this problem for allylic amination reactions. Most of the nitrogen reactants are protected as protonated salts, but the products can steadily deprotonate them a few at a time as the reaction progresses. —JSY Deprotonation of ammonium salts by a reaction product enables carbon–nitrogen bond formation without catalyst inhibition.

Electrocatalytic Allylic C-H Alkylation Enabled by a Dual-Function Cobalt Catalyst.

Abstract: The direct functionalization of allylic C-H bonds with nucleophiles minimizes pre-functionalization and converts inexpensive, abundantly available materials to value-added alkenyl-substituted products but remains challenging. Here we report an electrocatalytic allylic C-H alkylation reaction with carbon nucleophiles employing an easily available cobalt-salen complex as the molecular catalyst. These C(sp3)-H/C(sp3)-H cross-coupling reactions proceed through H2 evolution and require no external chemical oxidants. Importantly, the mild conditions and unique electrocatalytic radical process ensure excellent functional group tolerance and substrate compatibility with both linear and branched terminal alkenes. The synthetic utility of the electrochemical method is highlighted by its scalability (up to 200 mmol scale) under low loading of electrolyte (down to 0.05 equiv) and its successful application in the late-stage functionalization of complex structures.

Crystallographic snapshots of a B12-dependent radical SAM methyltransferase

Abstract: Abstract By catalysing the microbial formation of methane, methyl-coenzyme M reductase has a central role in the global levels of this greenhouse gas 1,2 . The activity of methyl-coenzyme M reductase is profoundly affected by several unique post-translational modifications 3–6 , such as a unique C -methylation reaction catalysed by methanogenesis marker protein 10 (Mmp10), a radical S- adenosyl- l -methionine (SAM) enzyme 7,8 . Here we report the spectroscopic investigation and atomic resolution structure of Mmp10 from Methanosarcina acetivorans , a unique B 12 (cobalamin)-dependent radical SAM enzyme 9 . The structure of Mmp10 reveals a unique enzyme architecture with four metallic centres and critical structural features involved in the control of catalysis. In addition, the structure of the enzyme–substrate complex offers a glimpse into a B 12 -dependent radical SAM enzyme in a precatalytic state. By combining electron paramagnetic resonance spectroscopy, structural biology and biochemistry, our study illuminates the mechanism by which the emerging superfamily of B 12 -dependent radical SAM enzymes catalyse chemically challenging alkylation reactions and identifies distinctive active site rearrangements to provide a structural rationale for the dual use of the SAM cofactor for radical and nucleophilic chemistry.

Switchable 1,2-Rearrangement Enables Expedient Synthesis of Structurally Diverse Fluorine-Containing Scaffolds

Abstract: Skeletal rearrangement that changes the connectivity of the molecule via cleavage and reorganization of carbon-carbon bonds is a fundamental and powerful strategy in complex molecular assembly. Because of the lack of effective methods to control the migratory tendency of different groups, achieving switchable selectivity in skeletal rearrangement has been a long-standing quest. Metal-based dyotropic rearrangement provides a unique opportunity to address this challenge. However, switchable dyotropic rearrangement remains unexplored. Herein, we show that such a problem could be solved by modifying the ligands on the metal catalyst and changing the oxidation states of the metal to control the migratory aptitude of different groups, thereby providing a ligand-controlled, switchable skeletal rearrangement strategy. Experimental and density functional theory calculation studies prove this rational design. The rearrangement occurs only when the nickel(II) intermediate is reduced to a more nucleophilic nickel(I) species, and the sterically hindered iPrPDI ligand facilitates 1,2-aryl/Ni dyotropic rearrangement, while the terpyridine ligand promotes 1,2-acyl/Ni dyotropic rearrangement. This method allows site-selective activation and reorganization of C-C bonds and has been applied for the divergent synthesis of four medicinally relevant fluorine-containing scaffolds from the same starting material.