Stoichiometric Reagents Research Articles

Electricity-Driven Strain-Release Cascade Cyclization of Bicyclo[1.1.0]butane (BCB): Stereoselective Synthesis of Functionalized Spirocyclobutyl Oxindoles.

Spirocyclobutyl oxindoles, characterized by their unique three-dimensional structures, are valuable building blocks for many pharmacophores and drug units. However, stereoselective synthetic strategies for these scaffolds remain underdeveloped, with most existing methods relying on transition metal catalysts and stoichiometric redox reagents. In this work, we introduce an electrochemical strain-release driven cascade spirocyclization of bicyclo[1.1.0]butane (BCB) derivatives for the stereoselective synthesis of functionalized spirocyclobutyl oxindoles. Tetrabutylammonium bromide serves a dual purpose as both a supporting electrolyte and brominating agent.The method offers a broad substrate scope, high atom economy, and excellent diastereoselectivity. The stereoselectivity of the product is controlled by minimizing the dipolar repulsion between the amide C=O and the C-Br bonds. We also explored the methodology's versatility by applying it to various functionalizations and demonstrated its scalability for practical use. The efficient derivatization of the products allowed for for the rapid creation a diverse library of functionalized spirocyclobutyl oxindoles.

Photoelectrocatalytic [4+2] Annulation for S-Heterocycle Assembly Enabled by Proton-Coupled Electron Transfer (PCET).

Cross-dehydrogenative couplings (CDC) present an efficient strategy for the assembly of biorelevant heterocycles, but are thus far largely limited to toxic transition metals and rather harsh reaction conditions. In sharp contrast, we, herein report on a mild photoelectrocatalyzed CDC-[4+2] annulation enabling the synthesis of functionalized isothiochromenes enabled by a proton-coupled electron transfer (PCET) strategy. The transformative photoelectrocatalysis obviated toxic transition-metal, high reaction temperatures, and stoichiometric chemical redox reagents. This approach was characterized by exceedingly mild conditions, ample substrate scope, and a commercially available catalyst. Gram-scale reactions and a telescoped synthesis route reflected the unique potential in the green synthesis of important S-heterocycles.

Visible-Light-Driven Synthesis of N-Alkyl α-Amino Acid Derivatives from Unactivated Alkyl Bromides and In Situ Generated Imines.

One-pot, multicomponent reactions are known for their green and efficient nature. We report a novel three-component reaction of alkyl amines, alkyl glyoxylates, and unactivated alkyl bromides under visible-light-induced palladium catalysis, yielding N-alkyl unnatural α-amino acid derivatives. This method offers mild conditions, broad substrate scope, and excellent functional group tolerance without requiring stoichiometric organometallic reagents. The approach has promising applications in protein engineering and drug discovery.

Asymmetric organocatalytic synthesis of chiral homoallylic amines.

In recent decades, the chiral allylation of imines emerged as a key methodology in the synthesis of alkaloids and natural products with 4-, 5- and 6-membered cyclic amine motifs. Initially reliant on stoichiometric reagents, synthetic chemists predominantly used N-substituted chiral imines, organometallic chiral reagents and achiral reagents with an equimolar chiral controller. However, recent years have witnessed the rise of asymmetric transition-metal catalysts and, importantly, organocatalytic allylation, reshaping the landscape of modern synthetic chemistry. This review explores the latest developments in the asymmetric allylation of imines, encompassing cutting-edge advances in hydrogen-bond catalysis and non-classical approaches. Furthermore, practical examples showcasing the application of these innovative methodologies in total synthesis are presented.

Halogen and Chalcogen Activation by Nucleophilic Catalysis.

The high utility of halogenated organic compounds has prompted the development of numerous transformations that install the carbon-halogen motif. Halogen functionalities, deemed as "functional and functionalizable" molecules due to their capacity to modulate diverse internal properties, constitute a pivotal strategy in drug discovery and development. Traditional routes to these building blocks have commonly involved multiple steps, harsh reaction conditions, and the use of stoichiometric and/or toxic reagents. With the emergence of solid halogen carriers such as N-halosuccinimides, and halohydantoins as popular sources of halonium ions, the past decade has witnessed enormous growth in the development of new catalytic strategies for halofunctionalization. This review aims to provide a nuanced perspective on nucleophilic activators and their roles in halogen activation. It will highlight critical discoveries in effecting racemic and asymmetric variants of these reactions, driven by the development of new catalysts, activation modes, and improved understanding of chemical reactivity and reaction kinetics.

N-Heteroocyclic Carbenes and N-Heterocycles as Synthetic Reagents and Building Blocks.

N-Heterocyclic carbenes (NHCs) have become important tools in modern synthetic chemistry due to their versatility as organocatalysts and ligands in organometallic complexes. Since their first isolation and characterization, NHCs have demonstrated significant utility in various catalytic processes, offering advantages such as strong σ-electron donation and the ability to stabilize reactive intermediates. However, beyond their well-documented roles in catalysis, the potential of NHCs as stoichiometric reagents and synthetic building blocks remains an underexplored yet promising area. This Mini-review aims to shed light on these lesser-known applications of NHCs and their N-heterocyclic precursors or derivatives in organic synthesis. Furthermore, we discuss how the unique electronic and steric properties of NHCs can be harnessed to develop new synthetic methodologies or construct interesting organic frameworks. By highlighting these emerging uses, we hope to encourage further research into the non-catalytic applications of NHCs, broadening their scope and impact in synthetic chemistry.

Catalytic Synthesis of Fluoroalkyl Ketones

Fluoroalkyl ketones are a class of structural motifs which are ubiquitous in bioactive molecules, and serve as synthons for diverse value‐added fluorine‐containing targets. The presence of fluorine significantly alters the lipophilicity and bioactivity of alkyl ketones as well as imposes additional challenges on the synthesis of fluoroalkyl ketones. Traditional methods for the synthesis of fluoroalkyl ketones heavily rely on multiple‐step manipulations which require stoichiometric reagents and suffer from low efficiency. Thus, the development of synthesizing fluoroalkyl ketones enabled by catalytic methods is highly valuable yet challenging. This Concept summarizes the recent renaissance in developing catalytic methods for the synthesis of fluoroalkyl ketones with diverse substitution patterns from different fluorine‐containing precursors. In addition, further efforts for catalytic method development are also discussed

Nickel‐Catalyzed Regio‐ and Stereoselective Reductive Alkylative Cyclization of 1,6‐Enynes with Alkyl Bromides

AbstractA nickel‐catalyzed reductive alkylative cyclization of 1,6‐enynes with alkyl bromides has been developed. This transformation avoids the use of stoichiometric organometallic reagents and introduces alkyl groups regio‐ and stereoselectively into the products. This method provides a platform for the synthesis of carbo‐ and heterocycles that are widely found in many natural products and biologically active molecules.

XAT-Catalysis for Intramolecular Biaryl Synthesis.

Radical ipso-substitution offers an alternative to organometallic approaches for biaryl synthesis, but usually requires stoichiometric reagents such as tributyltin hydride. Here, we demonstrate that visible light photoredox catalysis can be used for ipso-biaryl synthesis, via a halogen-atom transfer (XAT) regime. Using amide substrates that promote ipso- over unwanted ortho-addition, we demonstrate smooth biaryl formation with no constraint on the electronic character of the migrating arene ring. The photoreaction can be combined in one operation to achieve a formal arylation of the inert aniline C-N bond.

XAT‐Catalysis for Intramolecular Biaryl Synthesis

AbstractRadical ipso‐substitution offers an alternative to organometallic approaches for biaryl synthesis, but usually requires stoichiometric reagents such as tributyltin hydride. Here, we demonstrate that visible light photoredox catalysis can be used for ipso‐biaryl synthesis, via a halogen‐atom transfer (XAT) regime. Using amide substrates that promote ipso‐ over unwanted ortho‐addition, we demonstrate smooth biaryl formation with no constraint on the electronic character of the migrating arene ring. The photoreaction can be combined in one operation to achieve a formal arylation of the inert aniline C−N bond.

Organic Synthesis Away from Equilibrium: Contrathermodynamic Transformations Enabled by Excited-State Electron Transfer.

ConspectusChemists have long been inspired by biological photosynthesis, wherein a series of excited-state electron transfer (ET) events facilitate the conversion of low energy starting materials such as H2O and CO2 into higher energy products in the form of carbohydrates and O2. While this model for utilizing light-driven charge transfer to drive catalytic reactions thermodynamically "uphill" has been extensively adapted for small molecule activation, molecular machines, photoswitches, and solar fuel chemistry, its application in organic synthesis has been less systematically developed. However, the potential benefits of these approaches are significant, both in enabling transformations that cannot be readily achieved using conventional thermal chemistry and in accessing distinct selectivity regimes that are uniquely enabled by excited-state mechanisms. In this Account, we present work from our group that highlights the ability of visible light photoredox catalysis to drive useful organic transformations away from their equilibrium positions, addressing a number of long-standing synthetic challenges.We first discuss how excited-state ET enabled the first general methods for the catalytic anti-Markovnikov hydroamination of unactivated alkenes with alkyl amines. In these reactions, an excited-state iridium(III) photocatalyst reversibly oxidizes secondary amine substrates to their corresponding aminium radical cations (ARCs). These electrophilic N-centered radicals can then react with olefins to furnish valuable tertiary amine products with complete anti-Markovnikov regioselectivity. Notably, some of these products are less thermodynamically stable than their corresponding amine and alkene starting materials. We next present a strategy for light-driven C-C bond cleavage within various aliphatic alcohols mediated by homolytic activation of alcohol O-H bonds by excited-state proton-coupled electron transfer (PCET). The resulting alkoxy radical intermediates then undergo C-C β-scission to ultimately provide isomeric linear carbonyl products that are often higher in energy than their cyclic alcohol precursors. Applications of this chemistry for the light-driven depolymerization of lignin biomass, commercial phenoxy resin, hydroxylated polyolefin derivatives, and thermoset polymers are presented as well. We then describe a method for the contrathermodynamic positional isomerization of highly substituted olefins by means of cooperative photoredox and chromium(II) catalysis. In this work, generation of an allylchromium(III) species that can undergo highly regioselective in situ protodemetalation enables access to a less substituted and thermodynamically less stable positional isomer. Product selectivity in this reaction is determined by the large differential in oxidation potentials between differently substituted olefin isomers. Lastly, we discuss a light-driven deracemization reaction developed in collaboration with the Miller group, wherein a racemic urea substrate undergoes spontaneous optical enrichment upon visible light irradiation in the presence of an iridium(III) chromophore, a chiral Brønsted base, and a chiral peptide thiol. Excellent levels of enantioselectivity are achieved via sequential and synergistic proton transfer (PT) and H atom transfer (HAT) steps. Taken together, these examples highlight the ability of excited-state ET events to enable access to nonequilibrium product distributions across a wide range of catalytic, redox-neutral transformations in which photons are the only stoichiometric reagents.

Silver-Catalyzed Olefination of Aryl Aldehydes Using Propiolates.

Olefination of aldehydes is one of the fundamental reactions in organic synthesis. The commonly used Wittig olefination reaction however uses stoichiometric quantities reagents under basic conditions resulting in stoichiometric amounts of byproducts. Known catalytic alternate to the Wittig reaction requires stoichiometric amounts of silane reducing agents and high temperature. Herein, we report a base-free olefination of aryl aldehydes using propiolates as a surrogate for the Witting reagent under silver catalysis. Trimethyl orthoformate, in the presence of a silver catalyst adds to the alkynoate to form the nucleophilic silver allenolate which reacts with the reactive oxocarbenium ion formed from aldehyde under the reaction conditions. Subsequently, decarbonylation occurs to form the olefin. Trans olefin is formed exclusively from simple aryl aldehydes and cinnamaldehydes. Such a silver allenolate is conceptually novel and has not been explored so far.

Visible Light Induced Photocatalyst‐Free C−X (X=B, C, O, P,S, Se) Bond Formation of Aryl Halides

AbstractAryl halides are one of the most important chemical feedstocks in pharmaceuticals due to its easy accessibility, inexpensiveness, and widely utilized as aryl radical precursors in organic synthetic chemistry. Conventionally, the stoichiometric reagents such as AIBN/n‐Bu3SnH were used for generation of aryl radical from aryl halides, and suffered from requirement of toxic radical initiators, high temperature and thus, the development of simple, mild strategies for the generation of aryl radical from aryl halides are highly desirable. Recently, visible light mediated strategies received considerable attention, allowing the generation of aryl radical from aryl halides under mild reaction conditions. The present review described the recent breakthroughs and advancements in visible light mediated photocatalyst‐free C−B/C/O/P/Se/S bond formation of aryl halides.

Nickel-Catalyzed Reductive anti-Arylative Cyclization of Alkynyl Enones with Aryl Halides.

A nickel-catalyzed reductive anti-arylative cyclization of alkynyl enones with aryl halides has been developed. The reaction avoids the use of stoichiometric organometallic reagents and has a broad reaction scope and high functional group tolerance. This method offers an efficient way to access a variety of synthetically useful carbocycles that are widely found in many natural products and biologically active molecules.

Esterification as a Demonstration of Electrochemically Powered Catalytic Dehydration

AbstractThe reliance on wasteful stoichiometric reagents to accomplish dehydration reactions such as esterification, amidation, and alcohol substitution is a longstanding challenge in synthetic chemistry. To address this problem, an electrochemical approach has been developed as a new conceptual platform for dehydration reactions. As a proof-of-concept demonstration, an electrochemical esterification protocol has been described that proceeds at room temperature, without acid or base additives, and without consuming stoichiometric reagents. This approach therefore overcomes key complications of esterification chemistry, and we envision that it will similarly enable improvements to a range of important, related transformations.1 Introduction2 An Electrochemical Design for Catalytic Dehydration3 Electrochemical Esterification4 Conclusions

Cobalt- or rhodium-catalyzed synthesis of 1,2-dihydrophosphete oxides via C-H activation and formal phosphoryl migration.

A highly stereo- and chemoselective intermolecular coupling of diverse heterocycles with dialkynylphosphine oxides has been realized via cobalt/rhodium-catalyzed C-H bond activation. This protocol provides an efficient synthetic entry to functionalized 1,2-dihydrophosphete oxides in excellent yields via the merger of C-H bond activation and formal 1,2-migration of the phosphoryl group. Compared with traditional methods of synthesis of 1,2-dihydrophosphetes that predominantly relied on stoichiometric metal reagents, this catalytic system features high efficiency, a relatively short reaction time, atom-economy, and operational simplicity. Photophysical properties of selected 1,2-dihydrophosphete oxides are also disclosed.

NiH-catalyzed C-N bond formation: insights and advancements in hydroamination of unsaturated hydrocarbons.

The formation of C-N bonds is a fundamental aspect of organic synthesis, and hydroamination has emerged as a pivotal strategy for the synthesis of essential amine derivatives. In recent years, there has been a surge of interest in metal hydride-catalyzed hydroamination reactions of common alkenes and alkynes. This method avoids the need for stoichiometric organometallic reagents and overcomes problems associated with specific organometallic compounds that may impact functional group compatibility. Notably, recent developments have brought to the forefront olefinic hydroamination and hydroamidation reactions facilitated by nickel hydride (NiH) catalysis. The inclusion of suitable chiral ligands has paved the way for the realization of asymmetric hydroamination reactions in the realm of olefins. This review aims to provide an in-depth exploration of the latest achievements in C-N bond formation through intermolecular hydroamination catalyzed by nickel hydrides. Leveraging this innovative approach, a diverse range of alkene and alkyne substrates can be efficiently transformed into value-added compounds enriched with C-N bonds. The intricacies of C-N bond formation are succinctly elucidated, offering a concise overview of the underlying reaction mechanisms. It is our aspiration that this comprehensive review will stimulate further progress in NiH-catalytic techniques, fine-tune reaction systems, drive innovation in catalyst design, and foster a deeper understanding of the underlying mechanisms.

Nanocellulose as a Reaction Media and Stoichiometric Reagent for FeCl3-Mediated Reductive Functionalization of Nitro Compounds

Nanocellulose as a Reaction Media and Stoichiometric Reagent for FeCl₃-Mediated Reductive Functionalization of Nitro Compounds

Impact of Temperature an Order of Magnitude Larger Than Electrical Potential in Lignin Electrolysis with Nickel.

Lignin, a major component of plant biomass, is a promising sustainable alternative carbon-based feedstock to petroleum as a source of valuable aromatic compounds such as vanillin. However, lignin upgrading reactions are poorly understood due to its complex and variable molecular structure. This work focuses on electrocatalytic lignin upgrading, which is efficient and sustainable at moderate temperatures and pressures and does not require stoichiometric reagents. We used a meta-analysis of published lignin conversion and product yield data to define the operating range, to select the catalyst, and then performed electrocatalytic experiments. We quantified the impact of temperature and electrical potential on the formation rate of valuable products (vanillic acid, acetovanillone, guaiacol, vanillin, and syringaldehyde). We found that increasing temperature increases their formation rate by an order of magnitude more than increasing electrical potential. For example, increasing temperature from 21 to 180 °C increases the vanillin formation rate by +16.5 mg⋅L-1 ⋅h-1 ±1.7 mg⋅L-1 ⋅h-1 , while increasing electrical potential from 0 to 2 V increases the vanillin formation rate by -0.6 mg⋅L-1 ⋅h-1 ±1.4 mg⋅L-1 ⋅h-1 .

Heterogeneous Copper-Catalyzed Cross-Coupling for Sustainable Synthesis of Chiral Allenes: Application to the Synthesis of Allenic Natural Products.

Classical Crabbé type SN 2' substitutions of propargylic substrates has served as one of the standard methods for the synthesis of allenes. However, the stereospecific version of this transformation often requires either stoichiometric amounts of organocopper reagents or special functional groups on the substrates, and the chirality transfer efficiency is also capricious. Herein, we report a sustainable methodology for the synthesis of diverse 1,3-di and tri-substituted allenes by using a simple and cheap cellulose supported heterogeneous nanocopper catalyst (MCC-Amp-Cu(I/II)). This approach represents the first example of heterogeneous catalysis for the synthesis of chiral allenes. High yields and excellent enantiospecificity (up to 97 % yield, 99 % ee) were achieved for a wide range of di- and tri-substituted allenes bearing various functional groups. It is worth noting that the applied heterogeneous catalyst could be recycled at least 5 times without any reduced reactivity. To demonstrate the synthetic utility of the developed protocol, we have applied it to the total synthesis of several chiral allenic natural products.