Visible-Light Induced Radical Addition-Elimination Reaction for Constructing Allylic Sulfones from Sulfonyl Chlorides and Allyl Bromides.

Allyl sulfones are commonly present in bioactive compounds and organic building blocks. This work introduces a photocatalytic radical addition-elimination reaction involving readily accessible sulfonyl chlorides and allyl bromides. It delivers structurally diverse allylic sulfones in moderate to excellent yields, showcasing a high tolerance to functional groups. Notably, this method operates under mild reaction conditions without the need for oxidants, stoichiometric reducing metals, or additives.

Electrochemical Synthesis of Selenosulfonates from Diselenides and Sulfonyl Hydrazides.

The electrochemical oxidative radical-radical cross-coupling of sulfonyl hydrazides with diselenides for the synthesis of selenosulfonates was successfully accomplished. The method is applicable to a wide range of aromatic/aliphatic sulfonyl hydrazides and diselenides, providing products in good to excellent yields. Notably, this protocol stands out for its green and sustainable nature, as it does not rely on transition metals and oxidizing agents, and the starting materials are cost-effective and readily available.

Visible Light-Induced Hydroacylation of Benzylidenemalononitriles with Aroyl Chlorides Using Silane as a Hydrogen Donor.

A novel photoredox-catalyzed direct hydroacylation of benzylidenemalononitriles is described. In this method, aroyl chlorides are employed as a readily available and affordable source of acyl groups, while commercially available tris(trimethylsilyl)silane acts as both the hydrogen atom donor and electron donor. By eliminating the requirement for complex synthesis of acyl precursors and hydrogen atom-transfer (HAT) reagents, this approach offers a convenient and efficient strategy for the hydroacylation of benzylidenemalononitriles.

Electrosynthesis of 5-Aminocoumaran Derivatives from Olefins and Aminophenols.

The electrochemical synthesis of 5-aminocoumaran derivatives from easily oxidizable aminophenols and readily available olefins is described. The reaction efficiently produces 5-aminocoumarans in high yield under mild and environmentally friendly conditions without the necessity of catalysts, additives, oxidizing agents, or sacrificial reagents. Hydrogen as the sole byproduct of the reaction makes the method clean, highly atom-efficient, and step-economical.

Photoredox-Catalyzed Radical-Radical Cross-Coupling of α-Ketoesters with Ethers: Access to Sterically Hindered α-Hydroxy Esters.

We describe a photoredox catalysis method for synthesizing sterically hindered α-hydroxy esters from α-ketoesters and ethers through a radical-radical cross-coupling reaction. This approach utilizes commercially available Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst and inexpensive and readily available nBu4NBr as a hydrogen atom transfer catalyst. Unactivated tetrahydrofuran and other ethers effectively react with various α-ketoesters to yield the desired products. The efficiency of this reaction is highlighted by its broad substrate scope, good functional group tolerance, and mild reaction conditions.

Electrochemical C(sp2)-H/N-H "formal" cross-dehydrogenative coupling of olefins with benzotriazoles for synthesis of N-vinyl benzotriazoles.

The paper details an electrochemical method that couples olefins with benzotriazoles to form C(sp2)-N bonds, enabling the synthesis of N-vinyl benzotriazoles in moderate to good yields. nBu4NI functions as both an electrolyte and an iodine mediator, and the method does not require oxidants or metals. It is a highly atom-economical and clean reaction, with hydrogen as the sole byproduct.

Photoredox-Catalyzed Radical-Radical Cross-Coupling of Sulfonyl Chlorides with Trifluoroborate Salts.

Sulfones are widely found in natural products and drug molecules. Here, we disclose a strategy for direct synthesis of sulfone compounds with diverse structures by visible-light-catalyzed radical-radical cross-coupling of sulfonyl chlorides and trifluoroborate salts. Allyl, benzyl, vinyl, and aryl trifluoroborates can be successfully cross-coupled with (hetero)aryl and alkyl sulfonyl chlorides, respectively. This strategy features redox neutrality, good substrate generality, simple operation, and benign reaction conditions.

Electrochemical Synthesis of ß-Iodoesters by 1,2-Iodoesterization of Unactivated Alkenes with Carboxylic Acids and Tetrabutylammonium Iodide.

We report a novel and highly selective electrochemical method for the synthesis of ß-iodoesters via difunctionalization of alkenes. The reaction is carried out in an undivided cell under constant current conditions without any additives, catalysts, oxidants, and sacrificial reagents. Inexpensive and readily available tetrabutylammonium iodide not only acts as an electrolyte but also serves as an iodine source. The reaction shows high selectivity and good functional group tolerance, providing products in yields of up to 98%. This method is applicable not only to the iodofunctionalization of alkenes but also to the chloro- and bromofunctionalization of alkenes. The successful modification of drugs and natural products demonstrates the potential utility of this approach.

Electrochemical Cross-Dehydrogenative Coupling of Isochroman and Unactivated Ketones.

An unprecedented electrochemical cross-dehydrogenative coupling reaction between isochroman and unactivated ketones to directly synthesize α-substituted isochromans has been developed. This strategy provides a facile and efficient procedure to the direct activation of C(sp3)-H bond adjacent to the O atom of isochroman. The method features high atom economy, chemical oxidant-free, and mild conditions, in which methanesulfonic acid (MsOH) acts as both electrolyte and catalyst, making the process more convenient and environmentally friendly. Gram-scale experiment and synthesis of antitumor active compounds demonstrate the great potential of this protocol for practical applications.

Visible Light-Induced Cross-Dehydrocoupling of 3-Cyanocoumarins with Unactivated Aliphatic Aldehydes Enables Access to 4-Acylated Coumarins.

We report visible light-induced cross-dehydrocoupling of 3-cyanocoumarins with unactivated aliphatic aldehydes for the direct synthesis of 4-acylated coumarins. Inexpensive and readily available (n-Bu)4NBr was used as a precursor of the hydrogen atom transfer (HAT) catalyst and [Ir(ppy)2(dtbbpy)PF6] as a photocatalyst. A variety of aldehydes including linear, branched, cyclic, and α,ß-unsaturated aliphatic aldehydes were suitable for this reaction yielding the desired acylated coumarin derivatives in 41-98% yields. This method provides a mild, atom-economical, and environmentally friendly synthetic route for the direct acylation of 3-cyanocoumarins. This is the first example so far of C-4 aliphatic acylation of coumarins.

Electroreductive Hydroxymethylation of Imines with Ketones To Access ß-Amino Alcohols.

In this article, an electrochemical method for the direct synthesis of ß-amino alcohols from imines and ketones is described. Mechanistic studies, including a radical trapping experiment, electron paramagnetic resonance, cyclic voltammetry, and divided-cell electrolysis experiment, support the radical-involved reductive cross coupling of imines with ketones at the cathode. The use of abundant and easily prepared starting materials, high atom- and step-economy, and insensitivity to air and moisture make this synthetic strategy more efficient for the construction of various ß-amino alcohol derivatives.

Direct Hydroxylarylation of Benzylic Carbons (sp3/sp2/sp) via Radical-Radical Cross-Coupling Powered by Paired Electrolysis.

Diaryl alcohol moieties are widespread in pharmaceuticals. Existing methods for the synthesis of diaryl alcohols require the use of pre-functionalized benzylic alcohols, aromatic aldehydes, or ketones as starting materials. Herein, the first convergent paired electrochemical approach to the direct hydroxylarylation of unactivated benzylic carbons (sp3/sp2/sp) is proposed. This protocol features direct functionalization of unactivated benzylic C(sp3)-H bonds and benzylic sp2/sp-carbons, mild conditions (open air, room temperature), an environmentally friendly procedure (without any external catalyst/mediator/additive), and direct access to sterically hindered alcohols from inexpensive and readily available alkyl/alkenyl/alkynylbenzenes. Mechanistic studies, including divided-cell experiments, isotope labeling, radical trapping, electron paramagnetic resonance, reaction kinetics, and cyclic voltammetry, strongly support the proposed radical-radical cross-coupling between transient ketyl radicals and persistent radical anions. Gram-scale synthesis and diversification of drug derivatives have visualized the tremendous potential of this protocol for practical applications.

Direct Reductive Arylation of Imines with Electron-Deficient (Hetero) Arenes via Electrosynthesis to Access Benzylic Amines.

In this paper, a direct access to benzylic amines from imines and electron-deficient (hetero) arenes via electrochemical radical-radical cross-coupling is described. The reaction has the characteristics of the wide range of substrates, excellent functional group tolerance, metal-free and highly atom-economical. The insensitivity to air and moisture makes this synthetic strategy more efficient for the construction of various benzylic amine derivatives.

Safety, Pharmacokinetics/Pharmacodynamics, and Absolute Bioavailability of Dexmedetomidine Hydrochloride Nasal Spray in Healthy Subjects: A Randomized, Parallel, Escalating Dose Study.

Background: The present study evaluated the safety, pharmacokinetics/pharmacodynamics (PK/PD), and absolute bioavailability (Fabs) of Dex nasal spray in healthy adult subjects, which serves as a bridge for the subsequent study in children. Methods: Part 1: a double-blind, placebo-controlled, single ascending dose study was performed on 48 subjects. For 20-/40-µg groups, every 6/2 subjects received either Dex/placebo nasal spray or Dex/placebo injection in two periods. In total, 12/4 subjects each received 100 µg Dex/placebo nasal spray. Part 2: a randomized, double-blind, placebo-controlled study; 12/4 subjects received 150 µg Dex/placebo nasal spray. Part 3: a randomized, open, self-crossover study; 12 subjects received 20 µg and 100 µg Dex nasal spray in two periods alternately. The method of administration was optimized in Part 2 and Part 3. Results: In part 1, Dex nasal spray was well tolerated up to the maximum dose of 100 µg, whereas the Fabs was tolerated to only 28.9%-32.3%. In Part 2 and Part 3, the optimized nasal spray method was adopted to promote the Fabs of Dex nasal spray to 74.1%-89.0%. A severe adverse event was found in Part 2. In Part 3 (100 µg), the Ramsay score increased the most and lasted the longest, whereas the BIS score decreased most significantly. Conclusion: Using the optimized nasal spray method, a single dose of 20/100 µg of the test drug was safe and tolerable, and 100 µg may have approached or reached the plateau of sedation. In addition, it is found that the optimized method can greatly improve the bioavailability of the test drug, leading to its higher reference value.

Visible-Light-Catalyzed Radical-Radical Cross-Coupling Reaction of Benzyl Trifluoroborates and Carbonyl Compounds to Sterically Hindered Alcohols.

We report here an organic dye catalyzed direct radical-radical cross-coupling reaction based on the persistent free-radical effect (PRE), which is powered by visible light and does not require any external oxidants or reductants. In this reaction, benzyl trifluoroborates are oxidized by excited-state 4Cz-IPN to generate benzyl radicals, and the resulting boron trifluoride acts as a Lewis acid to reduce the reduction potential of carbonyl compounds. The dual roles of benzyl trifluoroborates enable aldehydes, ketones, diketones, and ketone esters to react with benzyl trifluoroborates to generate various sterically hindered alcohols.

Merging the Non-Natural Catalytic Activity of Lipase and Electrosynthesis: Asymmetric Oxidative Cross-Coupling of Secondary Amines with Ketones.

We describe the enantioselective oxidative cross-coupling of secondary amines with ketones by combining the non-natural catalytic activity of lipase with electrosynthesis. Various 2,2-disubstituted 3-carbonyl indoles with a stereogenic quaternary carbon center were synthesized from 2-substituted indoles in yields up to 78 % with good enantio- and diastereoselectivities (up to 96 : 4 e.r. and >20 : 1 d.r.). This unprecedented protocol demonstrated that hydrolase catalysis is compatible with electrosynthesis, and the reaction can be carried out in organic solvents with a broad substrate scope and good stereoselectivity. This work provides insights into enzymatic electrosynthesis.

Asymmetric oxidative Mannich reactions promoted by photocatalysis and electrochemistry.

The asymmetric Mannich reaction is an essential method in contemporary organic chemistry. As a representative of clean and green synthesis methods, photochemical and electrochemical oxidation strategies have re-emerged in recent years, providing new ideas for asymmetric Mannich reactions. Numerous chiral ß-amino carbonyl compounds have been accessed in satisfactory yields with excellent enantioselectivity via such novel asymmetric oxidative Mannich reactions. This minireview highlights plentiful advances in asymmetric oxidative Mannich reactions that rely on photoredox or anodic-oxidation and covers the literature from 2014 to date. Furthermore, the future development of this field is envisaged.

Photoredox Catalyzed Radical Cascade Aroylation (Sulfonylation)/Cyclization Enables Access to Fused Indolo-pyridones.

A visible-light-initiated radical cascade reaction toward the synthesis of structurally diverse fused Indolo-pyridones is described. The reaction involves the addition of aroyl or sulfonyl radicals to N-alkyl-acryloyl-1H-indole-3-carboxamides, cyclization, and oxidative aromatization. This telescoped method circumvents lengthy prefunctionalization steps of radical precursors, which is further underpinned by the superior compatibility with a series of C-centered radicals, allowing the rapid and facile construction of numerous valuable architectures.

Visible-Light-Mediated Additive-Free Decarboxylative Ketonization Reaction of Acrylic Acids: An Access to α-Thiocyanate Ketones.

Visible-light-mediated additive-free decarboxylative functionalization of acrylic acids has been developed. The reaction uses inexpensive organic dye 9,10-dicyanoanthracene as a photocatalyst and uses the ubiquitous dioxygen as both an oxygen source and an oxidant. Through this mild and environmentally friendly method, a series of important α-thiocyanate ketones can be generated from easily available acrylic acids and ammonium thiocyanate. In addition, the facile transformation of product α-thiocyanate ketones makes this method have great potential for application in organic and pharmaceutical chemistry.

Photoinduced umpolung addition of carbonyl compounds with α,ß-unsaturated esters enables the polysubstituted γ-lactone formation.

We herein report the photoinduced intermolecular umpolung addition of aromatic ketones/aldehydes with α,ß-unsaturated esters via ketyl radical intermediates. Following an intramolecular transesterification, a variety of γ-lactone derivatives are readily accessed. Mechanistic investigations demonstrate the significant role of Hantzsch ester, which serves both as the electron and proton donor.