Protocol Features Mild Conditions Research Articles

MnBr2‐Catalyzed Aerobic Oxyazidation of Fluoroolefins: Access to Fluoroalkylated β‐Hydroxy Aliphatic Azides

AbstractMnBr2‐catalyzed oxyazidation of fluoroolefins with molecular oxygen and TMSN3 is reported. This method gives rise to various useful fluoroalkylated β‐hydroxy aliphatic azides in 36%–97% yields. Importantly, this protocol features mild conditions, operationally simple, and gram‐scalable, it tolerates various functional groups and has been applied in the synthesis of diverse attractive bioactive compounds and analogous. Mechanism studies enable the detection of the intermediate and indicate that a radical reaction process is involved. The β‐fluoride elimination of α‐fluoroalkylated radicals via radical‐polar crossover pathway was completely inhibited in this reaction.magnified image

Solvent-free base-controlled addition reaction of H-phosphonates and H-phosphine oxides to α-CF3 styrenes: facile synthesis of β-CF3-substituted phosphonates and phosphine oxides.

A practical and efficient solvent-free synthesis of β-trifluoromethyl-substituted phosphonates and phosphine oxides via hydrophosphonylation and hydrophosphinylation of α-(trifluoromethyl)styrenes with H-phosphonates and H-phosphine oxides, respectively, was developed. The reaction proceeded smoothly within 2 h at room temperature without the cleavage of the rather fragile C-F bond in α-(trifluoromethyl)styrenes and afforded a wide variety of structurally diverse and valuable β-trifluoromethyl-containing phosphonates and phosphine oxides in moderate to good yields. This protocol features mild conditions, wide substrate scope, simple manipulation, and excellent functional group compatibility.

Formal (4+2) cycloaddition of azoalkenes with trifluoromethylimidoyl sulfoxonium ylides: synthesis of trifluoromethyl pyridazine derivatives.

CF3-substituted imidoyl sulfoxonium ylides (TFISYs) are extraordinarily versatile and powerful synthons for use in cyclization chemistry that affords diverse CF3-substituted N-heterocycles. We first reacted TFISYs as a two-atom synthon with readily available azoalkenes and then subjected the products to metal-free formal (4+2) cycloaddition chemistry. This protocol features mild conditions and broad substrate scope, is simple to operate, and provides highly functionalized trifluoromethylpyridazines that are widely found in bioactive molecules.

3,5-Di(trifluoromethyl)phenyl(cyano)iodonium triflate as a novel and potential activator for p-tolyl thioglycoside donors.

3,5-Di(trifluoromethyl)phenyl(cyano)iodonium triflate is described as an accessible, stable, and powerful thiophile that can activate batches of p-tolyl thioglycoside donors at room temperature. Various alcoholic acceptors were efficiently glycosylated, providing the desired glycosides. The novel activation protocol features mild conditions as well as high compatibility with some classic strategies for the stereoselective construction of some biologically relevant glycosidic linkages, as exemplified by α-idosides, α-galactoamines, β-mannosides, and β-rhamnosides.

Synthesis of spirocyclopropanes via iodine-promoted bimolecular cyclization of 2-benzylidene 1,3-indandiones

A novel and efficient iodine-promoted bimolecular annulation of 2-benzylidene 1,3-indandiones has been developed. Following this protocol, a series of spirocyclopropane derivatives were furnished in good to excellent yields. The present protocol features mild conditions, short reaction time, high efficiency, good chemoselectivity and remarkable functional group tolerance.

Direct α-C-H Alkylation of Structurally Diverse Alcohols via Combined Tavaborole and Photoredox Catalysis.

Herein, we report a method that uses antifungal tavaborole as a co-catalyst for direct α-C-H alkylation of structurally diverse alcohols through photoredox catalysis. The protocol features mild conditions, remarkable scope, and wide functional group tolerance, which allows for the construction of a wide array of highly functionalized alcohols, including homoserine derivatives and C-glycosyl amino acids. We also demonstrate the synthetic applications of this methodology to the late-stage functionalization of pharmaceuticals and natural products.

Copper-catalyzed enantioselective decarboxylative cyanation of β,γ-unsaturated carboxylic acids to access chiral allyl nitriles

Copper-catalyzed asymmetric radical cyanation reactions have emerged as a powerful platform for construction of a variety of enantioenriched cyano-containing compounds under mild conditions. Herein, we report a copper-catalyzed enantioselective decarboxylative cyanation of readily available β, γ -unsaturated carboxylic acids promoted by a hypervalent iodine(III) reagent. The key allyl radical can be efficiently formed through single-electron reduction of in-situ -generated phenyliodine(III) dicarboxylates by Cu(I) species. This protocol features mild conditions, wide substrate scope, and functional group tolerance, producing a diverse range of chiral allyl nitriles in moderate to good yields and with high regio- and enantioselectivities. The enantioenriched allyl nitrile products can be used for the preparation of various synthetically useful chiral intermediates through simple transformations. • Copper-catalyzed asymmetric radical cyanation reactions are developed • Enantioselective decarboxylative cyanation of β,γ -unsaturated carboxylic acids is shown • The reaction is promoted by a hypervalent iodine(III) reagent • Efficient generation of the highly reactive allyl radical powers the reaction Copper-catalyzed asymmetric radical cyanation reactions have emerged as a powerful platform for construction of enantioenriched cyano-containing compounds under mild conditions. Zhang and Huang et al. develop a copper-catalyzed enantioselective decarboxylative cyanation of readily available β,γ-unsaturated carboxylic acids promoted by a hypervalent iodine(III) reagent.

Formal [4+1] Annulation of Azoalkenes with CF3-Imidoyl Sulfoxonium Ylides and Dual Double Bond Isomerization Cascade: Synthesis of Trifluoromethyl-Containing Pyrazole Derivatives

A straightforward strategy for the metal-free construction of trifluoromethyl-containing pyrazole derivatives has been achieved from readily available α-halo hydrazones and CF3-imidoyl sulfoxonium ylides. The cascade transformation proceeds through the formal [4+1] cycloaddition followed by an unexpected dual double bond isomerization. The protocol features mild conditions, easy operation, excellent substrate compatibility, and good regioselectivity. The synthetic utility is demonstrated by scale-up reaction and further elaboration of the obtained pyrazole products.

Synthesis of Unsymmetric Thiosulfonates Starting from N-Substituted O-Thiocarbamates: Easy Access to the S–SO2 Bond

Using phenyliodine diacetate as an oxidant and nickel acetate as a promoter, a wide range of unsymmetric thiosulfonates could be furnished easily in moderate to excellent yields starting from N-substituted O-thiocarbamates and sodium sulfinates. This protocol features mild conditions, short reaction times, and high atomic utilization, which can provide an alternative method for the synthesis of unsymmetric thiosulfonates. In addition, the reaction could be scaled up on a gram scale, showing potential application value in industry.

Photocatalyzed Defluorinative Dichloromethylation of α-CF3 Alkenes Using CHCl3 as the Radical Source.

A visible-light-induced defluorinative dichloromethylation of α-CF3 alkenes was developed with cheap and readily accessible chloroform simultaneously as a dichloromethylation reagent and reaction medium, leading to the facile preparation of new polyhalogenated scaffolds. Notably, the change from CHCl3 to CDCl3 offers a straightforward pathway for accessing the deuterated analogues with excellent degrees of D incorporation. Mechanistic studies suggested the reaction underwent a radical addition of the dichloromethyl radical with alkenes, followed by sequential single-electron transfer and defluorination. This protocol features mild conditions, easy operation, facile scalability, and high efficiency, allowing convenient access to dichloronated gem-difluoroalkenes.

Boron-Promoted Umpolung Reaction of Sulfonyl Chlorides for the Stereospecific Synthesis of Thioglycosides via Reductive Deoxygenation Coupling Reactions.

S-Glycosides have broad biological activities and serve as stable mimics of natural O-glycoside counterparts and thus are of great therapeutic potential. Herein we disclose an efficient method for the stereospecific synthesis of 1-thioglycosides via a boron-promoted reductive deoxygenation coupling reaction from readily accessible sulfonyl chlorides and glycosyl bromides. Our protocol features mild conditions and excellent functional group tolerance and stereoselectivity. The translational potential of this metal-free approach is demonstrated by the late-stage glycodiversification of natural products and drug molecules.

Photoinduced Copper‐Catalyzed Asymmetric Three‐Component Coupling of 1,3‐Dienes: An Alternative to Kharasch–Sosnovsky Reaction

AbstractKharasch–Sosnovsky reaction is one of the most powerful methods for allylic oxidation of alkenes. However, the inherent radical mechanism and use of peroxides as both oxidants and oxygen nucleophiles render dearth of universal catalytic systems for highly enantioselective variants and limited scope. Herein, an alternative to the asymmetric Kharasch–Sosnovsky reaction that utilized a chiral copper catalyst and purple‐LED irradiation to enable the three‐component coupling of 1,3‐dienes, oxime esters, and carboxylic acids is reported. This protocol features mild conditions, remarkable scope and functional group tolerance as evidenced by >80 examples and utility in the late‐stage modification of pharmaceuticals and natural products. Detailed mechanistic studies provide evidences for the radical‐based reaction pathway.

Photoinduced Copper-Catalyzed Asymmetric Three-Component Coupling of 1,3-Dienes: An Alternative to Kharasch-Sosnovsky Reaction.

Kharasch-Sosnovsky reaction is one of the most powerful methods for allylic oxidation of alkenes. However, the inherent radical mechanism and use of peroxides as both oxidants and oxygen nucleophiles render dearth of universal catalytic systems for highly enantioselective variants and limited scope. Herein, an alternative to the asymmetric Kharasch-Sosnovsky reaction that utilized a chiral copper catalyst and purple-LED irradiation to enable the three-component coupling of 1,3-dienes, oxime esters, and carboxylic acids is reported. This protocol features mild conditions, remarkable scope and functional group tolerance as evidenced by >80 examples and utility in the late-stage modification of pharmaceuticals and natural products. Detailed mechanistic studies provide evidences for the radical-based reaction pathway.

Cascade Reaction of Tryptamine-Derived Isocyanides with Nitrile Oxides: Construction of Oxazine Fused-Spiroindoline Derivatives.

A one-step cascade reaction of tryptamine-derived isocyanides with in situ generated nitrile oxides for the synthesis of fused spiroindolines was described. The desired products could be efficiently synthesized in moderate to good yields (42-87%). The protocol features mild conditions, wide substrate scope, and high efficiency.

Enantioselective Synthesis of Indole-Fused Bicyclo[3.2.1]octanes via Palladium(II)-Catalyzed Cascade Reaction.

Indole-fused bicyclo[3.2.1]octanes are highly important structural units in natural products and biologically active compounds. However, there has been limited success in the enantioselective synthesis of these skeletons due to the complexity of the structure and the control of the enantioselectivity. Herein an enantioselective construction of indole-fused bicyclo[3.2.1]octanes bearing an all-carbon quaternary bridgehead stereocenter was developed via an aminopalladition-triggered Heck-type reaction. The protocol features mild conditions and good tolerance for a wide range of functional groups. The transformation can also be scaled up to demonstrate its practicability. The mechanistic studies reveal that the formation of an intermediate indol-3-yl palladium species via C-H activation should be ruled out.

Visible-Light-Promoted Polysubstituted Olefins Synthesis Involving Sulfur Ylides as Carbene Trapping Reagents.

A blue-light-emitting diode (LED) promoted coupling of aryl diazoacetates with sulfur ylides is described. This protocol features mild conditions, good functional group tolerance, and broad substrate scope for both aryl diazoacetates with sulfur ylides. Under optimal reaction conditions, a wide range of trisubstituted olefins is obtained in moderate to good yield, which can be further transferred to other biologically important heterocycles after a two-step simple operation.

Electrochemically Tuned Oxidative [4+2] Annulation and Dioxygenation of Olefins with Hydroxamic Acids.

This work represents the first [4+2] annulation of hydroxamic acids with olefins for the synthesis of benzo[c][1,2]oxazines scaffold via anode-selective electrochemical oxidation. This protocol features mild conditions, is oxidant free, shows high regioselectivity and stereoselectivity, broad substrate scope of both alkenes and hydroxamic acids, and is compatible with terpenes, peptides, and steroids. Significantly, the dioxygenation of olefins employing hydroxamic acid is also successfully achieved by switching the anode material under the same reaction conditions. The study not only reveals a new reactivity of hydroxamic acids and its first application in electrosynthesis but also provides a successful example of anode material-tuned product selectivity.

Electrochemically Tuned Oxidative [4+2] Annulation and Dioxygenation of Olefins with Hydroxamic Acids

AbstractThis work represents the first [4+2] annulation of hydroxamic acids with olefins for the synthesis of benzo[c][1,2]oxazines scaffold via anode‐selective electrochemical oxidation. This protocol features mild conditions, is oxidant free, shows high regioselectivity and stereoselectivity, broad substrate scope of both alkenes and hydroxamic acids, and is compatible with terpenes, peptides, and steroids. Significantly, the dioxygenation of olefins employing hydroxamic acid is also successfully achieved by switching the anode material under the same reaction conditions. The study not only reveals a new reactivity of hydroxamic acids and its first application in electrosynthesis but also provides a successful example of anode material‐tuned product selectivity.

Metal‐Free, Visible‐Light Promoted Intramolecular Azole C−H Bond Amination Using Catalytic Amount of I2: A Route to 1,2,3‐Triazolo[1,5‐a]quinazolin‐5(4H)‐ones

AbstractA metal‐free, visible‐light promoted intramolecular azole C−H bond amination for the rapid and efficient synthesis of pharmaceutical important 1,2,3‐triazolo[1,5‐a]quinazolin‐5(4H)‐ones has been developed. Employing 2‐(1,2,3‐triazol‐1‐yl)benzamides as the easily available precursors and catalytic amount of I2 as an initiator, the desired product were isolated in moderate to excellent yiels with a broad substrate scope and good functional group tolerance. Furthermore, this protocol features mild conditions, operational simplicity, and easy scale‐up. Preliminary mechanistic studies suggested that a radical pathway might be involved during the reaction.magnified image

Pd‐Catalyzed Site‐Selective Borylation of Simple Arenes via Thianthrenation†

Summary of main observation and conclusionSite‐selective borylation of simple arenes was realized in one pot via an electrophilic thianthrenation/Pd‐catalyzed borylation sequence. The key to achieve this operatically simple process is the use of Pd catalysis, which could tolerate the solvent and acidic conditions used in the thianthrenation step. This protocol features mild conditions, broad functional group tolerance, and simple manipulations, and is suitable for late‐stage functionalization of a wide range of pharmaceuticals and complex bioactive molecules.