Visible Light‐Induced Decarboxylative Alkylation of Heterocyclic Aromatics with Carboxylic Acids via Anthocyanin as a Photocatalyst

A visible light‐induced decarboxylative alkylation of heterocyclic aromatics with aliphatic carboxylic acids was developed by using anthocyanins as a photocatalyst under mild conditions. A series of alkylated heterocyclic compounds were obtained in moderate to good yields by using the metal‐free decarboxylative coupling reaction under blue light. This strategy uses cheap and readily available carboxylic acids as alkylation reagents with good functional group tolerance and environmental friendliness. It is worth noting that this is the first time that anthocyanin has been used to catalyze the Minisci‐type C?H alkylation. The mechanism of decarboxylation alkylation was studied by capturing the adduct of alkyl radical and hydroquinone, thus confirming a radical mechanism. This protocol provides an alternative visible light‐induced decarboxylative alkylation for the functionalization of heterocyclic aromatics.     

Expedient Iron‐Catalyzed C−H Allylation/Alkylation by Triazole Assistance with Ample Scope

Triazole assistance set the stage for a unified strategy for the iron‐catalyzed C?H allylation of arenes, heteroarenes, and alkenes with ample scope. The versatile catalyst also proved competent for site‐selective methylation, benzylation, and alkylation with challenging primary and secondary halides. Triazole‐assisted C?H activation proceeded chemo‐, site‐, and diastereo‐selectively, and the modular TAM directing group was readily removed in a traceless fashion under exceedingly mild reaction conditions.     

Photoredox Generation of Carbon‐Centered Radicals Enables the Construction of 1,1‐Difluoroalkene Carbonyl Mimics

Described is a facile, scalable route to access functional‐group‐rich gem ‐difluoroalkenes. Using visible‐light‐activated catalysts in conjunction with an arsenal of carbon‐radical precursors, an array of trifluoromethyl‐substituted alkenes undergoes radical defluorinative alkylation. Nonstabilized primary, secondary, and tertiary radicals can be used to install functional groups in a convergent manner, which would otherwise be challenging by two‐electron pathways. The process readily extends to other perfluoroalkyl‐substituted alkenes. In addition, we report the development of an organotrifluoroborate reagent to expedite the synthesis of the requisite trifluoromethyl‐substituted alkene starting materials.     

Catalytic,Enantioselective α‐Alkylation of Azlactones with Nonconjugated Alkenes by Directed Nucleopalladation

A palladium(II)‐catalyzed enantioselective α‐alkylation of azlactones with nonconjugated alkenes is described. The reaction employs a chiral BINOL‐derived phosphoric acid as the source of stereoinduction, and a cleavable bidentate directing group appended to the alkene to control the regioselectivity and stabilize the nucleopalladated alkylpalladium(II) intermediate in the catalytic cycle. A wide range of azlactones were found to be compatible under the optimal reaction conditions to afford products bearing α,α‐disubstituted α‐amino‐acid derivatives with high yields and high enantioselectivity.     

Copper‐Catalyzed Aerobic Decarboxylation/Ketooxygenation of Electron‐Deficient Alkenes

A copper‐catalyzed ketooxygenation of electron‐deficient alkenes was developed. This approach combines O?H alkylation, aerobic decarboxylation, and oxygenation in one transformation. Mechanistic investigation of this reaction showed that the copper salt is responsible for both generating the amidoxyl radical and promoting aerobic decarboxylation.     

Catalytic,Enantioselective α‐Alkylation of Azlactones with Nonconjugated Alkenes by Directed Nucleopalladation

A palladium(II)‐catalyzed enantioselective α‐alkylation of azlactones with nonconjugated alkenes is described. The reaction employs a chiral BINOL‐derived phosphoric acid as the source of stereoinduction, and a cleavable bidentate directing group appended to the alkene to control the regioselectivity and stabilize the nucleopalladated alkylpalladium(II) intermediate in the catalytic cycle. A wide range of azlactones were found to be compatible under the optimal reaction conditions to afford products bearing α,α‐disubstituted α‐amino‐acid derivatives with high yields and high enantioselectivity.     

Tetrabutylammonium decatungstate-photosensitized alkylation of electrophilic alkenes: Convenient functionalization of aliphatic C-H bonds

Tetrabutylammonium decatungstate (TBADT, 2 x 10(-3) m) is an effective photocatalyst for the alkylation of electrophilic alkenes (0.1 m, alpha,beta-unsaturated nitriles, esters, ketones) by alkanes, alcohols, and ethers. The products are in most cases obtained in >70 % isolated yields, through an experimentally very simple procedure. The kinetics of the radical processes following initial hydrogen abstraction by excited TBADT in deoxygenated MeCN have been studied. In the absence of a trap, back hydrogen transfer from reduced tungstate is the main pathway for alkyl radicals, while alpha-hydroxyalkyl radicals are oxidized to ketones by ground-state TBADT. With both radical types the reaction ceases at a few percent conversion. However, trapping by electrophilic alkenes is followed by reduction of the radical adduct and regeneration of the catalyst, which allows the alkylation to proceed up to complete alkene conversion with the mentioned good yields of products. With a nucleophilic (alpha-hydroxyalkyl) radical, alkylation is efficient (Phi = 0.58) and can also be carried out when degassing is omitted, the only difference being a short induction period. With a less reactive (cyclohexyl) radical, the quantum yield is lower (Phi = 0.06) and the reaction is considerably slowed in aerated solutions, but the chemical yield remains good.     

Asymmetric Construction of Axially Chiral 2‐Arylpyrroles by Chirality Transfer of Atropisomeric Alkenes

Axially chiral 2‐arylpyrrole frameworks are efficiently accessed through a direct chirality transfer strategy by rapid cyclization of enantioenriched atropisomeric alkenes, which are generated by organocatalytic asymmetric N‐alkylation reactions. This approach accommodates a broad scope of substrates with remarkably high chirality transfer efficiency, affording novel atropisomers with a fully substituted pyrrole moiety and high enantiopurities. Given the enantioenriched atropisomeric alkenes, novel heterocyclic 2‐arylazepine atropisomers were realized through a rationally designed ene reaction.     

β‐Selective Aroylation of Activated Alkenes by Photoredox Catalysis

Late‐stage synthesis of α,β‐unsaturated aryl ketones remains an unmet challenge in organic synthesis. Reported herein is a photocatalytic non‐chain‐radical aroyl chlorination of alkenes by a 1,3‐chlorine atom shift to form β‐chloroketones as masked enones that liberate the desired enones upon workup. This strategy suppresses side reactions of the enone products. The reaction tolerates a wide array of functional groups and complex molecules including derivatives of peptides, sugars, natural products, nucleosides, and marketed drugs. Notably, addition of 2,6‐di‐tert‐butyl‐4‐methyl‐pyridine enhances the quantum yield and efficiency of the cross‐coupling reaction. Experimental and computational studies suggest a mechanism involving PCET, formation and reaction of an α‐chloro‐α‐hydroxy benzyl radical, and 1,3‐chlorine atom shift.     

Radical Monofluoroalkylative Alkynylation of Olefins by a Docking–Migration Strategy

A radical‐mediated monofluoroalkylative alkynylation of alkenes is disclosed for the first time. The reaction demonstrates a remarkably broad substrate scope in which both activated and unactivated alkenes are suitable starting materials. The concurrent addition of an alkynyl and a monofluoroalkyl group onto an alkene proceeds through a docking–migration sequence, affording a vast array of valuable fluoroalkyl‐substituted alkynes. Many complex natural products and drug derivatives are readily functionalized, demonstrating that this method can be used for late‐stage alkynylation.     

Copper‐Catalyzed Cyanomethylation of Allylic Alcohols with Concomitant 1,2‐Aryl Migration: Efficient Synthesis of Functionalized Ketones Containing an α‐Quaternary Center

A copper‐catalyzed alkylation of allylic alcohols by alkyl nitriles with concomitant 1,2‐aryl migration was developed. Formation of the alkyl nitrile radical was followed by its intermolecular addition to alkenes and the migration of a vicinal aryl group with the concomitant generation of a carbonyl functionality to complete the domino sequence. Mechanistic studies suggested that 1,2‐aryl migration proceeded through a radical pathway (neophyl rearrangement). The protocol provided an efficient route to functionalized ketones containing an α‐quaternary center.     

Carboamination of Unactivated Alkenes through Three‐Component Radical Conjugate Addition

Two‐component Giese type radical additions are highly practical and established reactions. Herein, three‐component radical conjugate additions of unactivated alkenes to Michael acceptors are reported. Amidyl radicals, oxidatively generated from α‐amido oxy acids using redox catalysis, act as the third reaction component which add to the unactivated alkenes. The adduct radicals engage in Giese type additions to Michael acceptors to provide, after reduction, the three‐component products in an overall alkene carboamination reaction. Transformations which can be conducted under practical mild conditions feature high functional group tolerance and broad substrate scope.     

Formal Aza‐Wacker Cyclization by Tandem Electrochemical Oxidation and Copper Catalysis

In oxidative electrochemical organic synthesis, radical intermediates are often oxidized to cations on the way to final product formation. Herein, we describe an approach to transform electrochemically generated organic radical intermediates into neutral products by reaction with a metal catalyst. This approach combines electrochemical oxidation with Cu catalysis to effect formal aza‐Wacker cyclization of internal alkenes. The Cu catalyst is essential for transforming secondary and primary alkyl radical intermediates into alkenes. A wide range of 5‐membered N‐heterocycles including oxazolidinone, imidazolidinone, thiazolidinone, pyrrolidinone, and isoindolinone can be prepared under mild conditions.     

Enantioselective Template‐Directed [2+2] Photocycloadditions of Isoquinolones: Scope,Mechanism and Synthetic Applications

A strategy for the enantioselective [2+2] photocycloaddition of isoquinolones with alkenes is presented, in which the formation of a supramolecular complex between a chiral template and the substrate ensures high enantioface differentiation by shielding one face of the substrate. Fifteen different electron‐deficient alkenes and ten different substituted isoquinolones undergo efficient photocycloaddition, yielding the cyclobutane products in excellent yields and with outstanding regio‐, diastereo‐ and enantioselectivities (up to 99 % ee). The mechanism of the reaction is investigated by means of triplet sensitization/quenching and radical clock experiments, the results of which are consistent with the involvement of a triplet excited state and a 1,4‐biradical intermediate. The variety of functionalized cyclobutanes obtained using this approach can be further increased by straightforward synthetic transformations of the photoadducts, allowing rapid access to libraries of compounds for various applications.     

Silver‐Catalyzed Decarboxylative Allylation of Difluoroarylacetic Acids with Allyl Sulfones in Water

A practical silver‐catalyzed decarboxylative allylation of α,α‐difluoroarylacetic acids with allyl sulfones is described, which provides a variety of β,β‐difluorinated alkenes in good yields. Notably, the reaction proceeds smoothly in water with good functional group tolerance. The practicality and synthetic value of this process was demonstrated by scaled‐up experiment and elaboration of the products via reduction or Heck reaction. Primary mechanism investigations suggest that a radical process might be involved.     

Silylated Cyclohexadienes in Radical Chain Hydrosilylations

A new method for the mild radical hydrosilylation of alkenes and alkynes is described. Silylated cyclohexadienes that can be readily prepared on large scale are used as radical hydrosilylating reagents. Non‐activated alkenes and alkynes are hydrosilylated in high yields. The reaction can be combined with C C bond formation, as demonstrated for the preparation of silylated cycloalkanes from the corresponding dienes. Furthermore, radical hydrosilylations in combination with β‐fragmentation reactions for the synthesis of allylsilanes and hydrosilylations of aldehydes and ketones providing protected alcohols can be readily performed by this strategy.     

Consecutive approach to alkenes that combines radical addition of phosphorus hydrides with Horner-Wadsworth-Emmons-type reactions

[reaction: see text] Addition of diethyl thiophosphite to terminal alkenes, in the presence of a radical initiator, followed by deprotonation of the phosphonothioate and reaction with a ketone, offers a concise one-pot approach to substituted alkenes. This novel method, which can incorporate alkylation or acylation steps, can be applied to the stereoselective formation of sterically hindered tri- and tetrasubstituted alkenes.     

Chelation versus Non‐Chelation Control in the Stereoselective Alkenyl sp2 C−H Bond Functionalization Reaction

A hydroxy group chelation‐assisted stereospecific oxidative cross‐coupling reaction between alkenes was developed under mild reaction conditions. In the presence of palladium catalyst, the alkenes tethered with hydroxy functionality can couple efficiently with electron‐deficient alkenes to form the corresponding multi‐substituted olefin products. The hydroxy group on the substrate could play dual roles in reaction, acting as the directing group for alkenyl C−H bond activation and controlling the stereoselectivity of the products.     

Catalytic, enantioselective alkylation of alpha-imino esters: the synthesis of nonnatural alpha-amino acid derivatives.

Methodology for the practical synthesis of nonnatural amino acids has been developed through the catalytic, asymmetric alkylation of alpha-imino esters and N,O-acetals by enol silanes, ketene acetals, alkenes, and allylsilanes using chiral transition metal-phosphine complexes as catalysts (1-5 mol %). The alkylation products, which are prepared with high enantioselectivity (up to 99% ee) and diastereoselectivity (up to 25:1/anti:syn), are protected nonnatural amino acids that represent potential precursors to natural products and pharmaceuticals. A kinetic analysis of the catalyzed reaction of alkenes with alpha-imino esters is presented to shed light on the mechanism of this reaction.     

Radical Reductive Alkylation of Enamines: Conversion of the Products into Alkenes and Primary Amines

Procedures for the conversion of tertiary amines, obtained by radical reductive alkylation of enamines, into alkenes (Cope reaction) and primary amines (double β-elimination reaction) are presented.