Three-component Difunctionalization Research Articles

Enantioselective Ni-Catalyzed 1,2-Borylalkynylation of Unactivated Alkenes.

Enantioselective three-component difunctionalization of alkenes with boron reagents represents an attractive strategy for assembling three-dimensional chiral organoboron compounds. However, regio- and enantiocontrol comprise the pivot challenges in these transformations, which predominantly require the use of activated conjugated alkenes. Herein, by utilizing various carbonyl directing groups, including amides, sulfinamides, ketones, and esters, we succeed in realizing a nickel-catalyzed 1,2-borylalkynylation of unactivated alkenes to enable the simultaneous incorporation of a boron entity and an sp-fragment across the double bond. The products contain boryl, alkynyl, and carbonyl functional groups with orthogonal synthetic reactivities, offering three handles for further derivatization to access valuable intermediates. The utility of this ligand-enabled asymmetric protocol has been highlighted through the late-stage decoration of drug-relevant molecules.

Enantioselective domino alkyl arylation of vinyl phosphonates by combining photoredox and nickel catalysis

A nickel/photoredox mediated asymmetric domino alkyl arylation of vinyl phosphonates to generate a diverse array of enantioenriched α-aryl phosphonates is disclosed. This asymmetric three-component difunctionalization couples aryl halides and alkyl bromides with vinyl phosphonates, exhibiting excellent chemo- and regioselectivity under mild reaction conditions. The method avoids the need for pre-formed organometallics and phosphorus halides. Mechanistic and DFT studies suggest that photoexcited [4CzIPN]* oxidizes diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (HEH) to generate the [4CzIPN]•–, which then reduces the alkyl bromide to form alkyl radicals that undergo Giese addition to the vinyl phosphonate. At the same time, Ni0 oxidatively adds the aryl bromide followed by enantiodetermining oxidative radical trapping of the phosphonate-based radical by the tetrahedral NiII center followed by reductive elimination. Independent gradient model based on Hirshfeld partition (IGMH) analysis suggests that the orientation of the phosphonate group (P=O…π interaction) is expected to play an essential role in controlling the enantioselectivity.

An organo-photocatalyzed visible-light-driven multi-component approach for carbothioaryl/alkylation of activated alkenes via C(sp3)-H bond functionalization.

A visible-light-driven organophotocatalyzed multi-component approach for carbothiolation of activated alkenes is demonstrated under environmentally benign and redox-neutral conditions, involving direct C(sp3)-H functionalization followed by electrophilic alkyl/arylthiolation. The three-component difunctionalization reaction is a complete transition-metal and peroxide-free process conducted under milder conditions. In this composite reaction, by employing bench-stable reagents, the formation of two new C(sp3)-C(sp3) and C(sp3)-S bonds is achieved for a wide variety of substrates, showcasing the excellent functional group tolerance and chemoselectivity of the methodology. Furthermore, the scalability and utilization of natural sunlight instead of artificial blue LEDs, along with the use of an inexpensive and easy-to-prepare pyrylium salt as an organo-photocatalyst, make this protocol greener and more energy efficient.

Silver-Catalyzed, One-Pot, Three-Component Difunctionalization of Quinones: Synthesis of Indole-Functionalized p-Iminoquinone Derivatives

AbstractA one-pot, three-component difunctionalization of quinones with indoles and arylamines has been developed to synthesize indole functionalized p-iminoquinones derivatives. The approach employed AgOAc as the catalyst in the presence of 3-chlorophenylboronic acid, giving a series of indole functionalized p-iminoquinones derivatives in moderate to good yields. This catalytic approach represents a step-economic and convenient strategy for the difunctionalization of quinones. A plausible reaction pathway has been proposed based on a series of control experiments.

A three-component difunctionalization of N-alkenyl amides via organophotoredox radical-polar crossover.

Herein, we report a three-component organophotoredox coupling of N-alkenyl amides with α-bromocarbonyls and various nucleophiles. This transition metal-free difunctionalization protocol installs sequential C-C and C-Y (Y = S/O/N) bonds in alkenes. This reaction works with terminal and internal alkenes containing both cyclic and acyclic amides via radical-polar crossover.

Manganese-catalyzed chlorosulfonylation of terminal alkene and alkyne via convergent paired electrolysis

Convergent paired electrolysis is an energy-efficient model in organic synthesis, although the main obstacle with its use is matching properties of the intermediates generated in two electrodes. With the development of anodic-coupled electrosynthesis in three-component difunctionalization of alkene, a proposal for two-component difunctionalization of alkene and alkyne using a difunctional reagent has been raised. Herein, we develop a manganese-catalyzed, atom-transfer radical addition of the terminal aryl alkenes and alkynes with sulfonyl chlorides, in which manganese salt has the role of a chlorine atom-transfer catalyst as well as a redox mediator. This method generates analogs of chlorosulfonylated products of high regio- and stereoselectivity, which are derivatives of pharmaceutical drugs and natural products. Manganese-catalyzed electrochemical process Convergent paired electrolysis Chlorosulfonylation of alkene and alkyne Atom-transfer radical addition reaction Convergent paired electrolysis is an atom-economical and energy-efficient model in organic synthesis. Atom-transfer radical addition (ATRA) reaction is a general and facile protocol to realize α, β-functionalization of alkene and alkyne. Here, Lei et al. develop a manganese-catalyzed chlorosulfonylation of terminal alkene/yne via convergent paired electrolysis through ATRA.

Copper-Catalyzed Three-Component Carboboronation of Allenes Using Highly Strained Cyclic Ketimines as Electrophiles.

A diastereoselective copper and NHC-ligand-catalyzed three-component difunctionalization of allenes with bis(pinacolato)diboron and 2H-azirines to afford borylated allylaziridines is described. The reaction exhibits complete diastereoselectivity and good yields, and the further chlorination of the corresponding borylated products was also performed. It is believed that the high ring-strain force of 2H-azirines facilitates the reaction. More chemical transformations of borylated allylaziridines are also reported.

Iron-Catalyzed Three-Component Difunctionalization of Unactivated Alkenes

Key words iron catalysis - difunctionalization - Grignard reagents - alkyl halides

Nickel-Catalyzed Dicarbofunctionalization of Alkenes.

1,2-Dicarbofunctionalization of alkenes has emerged as an efficient synthetic strategy for preparing substituted molecules by coupling readily available alkenes with electrophiles and/or nucleophiles. Nickel complexes serve as effective catalysts owing to their tendency to undergo facile oxidative addition and slow β-hydride elimination, and their capability to access both two-electron and radical pathways. Two-component alkene functionalization reactions have achieved high chemo-, regio-, and stereoselectivities by tethering one of the coupling partners to the alkene substrate. Three-component reactions, however, often incorporate directing groups to control the selectivity. Only a few examples of directing-group-free difunctionalizations of unactivated alkenes have been reported. Therefore, great opportunities exist for the development of three-component difunctionalization reactions with broad substrate scopes and tunable chemo-, regio-, and stereoselectivities.

Recent Advances in Nickel-Catalyzed Three-Component Difunctionalization of Unactivated Alkenes

Catalytic, intermolecular difunctionalization of alkenes represents an efficient and diverse protocol for the buildup of molecular complexity from abundant materials by forging two chemical bonds in a single operation. Despite important progress in this area, transition-metal-catalyzed three-component difunctionalization of unactivated alkenes remains underdeveloped, mainly because of the low reactivity, reduced polarization, and high tendency toward β-hydride elimination of these compounds. In this context, nickel-catalyzed, selective, intermolecular difunctionalization methods that generally proceed via two distinct reaction pathways, migratory insertion of nickel species into alkenes and radical addition to alkenes, have been developed. This short review highlights recent advances in this area.1 Introduction2 Nickel-Catalyzed Three-Component Difunctionalization of Unactivated­ Alkenes via Migratory Insertion Processes3 Nickel-Catalyzed Three-Component Difunctionalization of Unactivated­ Alkenes via Radical Processes4 Conclusions and Perspectives

Recent advances in three-component difunctionalization of gem-difluoroalkenes.

Three-component difunctionalization of alkenes is regarded as one of the most attractive strategies in synthetic chemistry, because it enables the direct synthesis of useful and complex molecules from simple and readily available starting materials in a step-economic manner. gem-Difluoroalkenes, as a class of useful and readily available fluorine-containing raw materials, have been well investigated in two-component coupling reactions. This review focuses on the progress of three-component difunctionalization reactions of gem-difluoroalkenes. On the basis of the intermediates involved in these transformations, these three-component reactions of gem-difluoroalkenes could be categorized into four types: (1) involving an α-fluoroalkylated carbanion, (2) involving an α-fluoroalkylated carbon-metal species, (3) involving an α-fluoroalkylated radical, and (4) involving an α-fluoroalkylated carbocation. The typical transformations, the substrate scope, the reaction mechanisms, and their subsequent applications in the synthesis of bioactive molecules are discussed. Owing to the rapidly increasing interest in this area, we believe that this review will present a timely and comprehensive understanding of the recent progress in three-component difunctionalization reactions of gem-difluoroalkenes.

Copper-Catalyzed Three-Component Difunctionalization of Aromatic Alkenes with 2-Amino-1,4-naphthoquinones and α-Bromocarboxylates.

A copper-catalyzed three-component difunctionalization of aromatic alkenes to access 1,4-naphthoquinone derivatives with diverse structures is described. Experiments show that the difunctionalization reaction is accompanied by ester exchange reaction with the solvent. In this method, α-bromocarboxylates are used as radical precursors and 2-amino-1,4-naphthoquinones as radical trapping reagents. The substrate scope is broad because various aromatic alkenes, 2-amino-1,4-naphthoquinones, and α-bromocarboxylates are employed in the reaction, and corresponding products are obtained in moderate to good yields.

Silver-Catalyzed Three-Component Difunctionalization of Alkenes via Radical Pathways: Access to CF3-Functionalized Alkyl-Substituted 1,4-Naphthoquinone Derivatives.

A silver-catalyzed three-component difunctionalization of alkenes by using 2-amino- and 2-hydroxy-1,4-naphthoquinone derivatives as the radical-trapping reagents is reported. Various alkenes and 2-amino- or 2-hydroxy-1,4-naphthoquinones with diverse structures and electronic properties are applied to the reaction. The methodology provides an alternative method to access CF3-functionalized alkyl-substituted quinone derivatives which are prevalent structures in bioactive molecules. Furthermore, a plausible radical pathway for the reaction is proposed based on results from primary control experiments.

Three-component difunctionalization of alkenes leading to β-acetamido sulfides and β-acetoxy sulfides.

A novel method for the synthesis of β-acetamido sulfides via NBS-mediated aminosulfenylation of alkenes with thiophenols and nitriles under metal-free conditions has been described. And β-acetamido sulfides were also synthesized with 1-(arylthio)pyrrolidine-2,5-diones as substrates and HBr as an additive. On the other hand, iodine-catalyzed 1,2-acetoxysulfenylation of alkenes by using (diacetoxyiodo)benzene as an oxygen source to synthesise various β-acetoxy sulfides was described as well.