Manganese-Catalyzed Hydroarylation of Unactivated Alkenes

Transition-metal-catalyzed hydroarylation of unactivated alkenes with strategic use of remote coordinating functional groups has received significant attention recently to address the issues of both low reactivity and poor selectivity. The bidentate 8-aminoquinoline amide group is the most successfully adopted in unactivated alkenes for Pd and Ni catalysis. We describe the first manganese-catalyzed hydroarylation of unactivated alkenes bearing diverse simple functionalities with arylboronic acids. A series of δ- and γ-arylated amides, ketones, pyridines, and amines was accessed with excellent regioselectivity and in high yields. Hydroalkenylation of unactivated alkenes was also shown to be applicable under this manganese-catalysis regime. The method features earth-abundant manganese catalysis, easily available substrates, broad functional-group tolerance, and excellent regioselective control.     

A General Acid‐Mediated Hydroaminomethylation of Unactivated Alkenes and Alkynes

In comparison to the extensively studied metal‐catalyzed hydroamination reaction, hydroaminomethylation has received significantly less attention despite its considerable potential to streamline amine synthesis. State‐of‐the‐art protocols for hydroaminomethylation of alkenes rely largely on transition‐metal catalysis, enabling this transformation only under highly designed and controlled conditions. Here we report a broadly applicable, acid‐mediated approach to the hydroaminomethylation of unactivated alkenes and alkynes. This methodology employs cheap, readily available, and bench‐stable reactants and affords the desired amines with excellent functional group tolerance and impeccable regioselectivity. The broad scope of this transformation, as well as mechanistic investigations and in situ domino functionalization reactions are reported.     

Intermolecular Photocatalyzed Heck‐like Coupling of Unactivated Alkyl Bromides by a Dinuclear Gold Complex

A practical protocol for a photocatalyzed alkyl‐Heck‐like reaction of unactivated alkyl bromides and different alkenes promoted by dinuclear gold photoredox catalysis in the presence of an inorganic base is reported. Primary, secondary, and tertiary unactivated alkyl bromides with β‐hydrogen can be applied. Esters, aldehydes, ketones, nitriles, alcohols, heterocycles, alkynes, alkenes, ethers, and halogen moieties are all well tolerated. In addition to 1,1‐diarylalkenes, silylenolethers and enamides can also be applied, which further increases the synthetic potential of the reaction. The mild reaction conditions, broad substrate scope, and an excellent functional‐group tolerance deliver an ideal tool for synthetic chemists that can even be used for challenging late‐stage modifications of complex natural products.     

Copper‐Catalyzed Regioselective Borocarbonylative Coupling of Unactivated Alkenes with Alkyl Halides: Synthesis of β‐Boryl Ketones

The borocarbonylative coupling of unactivated alkenes with alkyl halides remains a challenge. In this communication, a Cu‐catalyzed borocarbonylative coupling of unactivated alkenes with alkyl halides for the synthesis of β‐boryl ketones has been developed. A broad range of β‐boryl ketone derivatives was prepared in moderate to excellent yields with complete regioselectivity.     

Full Selectivity Control in Cobalt(III)‐Catalyzed C−H Alkylations by Switching of the C−H Activation Mechanism

Selectivity control in hydroarylation‐based C−H alkylation has been dominated by steric interactions. A conceptually distinct strategy that exploits the programmed switch in the C−H activation mechanism by means of cobalt catalysis is presented, which sets the stage for convenient C−H alkylations with unactivated alkenes. Detailed mechanistic studies provide compelling evidence for a programmable switch in the C−H activation mechanism from a linear‐selective ligand‐to‐ligand hydrogen transfer to a branched‐selective base‐assisted internal electrophilic‐type substitution.     

Palladium‐Catalyzed Asymmetric Intramolecular Reductive Heck Desymmetrization of Cyclopentenes: Access to Chiral Bicyclo[3.2.1]octanes

A palladium‐catalyzed asymmetric reductive Heck reaction of unactivated aliphatic alkenes, with eliminable β‐hydrogen atoms, has been realized for the first time. A series of optically active bicyclo[3.2.1]octanes bearing chiral quaternary and tertiary carbon stereocenters were obtained in good yields with excellent enantioselectivities, exhibiting good functional‐group tolerance and scalability. Moreover, deuterated optically active bicyclo[3.2.1]octanes were also obtained in high efficiency.     

Iridium-Catalyzed Remote Site-Switchable Hydroarylation of Alkenes Controlled by Ligands

An iridium-catalyzed remote site-switchable hydroarylation of alkenes was reported, delivering the products functionalized at the subterminal methylene and terminal methyl positions on an alkyl chain controlled by two different ligands, respectively, in good yields and with good to excellent site-selectivities. The catalytic system showed good functional group tolerance and a broad substrate scope, including unactivated and activated alkenes. More importantly, the regioconvergent transformations of mixtures of isomeric alkenes were also successfully realized. The results of the mechanistic studies demonstrate that the reaction undergoes a chain-walking process to give an [Ar−Ir−H] complex of terminal alkene. The subsequent processes proceed through the modified Chalk–Harrod-type mechanism via the migratory insertion of terminal alkene into the Ir−C bond followed by C−H reductive elimination to afford the hydrofunctionalization products site-selectively.     

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.     

Nickel‐Catalyzed Reductive Cross‐Coupling of Aryl Halides with Monofluoroalkyl Halides for Late‐Stage Monofluoroalkylation

A combinatorial nickel‐catalyzed monofluoroalkylation of aryl halides with unactivated fluoroalkyl halides by reductive cross‐coupling has been developed. This method demonstrated high efficiency, mild conditions, and excellent functional‐group tolerance, thus enabling the late‐stage monofluoroalkylation of diverse drugs. The key to success was the combination of diverse readily available bidentate and monodentate pyridine‐type nitrogen ligands with nickel, which in situ generated a variety of readily tunable catalysts to promote fluoroalkylation with broad scope with respect to both coupling partners. This combinatorial catalysis strategy offers a solution for nickel‐catalyzed reductive cross‐coupling reactions and provides an efficient way to synthesize fluoroalkylated druglike molecules for drug discovery.     

Palladium(II)‐Catalyzed Enantioselective Azidation of Unactivated Alkenes

The first Pd‐catalyzed enantioselective azidation of unactivated alkenes has been established by using readily accessible 1‐azido‐1,2‐benziodoxol‐3(1H)‐one (ABX) as an azidating reagent, which affords a wide variety of structurally diverse 3‐N₃‐substituted piperidines in good yields with excellent enantioselectivity. The reaction features good functional‐group compatibility and mild reaction conditions. Notably, both an electrophilic azidating reagent and the sterically bulky chiral pyridinyl‐oxazoline (Pyox) ligand are crucial to the successful reaction.     

Redox-Neutral Nickel(II) Catalysis: Hydroarylation of Unactivated Alkenes with Arylboronic Acids

Reported here is the discovery of a redox-neutral Ni^II/Ni^II catalytic cycle which is capable of the linear-selective hydroarylation of unactivated alkenes with arylboronic acids for the first time. This novel catalytic cycle, enabled by the use of an electron-rich diimine ligand, features broad substrate scope, and excellent functional-group and heterocycle compatibility under mild reaction conditions in the absence of additional oxidants and reductants. Mechanistic investigations using kinetic analysis and deuterium-labelling experiments revealed the protonation to be the rate-determining step in this redox-neutral catalysis, and the reversible chain-walking nature of the newly developed diimine-Ni catalyst.     

Manganese‐Catalyzed C−H Functionalizations: Hydroarylations and Alkenylations Involving an Unexpected Heteroaryl Shift

A manganese‐catalyzed regio‐ and stereoselective hydroarylation of allenes is reported. The C−H functionalization method provides access to various alkenylated indoles in excellent yields. Moreover, a hydroarylation/cyclization cascade involving an unexpected C−N bond cleavage and aryl shift has been developed, which provides a new synthetic approach to substituted pyrroloindolones.     

Migratory Arylboration of Unactivated Alkenes Enabled by Nickel Catalysis

An unprecedented arylboration of unactivated terminal alkenes, featuring 1,n‐regioselectivity, has been achieved by nickel catalysis. The nitrogen‐based ligand plays an essential role in the success of this three‐component reaction. This transformation displays good regioselectivity and excellent functional‐group tolerance. In addition, the incorporation of a boron group into the products provides substantial opportunities for further transformations. Also demonstrated is that the products can be readily transformed into pharmaceutically relevant molecules. Unexpectedly, preliminary mechanistic studies indicate that although the metal migration favors the α‐position of boron, selective and decisive bond formation is favored at the benzylic position.     

Dimeric Manganese‐Catalyzed Hydroarylation and Hydroalkenylation of Unsaturated Amides

An unprecedented Mn(I)‐catalyzed selective hydroarylation and hydroalkenylation of unsaturated amides with commercially available organic boronic acids is reported. Alkenyl boronic acids have been successfully employed for the first time in Mn(I)‐catalyzed carbon–carbon bond formation. A wide array of β‐alkenylated amide products can be obtained in moderate to good yields, which offers practical access to five‐ and six‐membered lactams. This protocol has predictable regio‐ and chemoselectivity, excellent functional group compatibility and ease of operation in air, representing a significant step‐forward towards manganese‐catalyzed C?C coupling.     

Asymmetric Enzymatic Hydration of Unactivated,Aliphatic Alkenes

The direct enantioselective addition of water to unactivated alkenes could simplify the synthesis of chiral alcohols and solve a long‐standing challenge in catalysis. Here we report that an engineered fatty acid hydratase can catalyze the asymmetric hydration of various terminal and internal alkenes. In the presence of a carboxylic acid decoy molecule for activation of the oleate hydratase from E. meningoseptica, asymmetric hydration of unactivated alkenes was achieved with up to 93 % conversion, excellent selectivity (>99 % ee, >95 % regioselectivity), and on a preparative scale.     

Asymmetric Enzymatic Hydration of Unactivated,Aliphatic Alkenes

The direct enantioselective addition of water to unactivated alkenes could simplify the synthesis of chiral alcohols and solve a long‐standing challenge in catalysis. Here we report that an engineered fatty acid hydratase can catalyze the asymmetric hydration of various terminal and internal alkenes. In the presence of a carboxylic acid decoy molecule for activation of the oleate hydratase from E. meningoseptica, asymmetric hydration of unactivated alkenes was achieved with up to 93 % conversion, excellent selectivity (>99 % ee, >95 % regioselectivity), and on a preparative scale.     

A Highly Efficient Dimeric Manganese‐Catalyzed Selective Hydroarylation of Internal Alkynes

We have developed a general and site‐predictable manganese‐catalyzed hydroarylation of internal alkynes in the presence of water, under an air atmosphere without the involvement of ligand. The unique catalytic feature of this reaction is highlighted by comparison with other widely used transition metal catalysts including palladium, rhodium, nickel, or copper. The simple operation, high efficiency and excellent functional group compatibility make this protocol practical for more than 90 structurally diverse internal alkynes, overcoming the influence of both electronic and steric effect of alkynes. Its exclusive regio‐ and chemoselectivity originates from the unique reactivity of the manganese‐based catalyst towards an inherent double controlled strategy of sterically hindered propargyl alcohols without the installing of external directing groups. Its synthetic robustness and practicality have been illustrated by the concise synthesis of bervastatin, a hypolipidemic drug, and late‐stage modification of complex alkynes with precise regioselectivity.     

Highly efficient gold(III)-catalyzed intermolecular hydroarylation of unactivated alkenes with arenes under mild conditions

A simple and efficient method for functionalization of electron-rich arenes and heteroarenes with unactivated alkenes by Au(III)-catalyzed intermolecular hydroarylation under mild reaction conditions was developed. This method features a short reaction time (5 h) under mild conditions and has a broad substrate scope, including electron-rich arenes and heteroarenes, terminal and internal substituted aryl alkenes, and unactivated aliphatic alkenes.     

Cobalt(III)‐Catalyzed Aryl and Alkenyl CH Aminocarbonylation with Isocyanates and Acyl Azides

Expedient C? H aminocarbonylations of unactivated (hetero)arenes and alkenes were accomplished with a cobalt(III) catalyst that shows high functional group tolerance. The C? H functionalization occurred with excellent chemo‐, site‐, and diastereoselectivity and enabled step‐economical reactions with isocyanates or acyl azides.     

Platinum(II) Olefin Hydroarylation Catalysts: Tuning Selectivity for the anti‐Markovnikov Product

Pt^II complexes containing unsymmetrical (pyridyl)pyrrolide ligands are shown to catalyze the hydroarylation of unactivated alkenes with selectivity for the anti‐Markovnikov product. Substitution on the pyrrolide portion of the ligand allows effective tuning of the selectivity to anti‐Markovnikov alkylarene products, whereas substitution on the pyridyl portion can promote competitive alkenylarene production.