Palladium/Copper‐Catalyzed Oxidative Arylation of Terminal Alkenes with Aroyl Hydrazides

An unprecedented oxidative arylation reaction of terminal alkenes with simple aroyl hydrazides has been developed under aerobic conditions for the stereoselective synthesis of 1,2‐disubstituted alkenes. A range of aroyl hydrazides underwent palladium/copper‐catalyzed oxidative Mizoroki–Heck reaction with terminal alkenes open to air in a 1:1 mixture of dimethyl sulfoxide and acetonitrile to give structurally diverse 1,2‐disubstituted alkenes in moderate to excellent yields with excellent regio‐ and E‐selectivity. The reaction tolerated a wide variety of functional groups, such as alkoxy, hydroxy, amino, fluoro, chloro, bromo, cyano, nitro, ester, amide, imide, phosphine oxide, and sulfone groups, and, moreover, molecular oxygen and dimethyl sulfoxide were demonstrated to serve as terminal oxidants. This study provides a useful method for the stereoselective synthesis of 1,2‐disubstituted alkenes through direct transformation of the vinylic C?H bonds in terminal alkenes.     

Hydrodifluoromethylation of Alkenes with Difluoroacetic Acid

A facile method for the regioselective hydrodifluoromethylation of alkenes is reported using difluoroacetic acid and phenyliodine(III) diacetate in tetrahydrofuran under visible‐light activation. This metal‐free approach stands out as it uses inexpensive reagents, does not require a photocatalyst, and displays broad functional group tolerance. The procedure is also operationally simple and scalable, and provides access in one step to high‐value building blocks for application in medicinal chemistry.     

Stereoselective Synthesis of Trisubstituted Alkenes through Sequential Iron‐Catalyzed Reductive anti‐Carbozincation of Terminal Alkynes and Base‐Metal‐Catalyzed Negishi Cross‐Coupling

The stereoselective synthesis of trisubstituted alkenes is challenging. Here, we show that an iron‐catalyzed anti‐selective carbozincation of terminal alkynes can be combined with a base‐metal‐catalyzed cross‐coupling to prepare trisubstituted alkenes in a one‐pot reaction and with high regio‐ and stereocontrol. Cu‐, Ni‐, and Co‐based catalytic systems are developed for the coupling of sp‐, sp²‐, and sp³‐hybridized carbon electrophiles, respectively. The method encompasses a large substrate scope, as various alkynyl, aryl, alkenyl, acyl, and alkyl halides are suitable coupling partners. Compared with conventional carbometalation reactions of alkynes, the current method avoids pre‐made organometallic reagents and has a distinct stereoselectivity.     

Radical‐Mediated Three‐Component Coupling of Alkenes

A tandem radical process involving conjugate addition to an activated alkene followed by allylation is reported. B‐Alkylcatecholboranes, easily available via hydroboration of the corresponding alkenes, were used to generate the initial radicals. These radicals add efficiently to electrophilic alkenes such as phenyl vinyl sulfone, N‐phenylmaleimide, and dialkyl fumarate. In the last step of this one‐pot process, the radical adducts react with the allylic sulfones. The whole process can be considered as a unique and selective coupling of three different alkenes.     

Photoredox‐Catalyzed Stereoselective Conversion of Alkynes into Tetrasubstituted Trifluoromethylated Alkenes

A regio‐ and stereoselective synthesis of trifluoromethylated alkenes bearing four different substituents has been developed. Stereocontrolled sulfonyloxytrifluoromethylation of unsymmetric internal alkynes with an electrophilic CF₃ reagent, namely the triflate salt of the Yagupol’skii–Umemoto reagent, in the presence of an Ir photoredox catalyst under visible‐light irradiation afforded trifluoromethylalkenyl triflates with well‐predictable stereochemistry resulting from anti addition of the trifluoromethyl and triflate groups. Subsequent palladium‐catalyzed cross‐couplings led to tetrasubstituted trifluoromethylated alkenes in a highly stereoselective manner. The present method is the first example of a facile one‐pot synthesis of tetrasubstituted trifluoromethylated alkenes from simple alkynes.     

Enantioselective Copper‐Catalyzed Carboetherification of Unactivated Alkenes

Chiral saturated oxygen heterocycles are important components of bioactive compounds. Cyclization of alcohols onto pendant alkenes is a direct route to their synthesis, but few catalytic enantioselective methods enabling cyclization onto unactivated alkenes exist. Herein reported is a highly efficient copper‐catalyzed cyclization of γ‐unsaturated pentenols which terminates in C? C bond formation, a net alkene carboetherification. Both intra‐ and intermolecular C? C bond formations are demonstrated, thus yielding functionalized chiral tetrahydrofurans as well as fused‐ring and bridged‐ring oxabicyclic products. Transition‐state calculations support a cis‐oxycupration stereochemistry‐determining step.     

Thioamination of Alkenes with Hypervalent Iodine Reagents

An efficient thioamination of alkenes mediated by iodine(III) reagents is described. The use of different sulfur nucleophiles allows the flexible synthesis of 1,2‐aminothiols from alkenes. By employing chiral iodine(III) reagents, a stereoselective version of the thioamination protocol has also been developed.     

Oxydifluoromethylation of Alkenes by Photoredox Catalysis: Simple Synthesis of CF2H‐Containing Alcohols

We have developed a novel and simple protocol for the direct incorporation of a difluoromethyl (CF₂H) group into alkenes by visible‐light‐driven photoredox catalysis. The use of fac‐[Ir(ppy)₃] (ppy=2‐pyridylphenyl) photocatalyst and shelf‐stable Hu's reagent, N‐tosyl‐S‐difluoromethyl‐S‐phenylsulfoximine, as a CF₂H source is the key to success. The well‐designed photoredox system achieves synthesis of not only β‐CF₂H‐substituted alcohols but also ethers and an ester from alkenes through solvolytic processes. The present method allows a single‐step and regioselective formation of C(sp³)–CF₂H and C(sp³)?O bonds from C=C moiety in alkenes, such as hydroxydifluoromethylation, regardless of terminal or internal alkenes. Moreover, this methodology tolerates a variety of functional groups.     

Difunctionalization of Alkenes Involving Metal Migration

The direct difunctionalization of alkenes, a cheap and abundant feedstock, represents one of the most attractive strategies for increasing molecular complexity in synthetic organic chemistry. In contrast with the 1,2‐difunctionalization of alkenes, recent advances showcase alkene 1,n‐difunctionalizations (n≠2) involving metal migration is an emerging and rapidly growing area of research. This promising strategy not only opens a novel avenue for future development of alkene transformations, but also significantly expands upon the bond disconnections available in modern organic synthesis. This Minireview summarizes recent progress in the migratory difunctionalization of alkenes, with an emphasis on the driving force for metal migration.     

Mechanism of Ligand‐Controlled Regioselectivity‐Switchable Copper‐Catalyzed Alkylboration of Alkenes

Cu‐catalyzed alkylboration of alkenes with bis(pinacolato)diboron ((Bpin)₂) and alkyl halides provides a ligand‐controlled regioselectivity‐switchable method for the construction of complex boron‐containing compounds. Here, we employed DFT methods to elucidate the mechanistic details of this reaction and the origin of the different regioselectivity induced by Xantphos and Cy‐Xantphos. The calculation results reveal that the catalytic cycle mainly proceeds through the migratory insertion of alkenes on Cu‐Bpin complex, the oxidative addition of alkyl halides, and the reductive elimination of a C?C bond. Meanwhile, the rate‐ determining step is the oxidative addition of alkyl halides and the regioselectivity‐determining step is the migratory insertion of alkenes. The bulky cyclohexyl group of Cy‐Xantphos facilitates the approach of the substituents of alkenes to Bpin in the migratory insertion step and thus leads to the Markovnikov products. The less bulky phenyl group on Xantphos prefers keeping the substituents of alkenes away from the Bpin moiety in the migratory insertion step and thus results in anti‐Markovnikov products.     

Strained Alkenes in Natural Product Synthesis

Strained molecules continue to challenge the ingenuity of chemists as their high‐energy bonds serve as fuel for the promotion of complex synthetic transformations. Developments in this area have resulted in the recent emergence of strained alkenes as intermediates in natural product synthesis. This Minireview highlights these recent advances along with current developments toward understanding the unique reactivity of strained alkenes.     

Copper‐Catalyzed Alkynylboration of Alkenes with Diboron Reagents and Bromoalkynes

An efficient method for the synthesis of homopropargylboronates by copper‐catalyzed alkynylboration of alkenes with diboron reagents and bromoalkynes has been developed. The alkynylboration reaction features high selectivity and efficiency, mild reaction conditions, wide substrate scope, and functional‐group compatibility, and is a highly attractive complement to existing methods for the synthesis of homopropargylboronates. Both the boryl and alkynyl groups are good potential functional groups for the subsequent manipulations that provide access to a variety of important molecule structures.     

Polystyrene‐Supported (Catecholato)oxorhenium Complexes: Catalysts for Alcohol Oxidation with DMSO and for Deoxygenation of Epoxides to Alkenes with Triphenylphosphine

Polymer‐supported catalysts offer practical advantages for organic synthesis, such as improved product isolation, ease of catalyst recycling, and compatibility with parallel solution‐phase techniques. We have developed the (carboxypolystyrene‐catecholato)rhenium catalyst 2 derived from tyramine (=4‐(2‐aminoethyl)phenol), which is effective for alcohol oxidation with dimethylsulfoxide (DMSO) and for epoxide deoxygenation with triphenylphosphine. The supported [Re(catecholato)]catalyst 2 is air‐ and moisture‐stable and can be recovered and used repeatedly without decreasing activity. The procedures work with non‐halogenated solvents (toluene). DMSO for Re‐catalyzed alcohol oxidation is inexpensive and safer for transport and storage than commonly used peroxide reagents. The oxidation procedure was best suited for aliphatic alcohols, and the mild conditions were compatible with unprotected functional groups, such as those of alkenes, phenols, nitro compounds, and ketones (see Tables 1 and 2). Selective oxidation of secondary alcohols in the presence of primary alcohols was possible, and with longer reaction time, primary alcohols were converted to aldehydes without overoxidation. Epoxides (oxirans) were catalytically deoxygenated to alkenes with this catalyst and Ph₃P (see Table 3). Alkyloxiranes were converted to the alkenes with retention of configuration, while partial isomerization was observed in the deoxygenation of cis‐stilbene oxide ( cis‐1,2‐diphenyloxirane). These studies indicate that supported [Re(catecholato)] complexes are effective catalysts for O‐atom‐transfer reactions, and are well suited for applications in organic synthesis.     

Chiral Hetero‐ and Carbocyclic Compounds from the Asymmetric Hydrogenation of Cyclic Alkenes

Several types of chiral hetero‐ and carbocyclic compounds have been synthesized by using the asymmetric hydrogenation of cyclic alkenes. N,P‐Ligated iridium catalysts reduced six‐membered cyclic alkenes with various substituents and heterofunctionality in good to excellent enantioselectivity, whereas the reduction of five‐membered cyclic alkenes was generally less selective, giving modest enantiomeric excesses. The stereoselectivity of the hydrogenation depended more strongly on the substrate structure for the five‐ rather than the six‐membered cyclic alkenes. The major enantiomer formed in the reduction of six‐membered alkenes could be predicted from a selectivity model and isomeric alkenes had complementary enantioselectivity, giving opposite optical isomers upon hydrogenation. The utility of the reaction was demonstrated by using it as a key step in the preparation of chiral 1,3‐cis‐cyclohexane carboxylates.     

Visible‐Light‐Induced Hydrodifluoromethylation of Alkenes with a Bromodifluoromethylphosphonium Bromide

Bromodifluoromethylphosphonium bromide was solely used as the precursor of difluorocarbene. Herein, an unprecedented visible‐light‐induced hydrodifluoromethylation of alkenes with bromodifluoromethylphosphonium bromide using H₂O and THF as hydrogen sources for the synthesis of difluoromethylated alkanes is described. This difluoromethylation is characterized by mild reaction conditions, ready availability of reagents, and excellent functional‐group tolerance.     

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.     

Copper-Catalyzed Defluorinative Hydroarylation of Alkenes with Polyfluoroarenes

A catalytic defluorinative hydroarylation of alkenes with polyfluoroarenes in the presence of dppbz-ligated Cu catalyst and silanes was developed. This method provides a straightforward and alternative avenue to synthetic important polyfluorinated arenes with readily available and bench-stable alkenes as latent nucleophiles, and therefore avoids conventional reliance on stoichiometric quantities of organometallic reagents. This reaction proceeds under very mild conditions and exhibits good functional group compatibility and high level of regioselectivity. The synthetic potential of this method was further demonstrated by a gram-scale synthesis, and an array of experimental studies were also carried out to elaborate the probable mechanism.     

Blue LED Irradiation of Iodonium Ylides Gives Diradical Intermediates for Efficient Metal‐free Cyclopropanation with Alkenes

A facile and highly chemoselective synthesis of doubly activated cyclopropanes is reported where mixtures of alkenes and β‐dicarbonyl‐derived iodonium ylides are irradiated with light from blue LEDs. This metal‐free synthesis gives cyclopropanes in yields up to 96 %, is operative with cyclic and acyclic ylides, and proceeds with a variety of electronically‐diverse alkenes. Computational analysis explains the high selectivity observed, which derives from exclusive HOMO to LUMO excitation, instead of free carbene generation. The procedure is operationally simple, uses no photocatalyst, and provides access in one step to important building blocks for complex molecule synthesis.     

Cascade Multicomponent Synthesis of Indoles,Pyrazoles, and Pyridazinones by Functionalization of Alkenes

The development of multicomponent reactions for indole synthesis is demanding and has hardly been explored. The present study describes the development of a novel multicomponent, cascade approach for indole synthesis. Various substituted indole derivatives were obtained from simple reagents, such as unfunctionalized alkenes, diazonium salts, and sodium triflinate, by using an established straightforward and regioselective method. The method is based on the radical trifluoromethylation of alkenes as an entry into Fischer indole synthesis. Besides indole synthesis, the application of the multicomponent cascade reaction to the synthesis of pyrazoles and pyridazinones is described.