Intermolecular Alkene Research Articles

Cooperative Phosphine-Photoredox Catalysis Enables N-H Activation of Azoles for Intermolecular Olefin Hydroamination.

Catalytic intermolecular olefin hydroamination is an enabling synthetic strategy that offers direct and atom-economical access to a variety of nitrogen-containing compounds from abundant feedstocks. However, despite numerous advances in catalyst design and reaction development, hydroamination of N-H azoles with unactivated olefins remains an unsolved problem in synthesis. We report a dual phosphine and photoredox catalytic protocol for the hydroamination of numerous structurally diverse and medicinally relevant N-H azoles with unactivated olefins. Hydroamination proceeds with high anti-Markovnikov regioselectivity and N-site selectivity. The mild conditions and high functional group tolerance of the reaction permit the rapid construction of molecular complexity and late-stage functionalization of bioactive compounds. N-H bond activation is proposed to proceed via polar addition of the N-H azole to a phosphine radical cation, followed by P-N α-scission from a phosphoranyl radical intermediate. Reactivity and N-site selectivity are classified by azole N-H BDFE and nitrogen-centered radical spin density, respectively, which can serve as a useful predictive aid in extending the reaction to unseen azoles.

A computational mechanistic study of gold-catalyzed intermolecular alkene difunctionalization/cross-coupling reactions

A computational mechanistic study of gold-catalyzed intermolecular alkene difunctionalization/cross-coupling of aryl iodides with methanol was studied. By calculating the corresponding initial oxidative addition step mediated by the related chelating (P,N) ligands, our results uncover the essential roles of hemilabile Me-Dalphos to promote the oxidative addition process by minimizing the distortion of substrate and catalyst. For the nucleophile methanol, by comparing the mechanism of intermolecular alkene difunctionalization versus cross-coupling, the C(sp2)–C(sp3) reductive elimination is found more favorable than the corresponding C(sp2)–O formation, which contributes to the exclusive intermolecular alkene oxyarylation product. Furthermore, the different reactivity and selectivity of other nucleophiles such as tosyl amine and 1,3,5-trimethoxybenzene were compared. This mechanistic understanding will provide valuable guidance for the further development and wider application of gold-catalyzed redox reactions in synthetic chemistry.

Electrochemical Azidocyanation of Alkenes

AbstractThe difunctionalization of alkenes—a process that installs two functional groups in a single operation and transforms chemical feedstocks into value‐added products—is one of the most appealing synthetic methods in contemporary chemistry. However, the introduction of two distinct functional groups via two readily accessible nucleophiles remains a formidable challenge. Existing intermolecular alkene azidocyanation methods, which primarily focus on aryl alkenes and rely on stoichiometric chemical oxidants. We report herein an unprecedented electrochemical strategy for alkene azidocyanation that is compatible with both alkyl and aryl alkenes. This is achieved by harnessing the finely‐tuned anodic electron transfer and the strategic selection of copper/ligand complexes. The reactions of aryl alkenes were rendered enantioselective by employing a chiral ligand. Crucially, the mild conditions and well‐regulated electrochemical process assure exceptional tolerance for various functional groups and substrate compatibility with both terminal and internal alkyl alkenes.

Stereospecific Aminative Cyclizations Triggered by Intermolecular Aza-Prilezhaev Alkene Aziridination.

Under acidic reaction conditions (TFA), deprotection of BocNR(OSO2 R) reagents triggers intermolecular aminative cyclizations of alkenes equipped with pendant nucleophiles. The processes are predicated on a sequence of stereospecific intermolecular aza-Prilezhaev aziridination followed by stereospecific SN 2-like opening by the pendant nucleophile. The method offers broad scope with respect to the nucleophile (N-, O- or C-based), alkene and cyclization mode, allowing the installation of two contiguous stereocenters under operationally simple conditions.

Iridium(III)-Catalyzed Intermolecular C(sp3 )-H Amidation for the Synthesis of Chiral 1,2-Diamines.

Chiral 1,2-diamines are privileged scaffolds among bioactive natural products, active pharmaceutical ingredients, ligands for transition-metal-based asymmetric catalysis and organocatalysts. Despite this interest, the construction of chiral 1,2-diamine motifs still remains a challenge. To address this, an iridium(III)-catalyzed intermolecular C(sp3 )-H amidation reaction was developed. This method relies on the design of a new, cheap and cleavable exo-protecting/directing group derived from camphorsulfonic acid, which is directly installed from easily accessible precursors, and furnishes scalemic free 1,2-diamines upon cleavage of both nitrogen substituents. It was found applicable to both α-secondary and α-tertiary-1,2-diamines, for which a two-step protocol involving intermolecular olefin hydroamination and C(sp3 )-H amidation was developed. Kinetic and computational studies provided insights into the observed reactivity difference between pairs of diastereoisomeric substrates.

Iridium(III)‐Catalyzed Intermolecular C(sp3)‐H Amidation for the Synthesis of Chiral 1,2‐Diamines

AbstractChiral 1,2‐diamines are privileged scaffolds among bioactive natural products, active pharmaceutical ingredients, ligands for transition‐metal‐based asymmetric catalysis and organocatalysts. Despite this interest, the construction of chiral 1,2‐diamine motifs still remains a challenge. To address this, an iridium(III)‐catalyzed intermolecular C(sp3)‐H amidation reaction was developed. This method relies on the design of a new, cheap and cleavable exo‐protecting/directing group derived from camphorsulfonic acid, which is directly installed from easily accessible precursors, and furnishes scalemic free 1,2‐diamines upon cleavage of both nitrogen substituents. It was found applicable to both α‐secondary and α‐tertiary‐1,2‐diamines, for which a two‐step protocol involving intermolecular olefin hydroamination and C(sp3)‐H amidation was developed. Kinetic and computational studies provided insights into the observed reactivity difference between pairs of diastereoisomeric substrates.

Photosensitized O2 enables intermolecular alkene cyclopropanation by active methylene compounds.

Cyclopropanes are key features in many preclinical, clinical, and commercial drugs, as well as natural products. The most prolific technique for their synthesis is the metal-catalyzed reaction of an alkene with a diazoalkane, a highly energetic reagent requiring stringent safety precautions. Discovery of alternative innocuous reagents remains an ongoing challenge. Herein, we report a simple photoredox-catalyzed intermolecular cyclopropanation of unactivated alkenes with active methylene compounds. The reaction proceeds in neutral solvent under air or dioxygen (O2) with a photoredox catalyst excited by blue light-emitting diode light and an iodine co-catalyst that is either added as molecular iodine or generated in situ from alkyl iodides. Mechanistic investigations indicate that photosensitized O2 plays a vital role in the generation of carbon-centered radicals for both the addition of active methylene compounds to alkenes and the ring closure.

Photocatalytic, Intermolecular Olefin Alkylcarbofunctionalization Triggered by Haloalkyl Radicals Generated via Halogen Atom Transfer.

A visible-light-mediated, haloalkyl-radical-initiated, three-component olefin difunctionalization is reported. The application of haloalkyl radicals generated via halogen atom abstraction by α-aminoalkyl radicals has been demonstrated for accessing a new halogenated chemical space. Overall, the alkylcarbofunctionalization of styrenes was accomplished by employing them as (poly)haloalkyl radical acceptors and subsequent C-C bond formation with quinoxalinones.

Surmounting Byproduct Inhibition in an Intermolecular Catalytic Asymmetric Alkene Bromoesterification Reaction as Revealed by Kinetic Profiling.

Kinetic profiling has shown that a (DHQD)2PHAL-catalyzed intermolecular asymmetric alkene bromoesterification reaction is inhibited by primary amides, imides, hydantoins, and secondary cyclic amides, which are byproducts of common stoichiometric bromenium ion sources. Two approaches to resolving the inhibition are presented, enabling the (DHQD)2PHAL loading to be dropped from 10 to 1 mol % while maintaining high bromoester conversions in 8 h or less. Iterative post-reaction recrystallizations enabled a homochiral bromonaphthoate ester to be synthesized using only 1 mol % (DHQD)2PHAL.

Visible-light-driven three-component reductive 1,2-diarylation of alkenes

The intermolecular alkene 1,2-diarylation provides straightforward access to polyarylalkanes but suffers from substrate limitation, requiring directing auxiliaries or prefunctionalized aryl components. Herein, we report the development of a photocatalytic strategy that enables a three-component 1,2-diarylation of alkenes under mild reductive conditions using simple tertiary alkylamine as the terminal reductant. Readily accessible aryl iodides and cyanides serve as the C(sp2) electrophiles to simultaneously install two different aryl moieties across the olefins with high regioselectivity. This protocol exhibits a broad substrate scope for all of aryl, heteroatom-substituted, and even unactivated alkenes and can be easily scaled up to the gram-scale. Mechanistic studies reveal a halogen-atom transfer (XAT) of aryl iodides to transient aryl radicals while a single-electron transfer (SET) of aryl cyanides to persistent aryl radical anions, both allowing for a regiocontrollable radical relay sequence.

Electroreduction Enables Regioselective 1,2-Diarylation of Alkenes with Two Electrophiles.

Precisely introducing two similar functional groups into bulk chemical alkenes represents a formidable route to complex molecules. Especially, the selective activation of two electrophiles is in crucial demand, yet challenging for cross-electrophile-coupling. Herein, we demonstrate a redox-mediated electrolysis, in which aryl nitriles are both aryl radical precursors and redox-mediators, enables an intermolecular alkene 1,2-diarylation with a remarkable regioselectivity, thereby avoiding the involvement of transition-metal catalysts. This transformation utilizes cyanoarene radical anions for activating various aryl halides (including iodides, bromides, and even chlorides) and affords 1,2-diarylation adducts in up to 83 % yield and >20 : 1 regioselectivity with more than 80 examples, providing a feasible approach to complex bibenzyl derivatives.

Electroreduction Enables Regioselective 1,2‐Diarylation of Alkenes with Two Electrophiles

AbstractPrecisely introducing two similar functional groups into bulk chemical alkenes represents a formidable route to complex molecules. Especially, the selective activation of two electrophiles is in crucial demand, yet challenging for cross‐electrophile‐coupling. Herein, we demonstrate a redox‐mediated electrolysis, in which aryl nitriles are both aryl radical precursors and redox‐mediators, enables an intermolecular alkene 1,2‐diarylation with a remarkable regioselectivity, thereby avoiding the involvement of transition‐metal catalysts. This transformation utilizes cyanoarene radical anions for activating various aryl halides (including iodides, bromides, and even chlorides) and affords 1,2‐diarylation adducts in up to 83 % yield and >20 : 1 regioselectivity with more than 80 examples, providing a feasible approach to complex bibenzyl derivatives.

Aminium-Radical-Mediated Intermolecular Hydroamination of Nonactivated Olefins

AbstractAminium radicals are attractive intermediates in synthetic chemistry that readily participate in a series of C–N bond-forming processes. Here, we briefly discuss strategies for generating aminium radicals from various precursors in the context of intermolecular alkene amination, and we highlight recent advances in aminium-radical-mediated hydroaminations of nonactivated olefins to directly approach alkylamines.1 Introduction2 Intermolecular Hydroamination of Nonactivated Alkenes with Alkylamines under Photoredox Catalysis3 Intermolecular Hydroamination of Nonactivated Alkenes with Aliphatic Azides4 Conclusions

Nickel-catalyzed switchable asymmetric electrochemical functionalization of alkenes.

The development of general electrocatalytic methods for the diversity-oriented regio- and stereoselective functionalization of alkenes remains a challenge in organic synthesis. We present a switchable electrocatalytic method based on anodic oxidative activation for the controlled liberation of chiral α-keto radical species toward stereoselective organic transformations. Electrogenerated α-keto radical species capture alkene partners, allowing switchable intermolecular alkene difunctionalization and alkenylation in a highly stereoselective manner. In addition to acting as proton donors to facilitate H2 evolution at the cathode, the unique properties of alcohol additives play an important role in determining the distinct outcomes for alkene functionalization under electrocatalytic conditions.

Nickel-Catalyzed Reductive Dicarbofunctionalization of Vinylarenes Enabled by Electrochemical Process.

An intermolecular alkene dicarbofunctionalization via electrochemical reduction that combines alkyl and aryl iodides with styrene derivatives was herein reported. The multicomponent reaction exhibited several synthetic advantages including simple operation, wide substrate scope, and convenience of amplification. Mechanistic investigations, including cyclic voltammetry (CV), electron paramagnetic resonance (EPR), and radical trapping reactions, support the electrochemical nickel catalytic cycle and formation of alkyl radical species from alkyl iodides.

Probing the Free Energy Landscape of Organophotoredox-Catalyzed Anti-Markovnikov Hydrofunctionalization of Alkenes.

Experimental 13C kinetic isotope effects (KIEs) provide unprecedented mechanistic insight into three intermolecular anti-Markovnikov alkene hydrofunctionalization reactions─hydroesterification, hydroamination, and hydroetherification─enabled by organophotoredox catalysis. All three reactions are found to proceed via initial oxidation of the model alkenes to form a radical cation intermediate, followed by sequential nucleophilic attack and hydrogen-atom transfer to deliver the hydrofunctionalized product. A normal 13C KIE on the olefinic carbon that undergoes nucleophilic attack provides qualitative evidence for rate-limiting nucleophilic attack in all three reactions. Comparison to predicted 13C KIE values obtained from density functional theory (DFT) calculations for this step reveals that alkene oxidation has partial rate-limiting influence in hydroesterification and hydroamination, while the nucleophilic attack is solely rate-limiting in the hydroetherification reaction. The basic additive (2,6-lutidine) activates the nucleophile via deprotonation and is an integral part of the transition state for nucleophilic attack on the radical cation, providing an important design principle for the development of asymmetric versions of these reactions. A more electron-rich pyridine base (2,6-dimethoxypyridine) exhibits considerable rate enhancements in both inter- and intramolecular hydrofunctionalization reactions.

Organocatalytic One‐Pot Synthesis of Pseudo‐Terpenoids

AbstractStructurally complex cedrane scaffolds were synthesized in very good yields with high chemo‐ and diastereoselectivities in a sequential one‐pot manner. A combination of intermolecular olefination, intramolecular Michael and Michael reactions or intermolecular olefination, intramolecular Michael and aldol reactions were used as the key steps from the readily available hydroxy‐p‐quinone butanals and phosphoranes with catalytic amounts of quinine at ambient temperatures for a few hours. This is a unique one‐pot combination of coupling and annulation routes for the green synthesis of a library of tricyclic pseudo‐terpenoids (cedrane scaffolds) with high selectivity and yields. Organocatalytic ring isomerization was highlighted through transforming one ring into another one by retro‐cyclization. We have discussed thoroughly mechanistic aspects of these tandem coupling/annulation and ring isomerization reactions based on control experiments and X‐ray crystal structure analysis.

Chiral Hemilabile P,N-Ligand-Assisted Gold Redox Catalysis for Enantioselective Alkene Aminoarylation.

Enantioselective, intermolecular alkene arylamination was achieved through gold redox catalysis. Screening of ligands revealed chiral P,N ligands as the optimal choice, giving alkene aminoarylation with good yields (up to 80 %) and excellent stereoselectivity (up to 99 : 1 er). As the first example of enantioselective gold redox catalysis, this work confirmed the feasibility of applying a chiral ligand at the gold(I) stage, with the stereodetermining step (SDS) at the gold(III) intermediate, thus opening up a new way to conduct gold redox catalysis with stereochemistry control.

Enantioselective Intermolecular Murai-Type Alkene Hydroarylation Reactions

AbstractStrategies that enable the efficient assembly of complex building blocks from feedstock chemicals are of paramount importance to synthetic chemistry. Building upon the pioneering work of Murai and co-workers in 1993, C–H-activation-based enantioselective hydroarylations of alkenes offer a particularly promising framework for the step- and atom-economical installation of benzylic stereocenters. This short review presents recent intermolecular enantioselective Murai-type alkene hydroarylation methodologies and the mechanisms by which they proceed.1 Introduction2 Enantioselective Hydroarylation Reactions of Strained Bicyclic Alkenes3 Enantioselective Hydroarylation Reactions of Electron-Rich Acyclic Alkenes4 Enantioselective Hydroarylation Reactions of Electron-Poor Acyclic Alkenes5 Enantioselective Hydroarylation Reactions of Minimally Polarized Acyclic Alkenes6 Conclusion and Outlook

Palladium-Catalyzed Intermolecular Alkene Carboacylation via Ester C-O Bond Activation.

We report palladium-catalyzed intermolecular carboacylation of alkenes with ester electrophiles and tetraarylborate nucleophiles. Bicyclic alkenes react with a variety of pentafluorophenyl benzoate and alkanoate esters and sodium tetraarylborates to form ketone products in ≤99% yields. These reactions occur in the absence of a directing group and demonstrate esters are competent acyl electrophiles for intermolecular alkene carboacylation reactions.