Unactivated Alkenes Research Articles

Catalyst- and base-free visible light-enabled radical relay trihalomethylation/functional group-migration/carbonylation with CX3SO2Cl.

Herein, we report a visible light-enabled radical trihalomethylation/cyano-migration/carbonylation cascade reaction of 2-hydroxy-2-hex-5-enenitrile with CX3SO2Cl as the CX3-source (X = F, Cl) to obtain 5-oxo-2-(2,2,2-trihaloethyl)pentanenitrile compounds in the absence of a photocatalyst, transition metal and base. This reaction system is also effective to convert (benzo[d]thiazol-2-yl)-pent-4-enol to the corresponding 4-(benzo[d]thiazol-2-yl)-6,6,6-trihalo-hexanone products. These reactions occur under mild conditions, tolerate a wide range of functional groups, and provide alternative approaches for the 1,2-bifunctionalization reaction of unactivated olefins.

Palladium‐Catalyzed Inward Isomerization Hydroaminocarbonylation of Alkenes

In contrast to the kinetically favored outward isomerization‐hydrocarbonylation of alkenes, the disfavored inward isomerization‐hydrocarbonylation of alkenes remains an important challenge. Herein, we have developed a novel and effective palladium‐catalyzed inward isomerization‐hydroaminocarbonylation of unactivated alkenes and aniline hydrochlorides for the formation of synthetically valuable α‐aryl carboxylic amides in high yields and high site‐selectivities. The high efficiency of the reaction is attributed to a relay catalysis strategy, in which the Markovnikov‐favored [PdH]‐PtBu3 catalyst is responsible for inward isomerization, while the [PdH]‐Ruphos catalyst is responsible for hydroaminocarbonylation of the resulting conjugated aryl alkenes. The reaction exhibits highly functional group tolerance and provides a new method for formal carbonylation of remote C(sp3)‐H bond.

Palladium-Catalyzed Inward Isomerization Hydroaminocarbonylation of Alkenes.

In contrast to the kinetically favored outward isomerization-hydrocarbonylation of alkenes, the disfavored inward isomerization-hydrocarbonylation of alkenes remains an important challenge. Herein, we have developed a novel and effective palladium-catalyzed inward isomerization-hydroaminocarbonylation of unactivated alkenes and aniline hydrochlorides for the formation of synthetically valuable α-aryl carboxylic amides in high yields and high site-selectivities. The high efficiency of the reaction is attributed to a relay catalysis strategy, in which the Markovnikov-favored [PdH]-PtBu3 catalyst is responsible for inward isomerization, while the [PdH]-Ruphos catalyst is responsible for hydroaminocarbonylation of the resulting conjugated aryl alkenes. The reaction exhibits highly functional group tolerance and provides a new method for formal carbonylation of remote C(sp3)-H bond.

Photocatalytic alkenes to ring-fused quinazolin-4(3H)-ones via proton-transfer shuttle using TFA

Herein, a novel metal-free photocatalytic system is reported that enables intramolecular hydroarylation of unactivated alkenes via a proton transfer shuttle using TFA, providing a concise access to the formation of pyrroloquinazolinone and pyridyquinazolinone products in moderate to good yields. Mechanistic studies revealed that the protonated quinazolinone is the key radical precursor mediating the intramolecular cyclization reaction.

C(sp3)-C(sp3) Coupling of Cycloalkanes and Alkyl Halides via Dual Photocatalytic Hydrogen Atom Transfer and Nickel Catalysis.

Functionalization of C(sp3)-H bonds represents the most straightforward and atom-economical transformation in organic synthesis. An innovative approach integrating photocatalytic hydrogen atom transfer (HAT) and transition metal catalysis has made significant progress in the coupling of α-heterosubstituted C-H bonds with alkyl halides. However, unactivated alkanes were ineffective as a result of the preponderance of byproduct formation. Herein, we demonstrate direct HAT and nickel catalysis in the coupling of cycloalkanes and benzyl bromides/primary alkyl iodides. Additionally, tetrabutylammonium decatungstate (TBADT) was recovered and recycled.

Catalytic Photoredox Carbobromination of Unactivated Alkenes with α-Bromocarbonyls via the Mechanistically Distinct Radical-Addition Radical-Pairing Pathway

Catalytic Photoredox Carbobromination of Unactivated Alkenes with α-Bromocarbonyls via the Mechanistically Distinct Radical-Addition Radical-Pairing Pathway

Oxidative Alkenylation of (Hetero)aromatics with Unactivated Alkenes: Control of the Reaction Selectivity

AbstractAlkenylbenzene skeletons represent one of the most widely occurring structural motifs in pharmaceutical drugs, natural products, and advanced materials. The construction of alkenylbenzenes is promising through the use of a straightforward oxidative alkenylation protocol, particularly from unactivated alkenes. This is significant because unactivated alkenes are inexpensive raw materials that can be obtained in bulk quantities from petrochemical feedstocks and renewable resources. However, controlling the reactivity and regioselectivity of olefination with unbiased olefins remains a significant challenge, necessitating continuous efforts and potentially having a substantial impact on both organic synthesis and the industry. This review aims to provide an overview of the latest advances in regiocontrol strategies for oxidative alkenylation reactions with unactivated alkenes, which can be categorized into three types: 1) ligand‐promoted/accelerated reactions; 2) prefunctionalized olefins‐facilitated reactions; 3) directing group‐induced reactions.

A Bimolecular Homolytic Substitution-Enabled Platform for Multicomponent Cross-Coupling of Unactivated Alkenes.

The construction of C(sp3)-C(sp3) bonds remains one of the most difficult challenges in cross-coupling chemistry. Here, we report a photoredox/nickel dual catalytic approach that enables the simultaneous formation of two C(sp3)-C(sp3) linkages via trimolecular cross-coupling of alkenes with alkyl halides and hypervalent iodine-based reagents. The reaction harnesses a bimolecular homolytic substitution (SH2) mechanism and chemoselective halogen-atom transfer (XAT) to orchestrate the regioselective addition of electrophilic and nucleophilic alkyl radicals across unactivated alkenes without the need for a directing auxiliary. Utility is highlighted through late-stage (fluoro)alkylation and (trideutero)methylation of C═C bonds bearing different substitution patterns, offering straightforward access to drug-like molecules comprising sp3-hybridized carbon scaffolds.

Photocatalytic Synthesis of β-Keto Primary Chlorides by Selective Chlorocarbonylation of Olefins.

Functionalized primary alkyl chlorides are precursors to a plethora of scaffolds but their access from chemical feedstocks remains challenging. Herein, we report a concise dual Ni/photoredox catalytic protocol for regioselective chlorocarbonylation of unactivated alkenes that enables rapid access to β-keto primary chlorides. The catalytic process features an extensive substrate scope, scalability and functional group tolerance. The Ni/photocatalytic Cl⋅ generation and subsequent cross-coupling is implicated for the process based on the control experiments and DFT study. The synthetic utility of the protocol has been further corroborated through functionalization of complex substrates and modifications of the product.

Photocatalytic Synthesis of β‐Keto Primary Chlorides by Selective Chlorocarbonylation of Olefins

AbstractFunctionalized primary alkyl chlorides are precursors to a plethora of scaffolds but their access from chemical feedstocks remains challenging. Herein, we report a concise dual Ni/photoredox catalytic protocol for regioselective chlorocarbonylation of unactivated alkenes that enables rapid access to β‐keto primary chlorides. The catalytic process features an extensive substrate scope, scalability and functional group tolerance. The Ni/photocatalytic Cl⋅ generation and subsequent cross‐coupling is implicated for the process based on the control experiments and DFT study. The synthetic utility of the protocol has been further corroborated through functionalization of complex substrates and modifications of the product.

Catalyst/Metal/Solvent-Free Markovnikov Hydrothiolation of Unactivated Alkenes with Dithiocarbamic Acids.

Catalyst-free Markovnikov-selective hydrothiolation of unactivated alkenes still remains a great challenge. Herein, we develop a catalyst/metal/solvent-free methodology for the Markovnikov hydrothiolation of unactivated alkenes with in situ prepared dithiocarbamic acids, providing a wide array of alkyl dithiocarbamates. A variety of terminal, internal, cyclic, and acyclic unactivated alkenes were applied successfully in this protocol. This three-component thiol-ene reaction can be considered as a new family of click reactions.

Electroreduction of unactivated alkenes using water as hydrogen source

Herein, we report an electroreduction of unactivated alkyl alkenes enabled by [Fe]-H, which is provided through the combination of anodic iron salts and the silane generated in situ via cathodic reduction, using H2O as an H-source. The catalytic amounts of Si-additive work as an H-carrier from H2O to generate a highly active silane species in situ under continuous electrochemical conditions. This approach shows a broad substrate scope and good functional group compatibility. In addition to hydrogenation, the use of D2O instead of H2O provides the desired deuterated products in good yields with excellent D-incorporation (up to >99%). Further late-stage hydrogenation of complex molecules and drug derivatives demonstrate potential application in the pharmaceutical industry. Mechanistic studies are performed and provide support for the proposed mechanistic pathway.

Insights into Recent Nickel-Catalyzed Reductive and Redox C-C Coupling of Electrophiles, C(sp3)-H Bonds and Alkenes.

ConspectusTransition metal-catalyzed reductive cross-coupling of two carbon electrophiles, also known as cross-electrophile coupling (XEC), has transformed the landscape of C-C coupling chemistry. Nickel catalysts, in particular, have demonstrated exceptional performance in facilitating XEC reactions, allowing for diverse elegant transformations by employing various electrophiles to forge C-C bonds. Nevertheless, several crucial challenges remain to be addressed. First, the intrinsic chemoselectivity between two structurally similar electrophiles in Ni-catalyzed C(sp3)-C(sp3) and C(sp2)-C(sp2) cross-coupling has not been well understood; this necessitates an excess of one of the coupling partners to achieve synthetically useful outcomes. Second, the substitution of economically and environmentally benign nonmetal reductants for Zn/Mn can help scale up XEC reactions and avoid trace metals in pharmaceutical products, but research in this direction has progressed slowly. Finally, it is highly warranted to leverage mechanistic insights from Ni-catalyzed XEC to develop innovative thermoredox coupling protocols, specifically designed to tackle challenges associated with difficult substrates such as C(sp3)-H bonds and unactivated alkenes.In this Account, we address the aforementioned issues by reviewing our recent work on the reductive coupling of C-X and C-O electrophiles, the thermoredox strategy for coupling associated with C(sp3)-H bonds and unactivated alkenes, and the use of diboron esters as nonmetal reductants to achieve reductive coupling. We focus on the mechanistic perspectives of the transformations, particularly how the key C-NiIII-C intermediates are generated, in order to explain the chemoselective and regioselective coupling results. The Account consists of four sections. First, we discuss the Zn/Mn-mediated chemoselective C(sp2)-C(sp2) and C(sp3)-C(sp3) bond formations based on the coupling of selected alkyl/aryl, allyl/benzyl, and other electrophiles. Second, we describe the use of diboron esters as versatile reductants to achieve C(sp3)-C(sp3) and C(sp3)-C(sp2) couplings, with an emphasis on the mechanistic consideration for the construction of C(sp3)-C(sp2) bonds. Third, we discuss leveraging C(sp3)-O bonds for effective C(sp3)-C bond formation via in situ halogenation of alcohols as well as the reductive preparation of α-vinylated and -arylated unusual amino esters. In the final section, we illustrate the thermoredox functionalization of challenging C(sp3)-H bonds with aryl and alkyl halides to afford C(sp3)-C bonds by taking advantage of the compatibility of Zn with the oxidant di-tert-butylperoxide (DTBP). Furthermore, we discuss a Ni-catalyzed and SiH/DTBP-mediated hydrodimerization of terminal alkenes to selectively forge head-to-head and methyl branched C(sp3)-C(sp3) bonds. This process, conducted in the presence or absence of catalytic CuBr2, provides a solution to a long-standing challenge: site-selective hydrocoupling of unactivated alkenes to produce challenging C(sp3)-C(sp3) bonds.

Ligand Field Sensitive Spin Acceleration in the Iron-Catalyzed [2 + 2] Cycloaddition of Unactivated Alkenes and Dienes.

Redox-active pyridine(diimine) (PDI) iron catalysts promote the reversible [2 + 2] cycloaddition of alkenes and dienes to cyclobutane derivatives that have applications ranging from fuels to chemically recyclable polymers. Metallacycles were identified as key intermediates, and spin crossover from the singlet to the triplet surface was calculated to facilitate the reductive coupling step responsible for the formation of the four-membered ring. In this work, a series of sterically and electronically differentiated PDI ligands was studied for the [2 + 2] cycloaddition of ethylene and butadiene to vinylcyclobutane. Kinetic studies revealed that the fastest and slowest turnover were observed with equally electron-deficient supporting ligands that either feature phenyl-substituted imine carbon atoms (MeBPDI) or a pyrazine core (MePZDI). While the oxidative cyclization was comparatively slow for both catalysts, the rate of reductive coupling─determined by stoichiometric 13C2H4 labeling studies─correlated with the turnover frequencies. Two-state density functional theory studies and the distinct electronic structures of related (iPrBPDI) and (iPrPZDI) iron methyl complexes revealed significantly different ligand field strengths due to either diminished ligand σ-donation (MeBPDI) or promoted metal π-backbonding (MePZDI). Spin acceleration, leading to fast reductive coupling and catalytic turnover, was promoted in the case of the weaker ligand field and depends on both the nature and position of the electron-withdrawing group. This study provides strong evidence for the role of two-state reactivity in C(sp3)-C(sp3) bond formation and insights on how ligand design either promotes or inhibits spin acceleration in earth-abundant metal catalysis.

Aziridination via Nitrogen-Atom Transfer to Olefins from Photoexcited Azoxy-Triazenes.

Herein, we report that readily accessible azoxy-triazenes can serve as nitrogen atom sources under visible light excitation for the phthalimido-protected aziridination of alkenes. This approach eliminates the need for external oxidants, precious transition metals, and photocatalysts, marking a departure from conventional methods. The versatility of this transformation extends to the selective aziridination of both activated and unactivated multisubstituted alkenes of varying electronic profiles. Notably, this process avoids the formation of competing C-H insertion products. The described protocol is operationally simple, scalable, and adaptable to photoflow conditions. Mechanistic studies support the idea that the photofragmentation of azoxy-triazenes results in the generation of a free singlet nitrene. Furthermore, a mild photoredox-catalyzed N-N cleavage of the protecting group to furnish the free aziridines is reported. Our findings contribute to the advancement of sustainable and practical methodologies for the synthesis of nitrogen-containing compounds, showcasing the potential for broader applications in synthetic chemistry.

Photo- and Cobalt-Catalyzed Synthesis of Heterocycles via Cycloisomerization of Unactivated Olefins.

We report a general, intramolecular cycloisomerization of unactivated olefins with pendant nucleophiles. The reaction proceeds under mild conditions and tolerates ethers, esters, protected amines, acetals, pyrazoles, carbamates, and arenes. It is amenable to N-, O-, as well as C-nucleophiles, yielding a number of different heterocycles including, but not limited to, pyrrolidines, piperidines, oxazolidinones, and lactones. Use of both a benzothiazinoquinoxaline as organophotocatalyst and a Co-salen catalyst obviates the need for stoichiometric oxidant or reductant. We showcase the utility of the protocol in late-stage drug diversification and synthesis of several small natural products.

Photochemische Cobaltkatalysierte Synthese von Heterozyklen durch die Zykloisomerisierung Nichtaktivierter Olefine

AbstractEine allgemeine, intramolekulare Zykloisomerisierung nichtaktivierter Olefine mit Nukleophilen wird beschrieben. Die Reaktion erfolgt unter milden Bedingungen und toleriert Ether, Ester, geschützte Amine, Acetale, Pyrazole, Carbamate und Arene. Sie ist zugänglich für N‐, O‐ und C‐Nukleophile, wobei eine Reihe verschiedener Heterozyklen gebildet werden kann, darunter Pyrrolidine, Piperidine, Oxazolidinone und Lactone. Durch die Kombination eines Benzothiazinoquinoxalins als Organophotokatalysator und eines Cobaltsalen‐Katalysators sind keine stöchiometrischen Oxidations‐ oder Reduktionsmittel erforderlich. Wir zeigen den Nutzen des Protokolls für die Diversifizierung von Arzneimitteln sowie die Synthese mehrerer kleiner Naturstoffe.

Nickel-Catalyzed Hydrofluorination in Unactivated Alkenes: Regio- and Enantioselective C-F Bond Formation.

Catalytic formation of a regio- and enantioselective C-F bond chiral center from readily available alkenes is a crucial goal, yet it continues to pose significant challenges in organic synthesis. Here, we report the regioselective formation of C-F bonds facilitated by NiH catalysis and a coordination directing strategy that enables precise hydrofluorination of both terminal and internal alkenes. Notably, we have optimized this methodology to achieve high enantioselectivity in creating aliphatic C-F stereogenic centers especially with β,γ-alkenyl substrates, using a tailored chiral Bn-BOx ligand. Another pivotal finding in our research is the identification of the (+)-nonlinear effect under optimized conditions, allowing for high enantioselectivity even with moderately enantiomerically enriched chiral ligands. Given the significant role of fluorine in pharmaceuticals and synthetic materials, this research offers essential insights into the regioselective and enantioselective formation of C-F bond chiral centers, paving the way for the efficient production of valuable fluorinated compounds.

Theoretical insights into Rh-catalyzed hydroamidation: Mechanism and chemoselectivity

Rh-catalyzed hydroamidation of unactivated alkenes were investigated by a density functional theory study. The catalytic cycle proceeds through β-H elimination, alkene addition, CO2 extrusion, nitrene migratory insertion and protodemetalation. CO2 extrusion is the rate-determining step for the overall reaction. More importantly, the hydroamidation-to-aziridination and hydroamidation-to-amidation chemoselectivities have been investigated and the origins of impossibilities of CC bond aziridination and C(sp2/sp3)H bond amidations have been elucidated. The Rh-nitrene group is more inclined to insert RhC bond rather than CC and C(sp2/sp3)H bonds to form the new CN bond of hydroamidation products. These calculation results provide valuable information for further selective synthesis of amides.

Rhodium-Catalyzed Asymmetric Aziridination of Unactivated Terminal Olefins

Rhodium-Catalyzed Asymmetric Aziridination of Unactivated Terminal Olefins