Nonactivated Alkenes Research Articles

Sodium Hypophosphite as a Halogen Atom Transfer (XAT) Agent under Photocatalytic Conditions.

The ability of sodium hypophosphite to generate the phosphorus-centered radical, which can activate the carbon-halogen bond via the halogen atom transfer (XAT) is described. The hydroalkylation of nonactivated alkenes with methyl bromoacetate was performed using sodium hypophosphite as reducing agent under photocatalytic conditions. The key phosphorus centered radical is formed from the hypophosphite anion by hydrogen atom abstraction.

Confined Acid Catalyzes the Enantioselective Hydroamination of Non-Activated Olefins

Confined Acid Catalyzes the Enantioselective Hydroamination of Non-Activated Olefins

Intermolecular [2π+2σ] Cycloaddition of Bicyclo[1.1.0]butane with Non-Activated Alkenes

Intermolecular [2π+2σ] Cycloaddition of Bicyclo[1.1.0]butane with Non-Activated Alkenes

Iron photocatalysis via Brønsted acid-unlocked ligand-to-metal charge transfer

Reforming sustainable 3d-metal-based visible light catalytic platforms for inert bulk chemical activation is highly desirable. Herein, we demonstrate the use of a Brønsted acid to unlock robust and practical iron ligand-to-metal charge transfer (LMCT) photocatalysis for the activation of multifarious inert haloalkylcarboxylates (CnXmCOO−, X = F or Cl) to produce CnXm radicals. This process enables the fluoro-polyhaloalkylation of non-activated alkenes by combining easily available Selectfluor as a fluorine source. Valuable alkyl fluorides including potential drug molecules can be easily obtained through this protocol. Mechanistic studies indicate that the real light-harvesting species may derive from the in situ-assembly of Fe3+, CnXmCOO−, H+, and acetonitrile solvent, in which the Brønsted acid indeed increases the efficiency of LMCT between the iron center and CnXmCOO− via hydrogen-bond interactions. We anticipate that this Brønsted acid-unlocked iron LMCT platform would be an intriguing sustainable option to execute the activation of inert compounds.

Bicyclo[1.1.0]butyl Radical Cations: Synthesis and Application to [2π+2σ] Cycloaddition Reactions.

As the chemistry that surrounds the field of strained hydrocarbons, such as bicyclo[1.1.0]butane, continues to expand, it becomes increasingly advantageous to develop alternative reactivity modes that harness their unique properties to access new regions of chemical space. Herein, we report the use of photoredox catalysis to promote the single-electron oxidation of bicyclo[1.1.0]butanes. The synthetic utility of the resulting radical cations is highlighted by their ability to undergo highly regio- and diastereoselective [2π + 2σ] cycloaddition reactions. The most notable feature of this transformation is the breadth of alkene classes that can be employed, including nonactivated alkenes, which have so far been elusive for previous strategies. A rigorous mechanistic investigation, in conjunction with DFT computation, was undertaken in order to better understand the physical nature of bicyclo[1.1.0]butyl radical cations and thus provides a platform from which further studies into the synthetic applications of these intermediates can be built upon.

Efficient Radical-Mediated Intermolecular α-Alkylation Reactions of Carbonyl Compounds with Nonactivated Alkenes.

Alkylation reactions are fundamental carbon-carbon bond-forming reactions in synthetic organic chemistry. Among them, intermolecular α-alkylation reactions of carbonyl compounds with alkenes are important because they are more atom-economical than the equivalent processes using alkyl halides. However, intermolecular reactions with nonactivated alkenes such as 1-hexene, which can allow the use of a wide range of valuable substrates, have been considered to be very challenging for a long time. In this review, radical-mediated intermolecular α-alkylation reactions of carbonyl compounds with nonactivated alkenes are discussed. The examples are grouped into three types of reactions: peroxide-mediated reactions, metal-oxidant-mediated reactions, and photoactivated reactions. Photoredox-catalyzed alkylation reactions under visible-light irradiation are discussed as a particularly promising recent hot topic. This review provides brief history and new prospects on the α-alkylation process with nonactivated alkenes using α-carbonyl radical species.

Visible-light-induced cascade radical cyclization for the synthesis of amide-functionalized fused quinazolinones

A light-induced non-activated olefin cascade radical addition/cyclization reaction was proposed, leading to the successful synthesis of 39 quinazolinone derivatives containing amide moieties, with yields up to 88 %. The reaction mechanism was studied by radical strapping test and DFT methods, verifying an oxidative-triggered cascade process promoted by the acylamino radicals. This strategy features mild conditions and broad substrate compatibility, providing a high atom-economical synthesis method for diverse quinazolinone.

Synthesis of N-H Aziridines from Unactivated Olefins Using Hydroxylamine-O-Sulfonic Acids as Aminating Agent.

Herein, we presented a practical methodology for the intermolecular aziridination of alkenes, using HOSA as the aminating agent, alongside pyridine or piperidine as the base, within HFIP solvent system. Notably, this approach showcases excellent reactivity, especially with nonactivated alkenes, and facilitates the transformation of various alkenes substrates, including mono-, di-, tri, and tetra-substituted alkenes, into aziridines with moderate to excellent yield. This method presents a promising avenue for synthesizing aziridines from a wide range of alkenes, featuring the benefits of straightforward operation, mild reaction conditions, extensive substrate compatibility, and scalability.

Site-selective carbonylation of arenes via C(sp2)-H thianthrenation: Palladium-catalyzed direct access to α,β-unsaturated ketones

Herein, an efficient palladium-catalyzed carbonylative Heck reaction of aryl thianthrenium salts with carbon monoxide and alkenes has been developed. This protocol can greatly reduce the quantity of olefins used in the carbonylative Heck reaction. In addition, the reaction can also proceed when the coupling partner is a non-activated olefin which is not common in such carbonylative Heck reactions. Combined with C–H thianthrenation of aromatic hydrocarbons, this work provides an efficient method for the site-selective C–H carbonylative Heck reaction of aromatic hydrocarbons. It may serve as a significant late-stage carbonylation tool for the modification of complex molecules in the future.

Functionalization of Alkenes with Difluoromethyl Nitrile Oxide to Access the Difluoromethylated Derivatives.

Electron-rich, electron-deficient, and non-activated alkenes can be rapidly functionalized by in situ-generated difluoromethyl nitrile oxide. The (3+2) cycloaddition proceeds at room temperature, has broad functional group tolerance, and can be used for the late-stage modification of bioactive molecules (finasteride and carbamazepine). The obtained CF2H-isoxazolines can be easily transformed into CF2H-containing building blocks for medicinal chemistry: amines, amino acids, amino alcohols, and spirocyclic scaffolds.

Direct Construction of C-Alkyl Glycosides from Non-Activated Olefins via Nickel-Catalyzed C(sp3)─C(sp3) Coupling Reaction.

Among C-glycosides, C-alkyl glycosides are significant building blocks for natural products and glycopeptides. However, research on efficient construction methods for C-alkyl glycosides remains relatively limited. Compared with Michael acceptors, non-activated olefins are more challenging substrates and have rarely been employed in the construction of C-glycosides. Here, a highly efficient and convenient approach for the synthesis of C-alkyl glycosides through a nickel-catalyzed C(sp3)-C(sp3) coupling reaction is presented. A distinctive feature of this method is its utilization of non-activated olefins as the anomeric radical acceptors for hydroalkylation, allowing for the direct formation of C-glycoside bonds in a single step. Furthermore, this method demonstrates excellent compatibility with a broad scope of highly reactive functional groups. Mechanistic investigations suggest that the reaction proceeds via a free radical pathway, leading predominantly to the formation of products with α-configuration. Overall, this innovative methodology offers a versatile and practical approach for the synthesis of C-alkyl glycosides, offering new avenues for the production of intricate glycosides with potential applications in drug discovery and chemical biology.

Dual ligand-enabled iron and halogen-containing carboxylate-based photocatalysis for chloro/fluoro-polyhaloalkylation of alkenes

Dual ligand-enabled iron photocatalysis for the conversion of all kinds of halogen-containing carboxylates (CnXmCOO−, X: F, Cl, Br) to CnXm radicals is disclosed for chloro/fluoro-polyhaloalkylation of non-activated alkenes.

(NH4)2S2O8 promoted tandem radical cyclization of quinazolin-4(3H)-ones with oxamic acids for the construction of fused quinazolinones under metal-free conditions.

A novel cascade radical addition/cyclization reaction of non-activated olefins and oxamic acids has been proposed. Under transition metal-free conditions, 36 quinazolinone derivatives containing an amide moiety were successfully synthesized, with the highest yield being 81%. This method involves the preparation of aminoacyl fused quinazolinone derivatives under mild conditions, offering advantages such as a high yield, a broad substrate compatibility, and a high atom economy.

Quinolinamide-Enabled Nickel-Catalyzed Regio- and Diastereoselective γ,δ-Arylalkylation of Nonactivated Alkenes

AbstractA quinolinamide-enabled nickel-catalyzed γ,δ-arylalkylation of homoallylic amines with aryl iodides and organozinc compounds has been developed. The cleavable quinolinamide directing group facilitates the stabilization of a five-membered nickelacycle, and enables the dicarbofunctionalization of nonactivated alkenes with excellently regio-, chemo-, and diastereoselectivity. The reaction with internal alkenes proceeds stereospecifically to provide valuable γ-alkyl-δ-aryl-substituted amines with two vicinal stereocenters. The scope of substrates and the utility of the protocol have been thoroughly studied.

Nickel/photoredox dual catalyzed arylalkylation of nonactivated alkenes

Alkene dicarbofunctionalization is an efficient strategy and operation-economic fashion for introducing complexity in molecules. A nickel/photoredox dual catalyzed arylalkylation of nonactivated alkenes for the simultaneous construction of one C(sp3)−C(sp3) bond and one C(sp3)−C(sp2) bond has been developed. The mild catalytic method provided valuable indanethylamine derivatives with wide substrate scope and good functional group compatibility. An enantioselective dicarbofunctionalization was also achieved with pyridine-oxazoline as a ligand. The efficiency of metallaphotoredox dicarbofunctionalization was demonstrated for the concise synthesis of pharmaceutically active compounds.

Photoinduced Efficient Catalytic α-Alkylation Reactions of Active Methylene and Methine Compounds with Nonactivated Alkenes.

In catalytic α-alkylation reactions of carbonyl compounds, although SN2-type substitution reactions of enolates with alkyl halides are a conventional methodology, addition reactions with alkenes are more desirable because of their atom-economical character; however, reactions with nonactivated alkenes are challenging. Here, we developed highly efficient catalytic α-alkylation reactions of active methylene and methine compounds with nonactivated alkenes such as 1-decene using an organophotocatalyst and lithium thiophenoxide as a Lewis acid/Brønsted base/hydrogen atom transfer (HAT) multifunctional catalyst under blue-light irradiation. The reaction was also performed with a higher degree of efficiency under a continuous-flow system to obtain the products in multigram scales. The present reaction system enables highly efficient and practical α-alkylation reactions of active methylene and methine compounds to be achieved.

Isocyanides as Acceptor Groups in MHAT Reactions with Unactivated Alkenes.

The use of isocyanides as acceptor groups in metal-hydride hydrogen atom transfer (MHAT) coupling reactions with nonactivated alkenes to form heterocycles is described. Monosubstituted alkenes couple and cyclize directly, whereas more substituted alkenes proceed via a two-step, one-pot procedure involving MHAT reductive cyclization followed by a MHAT Minisci coupling upon the addition of acid. To highlight the utility of the methodology, a diverse variety of substituted heterocycles such as phenanthridines, indoles, and isoquinolines were prepared.

Synthesis of 1,2‐Dialkylaminoethers via Photoredox Catalyzed Hydroamination of Vinylethers

AbstractHerein, a general applicable method for the atom‐economic catalytic construction of a broad range of 1,2‐dialkylaminoethers is presented. By taking advantage of an elaborated protocol for the photocatalyzed anti‐Markovnikov selective hydroamination of nonactivated alkenes, a series of 1,2‐dialkylaminoethers was accessed by reacting readily available vinyl ethers with secondary alkyl amines. It was demonstrated that the reaction can be performed at low catalyst loadings while the commonly employed triisopropylbenzene thiol Hydrogen Atom Transfer (HAT)‐catalyst was replaced by an easier accessible mesityl thiol. Furthermore, the inexpensive and readily available diphenyl disulfide was proven as suitable HAT‐catalyst alternative for the efficient hydroamination of simple vinyl ethers.

Stereoselective Synthesis of Multisubstituted Alkenes via Ruthenium-Catalyzed Remote Migration Arylation of Nonactivated Olefins.

Polysubstituted alkenes are an important class of organic intermediates that widely exist in various natural products and drug molecules. Herein, we reported a stereoselective synthesis of multisubstituted alkenes via ruthenium-catalyzed remote migration arylation of nonactivated olefins. This strategy exhibited wide substrate suitability and excellent functional group tolerance. In addition, we demonstrated the indispensable role of two types of ruthenium through mechanism experiments.

Late-Stage, Stereoretentive, and Site-Selective Modification of Synthetic Peptides by Using Photoredox Catalysis.

Late-stage functionalisation is an attractive method to generate peptide analogues containing non-natural residues. It is shown that cysteine residues can be activated as Crich-type thioethers, either by alkylation of a synthetic cysteine-continuing peptide or by incorporation of a modified cysteine unit into solid phase or solution phase peptide synthesis. Photoredox catalysed reaction of the thioether generates an alanyl radical intermediate in a stereoretentive and site-selective manner, even in the presence of free cysteine residues. The radical can react with non-activated alkenes to form non-natural residues bearing aliphatic, hydrophobic units. A method to avoid unwanted alkylation of amine residues was identified and the process was applied to the functionalization of both linear and cyclic synthetic peptides.