Mild and Low‐Pressure fac‐Ir(ppy)3‐Mediated Radical Aminocarbonylation of Unactivated Alkyl Iodides through Visible‐Light Photoredox Catalysis

A novel, mild and facile preparation of alkyl amides from unactivated alkyl iodides employing a fac‐Ir(ppy)₃‐catalyzed radical aminocarbonylation protocol has been developed. Using a two‐chambered system, alkyl iodides, fac‐Ir(ppy)₃, amines, reductants, and CO gas (released ex situ from Mo(CO)₆), were combined and subjected to an initial radical reductive dehalogenation generating alkyl radicals, and a subsequent aminocarbonylation with amines affording a wide range of alkyl amides in moderate to excellent yields.     

Organic Photocatalytic Cyclization of Polyenes: A Visible‐Light‐Mediated Radical Cascade Approach

A visible‐light‐mediated, organic photocatalytic stereoselective radical cascade cyclization of polyprenoids is described. The desired cascade cyclization products are achieved in good yields and high stereoselectivities with eosin Y as photocatalyst in hexafluoro‐2‐propanol. The catalyst system is also suitable for 1,3‐dicarbonyl compounds, which require only catalytic amounts of LiBr to promote the formation of the corresponding enols.     

Domino Radical Addition/Oxidation Sequence with Photocatalysis: One‐Pot Synthesis of Polysubstituted Furans from α‐Chloro‐Alkyl Ketones and Styrenes

A new domino reaction has been developed that allows the combination of styrenes and α‐alkyl ketone radicals to afford a wide array of polysubstituted furans in good to excellent yields under mild and simple reaction conditions. The key to success of this novel protocol is the use of photocatalyst fac‐Ir(ppy)₃ and oxidant K₂S₂O₈. Mechanistic studies by a radical scavenger and photoluminescence quenching suggest that a radical addition/oxidation pathway is operable.     

Photoinduced Radical Borylation of Alkyl Bromides Catalyzed by 4‐Phenylpyridine

Utilizing pyridine catalysis, we developed a visible‐light‐induced transition‐metal‐free radical borylation reaction of unactivated alkyl bromides that features a broad substrate scope and mild reaction conditions. Mechanistic studies revealed a novel nucleophilic substitution/photoinduced radical formation pathway, which could be utilized to trigger a variety of radical processes.     

Aryl Radical‐Mediated Alkenylation of Alkyl Halides

The free‐radical alkenylation of a range of alkyl iodides with a vinyldisulfones has been carried out, leading to the desired vinylsulfones in moderate to good yields under mild conditions. The process is initiated by an aryl radical which abstracts the iodine atom from the alkyl iodide to form a C‐centered radical intermediate, the addition of which onto the vinyldisulfone providing the final vinylsulfone. The aryl radical is generated in situ through a single‐electron transfer from an electron donor‐acceptor complex (EDA) formed between a diaryliodonium salt (Ph₂I⁺ PF₆^?) and triethylamine.     

Metal‐Free Oxidative Radical Addition of Carbonyl Compounds to α,α‐Diaryl Allylic Alcohols: Synthesis of Highly Functionalized Ketones

A metal‐free direct alkylation of simple carbonyl compounds (ketones, esters, and amides) with α,α‐diaryl allylic alcohols is described. The protocol provides facile access to highly functionalized dicarbonyl ketones by a radical addition/1,2‐aryl migration cascade. The regioselectivity of the reaction was precisely controlled by the nature of the carbonyl compound.     

Visible‐Light Photoredox‐Catalyzed C−H Difluoroalkylation of Hydrazones through an Aminyl Radical/Polar Mechanism

An unprecedented visible‐light‐induced direct C?H bond difluoroalkylation of aldehyde‐derived hydrazones was developed. This reaction represents a new way to synthesize substituted hydrazones. The salient features of this reaction include difluorinated hydrazone synthesis rather than classical amine synthesis, extremely mild reaction conditions, high efficiency, wide substrate scope, ease in further transformations of the products, and one‐pot syntheses. Mechanistic analyses and theoretical calculations indicate that this reaction is enabled by a novel aminyl radical/polar crossover mechanism, with the aminyl radical being oxidized into the corresponding aminyl cation through a single electron transfer (SET) process.     

Arginine‐Facilitated α‐ and π‐Radical Migrations in Glycylarginyltryptophan Radical Cations

We have used model tripeptides GXW (with X being one of the amino acid residues glycine (G), alanine (A), leucine (L), phenylalanine (F), glutamic acid (E), histidine (H), lysine (K), or arginine (R)) to study the effects of the basicity of the amino acid residue on the radical migrations and dissociations of odd‐electron molecular peptide radical cations M^.+ in the gas phase. Low‐energy collision‐induced dissociation (CID) experiments revealed that the interconvertibility of the isomers [G^.XW]⁺ (radical centered on the N‐terminal α‐carbon atom) and [GXW]^.+ (radical centered on the π system of the indolyl ring) generally increased upon increasing the proton affinity of residue X. When X was arginine, the most basic amino acid, the two isomers were fully interconvertible and produced almost identical CID spectra despite the different locations of their initial radical sites. The presence of the very basic arginine residue allowed radical migrations to proceed readily among the [G^.RW]⁺ and [GRW]^.+ isomers prior to their dissociations. Density functional theory calculations revealed that the energy barriers for isomerizations among the α‐carbon‐centered radical [G^.RW]⁺, the π‐centered radical [GRW]^.+, and the β‐carbon‐centered radical [GRW_β^.]⁺ (ca. 32–36 kcal mol⁻¹) were comparable with those for their dissociations (ca. 32–34 kcal mol⁻¹). The arginine residue in these GRW radical cations tightly sequesters the proton, thereby resulting in minimal changes in the chemical environment during the radical migrations, in contrast to the situation for the analogous GGW system, in which the proton is inefficiently stabilized during the course of radical migration.     

Photoredox Catalytic α‐Alkoxypentafluorosulfanylation of α‐Methyl‐ and α‐Phenylstyrene Using SF6

SF₆ was applied as pentafluorosulfanylation reagent to prepare ethers with a vicinal SF₅ substituent through a one‐step method involving photoredox catalysis. This method shows a broad substrate scope with respect to applicable alcohols for the conversion of α‐methyl and α‐phenyl styrenes. The products bear a new structural motif with two functional groups installed in one step. The alkoxy group allows elimination and azidation as further transformations into valuable pentafluorosulfanylated compounds. These results confirm that non‐toxic SF₆ is a useful SF₅ transfer reagent if properly activated by photoredox catalysis, and toxic reagents are completely avoided. In combination with light as an energy source, a high level of sustainability is achieved. Through this method, the proposed potential of the SF₅ substituent in medicinal chemistry, agrochemistry, and materials chemistry may be exploited in the future.     

A Visible‐Light‐Mediated Radical Smiles Rearrangement and its Application to the Synthesis of a Difluoro‐Substituted Spirocyclic ORL‐1 Antagonist

A visible‐light‐mediated radical Smiles rearrangement has been developed to address the challenging synthesis of the gem‐difluoro group present in an opioid receptor‐like 1 (ORL‐1) antagonist that is currently in development for the treatment of depression and/or obesity. This method enables the direct and efficient introduction of the difluoroethanol motif into a range of aryl and heteroaryl systems, representing a new disconnection for the synthesis of this versatile moiety. When applied to the target compound, the photochemical step could be conducted on 15 g scale using industrially relevant [Ru(bpy)₃Cl₂] catalyst loadings of 0.01 mol %. This transformation is part of an overall five‐step route to the antagonist that compares favorably to the current synthetic sequence and demonstrates, in this specific case, a clear strategic benefit of photocatalysis.     

Stereoselective Synthesis of α‐Linked 2‐Deoxy Glycosides Enabled by Visible‐Light‐Mediated Reductive Deiodination

2‐Deoxy sugars and their derivatives occur abundantly in many pharmaceutically important natural products. However, the construction of specific 2‐deoxy‐glycosidic bonds remains as a challenge. Herein, we report an efficient way to prepare 2‐deoxy‐α‐glycosides by glycosylation of 2‐iodo‐glycosyl acetate and subsequent visible‐light‐mediated tin‐free reductive deiodination. We have successfully applied the postglycosylational‐deiodination strategy in the synthesis of more than 30 mono‐, di‐, tri‐, tetra‐ and pentadeoxysaccharides with excellent stereoselectivity and efficiency. This method has also been applied to the synthesis of a 2‐deoxy‐tetrasaccharide containing four α‐linkages.     

Visible‐Light‐Mediated Decarboxylative Radical Additions to Vinyl Boronic Esters: Rapid Access to γ‐Amino Boronic Esters

The synthesis of alkyl boronic esters by direct decarboxylative radical addition of carboxylic acids to vinyl boronic esters is described. The reaction proceeds under mild photoredox catalysis and involves an unprecedented single‐electron reduction of an α‐boryl radical intermediate to the corresponding anion. The reaction is amenable to a diverse range of substrates, including α‐amino, α‐oxy, and alkyl carboxylic acids, thus providing a novel method to rapidly access boron‐containing molecules of potential biological importance.     

Silver‐Mediated Intermolecular 1,2‐Alkylarylation of Styrenes with α‐Carbonyl Alkyl Bromides and Indoles

A new iron‐facilitated silver‐mediated radical 1,2‐alkylarylation of styrenes with α‐carbonyl alkyl bromides and indoles is described, and two new C?C bonds were generated in a single step through a sequence of intermolecular C(sp³)?Br functionalization and C(sp²)?H functionalization across the alkenes. This method provides an efficient access to alkylated indoles with broad substrate scope and excellent selectivity.     

Decarbonylative Radical Coupling of α‐Aminoacyl Tellurides: Single‐Step Preparation of γ‐Amino and α,β‐Diamino Acids and Rapid Synthesis of Gabapentin and Manzacidin A

A new radical‐based coupling method has been developed for the single‐step generation of various γ‐amino acids and α,β‐diamino acids from α‐aminoacyl tellurides. Upon activation by Et₃B and O₂ at ambient temperature, α‐aminoacyl tellurides were readily converted into α‐amino carbon radicals through facile decarbonylation, which then reacted intermolecularly with acrylates or glyoxylic oxime ethers. This mild and powerful method was effectively incorporated into expeditious synthetic routes to the pharmaceutical agent gabapentin and the natural product (?)‐manzacidin A.