Photoredox Catalysis of Aromatic β-Ketoesters for in Situ Production of Transient and Persistent Radicals for Organic Transformation

Radical formation is the initial step for conventional radical chemistry. Reported herein is a unified strategy to generate radicals in situ from aromatic β-ketoesters by using a photocatalyst. Under visible-light irradiation, a small amount of photocatalyst fac-Ir(ppy)₃ generates a transient α-carbonyl radical and persistent ketyl radical in situ. In contrast to the well-established approaches, neither stoichiometric external oxidant nor reductant is required for this reaction. The synthetic utility is demonstrated by pinacol coupling of ketyl radicals and benzannulation of α-carbonyl radicals with alkynes to give a series of highly substituted 1-naphthols in good to excellent yields. The readily available photocatalyst, mild reaction conditions, broad substrate scope, and high functional-group tolerance make this reaction a useful synthetic tool.     

An Olefinic 1,2‐Boryl‐Migration Enabled by Radical Addition: Construction of gem‐Bis(boryl)alkanes

A series of in situ formed alkenyl diboronate complexes from alkenyl Grignard reagents (commercially available or prepared from alkenyl bromides and Mg) with B₂Pin₂ (bis(pinacolato)diboron) react with diverse alkyl halides by a Ru photocatalyst to give various gem‐bis(boryl)alkanes. Alkyl radicals add efficiently to the alkenyl diboronate complexes, and the adduct radical anions undergo radical‐polar crossover, specifically, a 1,2‐boryl‐anion shift from boron to the α‐carbon sp² center. This transformation shows good functional‐group compatibility and can serve as a powerful synthetic tool for late‐stage functionalization in complex compounds. Measurements of the quantum yield reveal that a radical‐chain mechanism is operative in which the alkenyl diboronates acts as reductive quencher for the excited state of the photocatalyst.     

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.     

Enolizable Carbonyls and N,O‐Acetals: A Rational Approach for Room‐Temperature Lewis Superacid‐Catalyzed Direct α‐Amidoalkylation of Ketones and Aldehydes

An efficient catalytic room‐temperature direct α‐amidoalkylation of carbonyl donors, that is, ketones and aldehydes with unbiased N,O‐acetals, is described. Sn(NTf₂)₄ is an optimal catalyst to promote this challenging transformation at low loading and the reaction shows promising scope. A comprehensive and rational evaluation of this reaction has led to the establishment of an empirical scale of nucleophilic reactivity for a broad set of ketones that should be helpful in the synthetic design and development of carbonyl α‐functionalization methods.     

Enantio‐ and Site‐Selective α‐Fluorination of N‐Acyl 3,5‐Dimethylpyrazoles Catalyzed by Chiral π–CuII Complexes

Catalytic enantioselective α‐fluorination reactions of carbonyl compounds are among the most powerful and efficient synthetic methods for constructing optically active α‐fluorinated carbonyl compounds. Nevertheless, α‐fluorination of α‐nonbranched carboxylic acid derivatives is still a big challenge because of relatively high pK_a values of their α‐hydrogen atoms and difficulty of subsequent synthetic transformation without epimerization. Herein we show that chiral copper(II) complexes of 3‐(2‐naphthyl)‐l ‐alanine‐derived amides are highly effective catalysts for the enantio‐ and site‐selective α‐fluorination of N‐(α‐arylacetyl) and N‐(α‐alkylacetyl) 3,5‐dimethylpyrazoles. The substrate scope of the transformation is very broad (25 examples including a quaternary α‐fluorinated α‐amino acid derivative). α‐Fluorinated products were converted into the corresponding esters, secondary amides, tertiary amides, ketones, and alcohols with almost no epimerization in high yield.     

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.     

Borane‐Catalyzed Reductive α‐Silylation of Conjugated Esters and Amides Leaving Carbonyl Groups Intact

Described herein is the development of the B(C₆F₅)₃‐catalyzed hydrosilylation of α,β‐unsaturated esters and amides to afford synthetically valuable α‐silyl carbonyl products. The α‐silylation occurs chemoselectively, thus leaving the labile carbonyl groups intact. The reaction features a broad scope of both acyclic and cyclic substrates, and the synthetic utility of the obtained α‐silyl carbonyl products is also demonstrated. Mechanistic studies revealed two operative steps: fast 1,4‐hydrosilylation of conjugated carbonyls and then slow silyl group migration of a silyl ether intermediate.     

Visible‐Light Photocatalytic Radical Alkenylation of α‐Carbonyl Alkyl Bromides and Benzyl Bromides

Through the use of [Ru(bpy)₃Cl₂] (bpy=2,2′‐bipyridine) and [Ir(ppy)₃] (ppy=phenylpyridine) as photocatalysts, we have achieved the first example of visible‐light photocatalytic radical alkenylation of various α‐carbonyl alkyl bromides and benzyl bromides to furnish α‐vinyl carbonyls and allylbenzene derivatives, prominent structural elements of many bioactive molecules. Specifically, this transformation is regiospecific and can tolerate primary, secondary, and even tertiary alkyl halides that bear β‐hydrides, which can be challenging with traditional palladium‐catalyzed approaches. The key initiation step of this transformation is visible‐light‐induced single‐electron reduction of C? Br bonds to generate alkyl radical species promoted by photocatalysts. The following carbon? carbon bond‐forming step involves a radical addition step rather than a metal‐mediated process, thereby avoiding the undesired β‐hydride elimination side reaction. Moreover, we propose that the Ru and Ir photocatalysts play a dual role in the catalytic system: they absorb energy from the visible light to facilitate the reaction process and act as a medium of electron transfer to activate the alkyl halides more effectively. Overall, this photoredox catalysis method opens new synthetic opportunities for the efficient alkenylation of alkyl halides that contain β‐hydrides under mild conditions.     

Highly Diastereoselective Synthesis of α‐Difluoromethyl Amines from N‐tert‐Butylsulfinyl Ketimines and Difluoromethyl Phenyl Sulfone

The first highly efficient and stereoselective difluoromethylation of structurally diverse N‐tert‐butylsulfinyl ketimines has been achieved with an in situ generated PhSO₂CF₂^? anion, which provides a powerful synthetic method for the preparation of a variety of structurally diverse homochiral α‐difluoromethyl tertiary carbinamines, including α‐difluoromethyl allylic amines and α‐difluoromethyl propargylamines. The stereocontrol mode of the present diastereoselective difluoromethylation of ketimines was found to be different from that of other known fluoroalkylations of N‐tert‐butylsulfinyl aldimines, which suggests that a cyclic six‐membered transition state may be involved in the reaction.     

Iminyl‐Radicals by Oxidation of α‐Imino‐oxy Acids: Photoredox‐Neutral Alkene Carboimination for the Synthesis of Pyrrolines

The visible‐light‐promoted decarboxylation of α‐imino‐oxy propionic acids for the generation of iminyl radicals has been accomplished through the use of Ir(dFCF₃ppy)₂(dtbbpy)PF₆ as a photoredox catalyst. Different from visible‐light‐promoted homolysis and single‐electron reduction of oxime derivatives, this strategy provides a novel catalytic cycle for alkene carboimination through a sequence comprising N‐radical generation, iminyl radical cyclization, intermolecular conjugate addition to a Michael acceptor, and single‐electron reduction to afford various pyrroline derivatives in an overall redox‐neutral process. The indolizidine alkaloid skeleton could be easily constructed from a pyrroline derivative prepared by this synthetic method.     

Solvent‐Free One‐Step Photochemical Hydroxylation of Benzene Derivatives by the Singlet Excited State of 2,3‐Dichloro‐5,6‐dicyano‐p‐benzoquinone Acting as a Super Oxidant

Photoinduced hydroxylation of neat deaerated benzene to phenol occurred under visible‐light irradiation of 2,3‐dichloro‐5,6‐dicyano‐p‐benzoquinone (DDQ), which acts as a super photooxidant in the presence of water. Photocatalytic solvent‐free hydroxylation of benzene derivatives with electron‐withdrawing substituents such as benzonitrile, nitrobenzene, and trifluoromethylbenzene used as neat solvents has been achieved for the first time by using DDQ as a super photooxidant to yield the corresponding phenol derivatives and 2,3‐dichloro‐5,6‐dicyanohydroquinone (DDQH₂) in the presence of water under deaerated conditions. In the presence of dioxygen and tert‐butyl nitrite, the photocatalytic hydroxylation of neat benzene occurred with DDQ as a photocatalyst to produce phenol. The photocatalytic reactions are initiated by oxidation of benzene derivatives with the singlet and triplet excited states of DDQ to form the corresponding radical cations, which associate with benzene derivatives to produce the dimer radical cations, which were detected by the femto‐ and nanosecond laser flash photolysis measurements to clarify the photocatalytic reaction mechanisms. Radical cations of benzene derivatives react with water to yield the OH‐adduct radicals. On the other hand, DDQ ^{. ?} produced by the photoinduced electron transfer from benzene derivatives reacts with the OH‐adduct radicals to yield the corresponding phenol derivatives and DDQH₂. DDQ is recovered by the reaction of DDQH₂ with tert‐butyl nitrite when DDQ acts as a photocatalyst for the hydroxylation of benzene derivatives by dioxygen.     

An Alternative to the Classical α‐Arylation: The Transfer of an Intact 2‐Iodoaryl from ArI(O2CCF3)2

The α‐arylation of carbonyl compounds is generally accomplished under basic conditions, both under metal catalysis and via aryl transfer from the diaryl λ³‐iodanes. Here, we describe an alternative metal‐free α‐arylation using ArI(O₂CCF₃)₂ as the source of a 2‐iodoaryl group. The reaction is applicable to activated ketones, such as α‐cyanoketones, and works with substituted aryliodanes. This formal C? H functionalization reaction is thought to proceed through a [3,3] rearrangement of an iodonium enolate. The final α‐(2‐iodoaryl)ketones are versatile synthetic building blocks.     

Methyl‐Selective α‐Oxygenation of Tertiary Amines to Formamides by Employing Copper/Moderately Hindered Nitroxyl Radical (DMN‐AZADO or 1‐Me‐AZADO)

Methyl‐selective α‐oxygenation of tertiary amines is a highly attractive approach for synthesizing formamides while preserving the amine substrate skeletons. Therefore, the development of efficient catalysts that can advance regioselective α‐oxygenation at the N‐methyl positions using molecular oxygen (O₂) as the terminal oxidant is an important subject. In this study, we successfully developed a highly regioselective and efficient aerobic methyl‐selective α‐oxygenation of tertiary amines by employing a Cu/nitroxyl radical catalyst system. The use of moderately hindered nitroxyl radicals, such as 1,5‐dimethyl‐9‐azanoradamantane N‐oxyl (DMN‐AZADO) and 1‐methyl‐2‐azaadamanane N‐oxyl (1‐Me‐AZADO), was very important to promote the oxygenation effectively mainly because these N‐oxyls have longer life‐times than less hindered N‐oxyls. Various types of tertiary N‐methylamines were selectively converted to the corresponding formamides. A plausible reaction mechanism is also discussed on the basis of experimental evidence, together with DFT calculations. The high regioselectivity of this catalyst system stems from steric restriction of the amine‐N‐oxyl interactions.     

Copper‐Catalyzed Radical/Radical CH/PH Cross‐Coupling: α‐Phosphorylation of Aryl Ketone O‐Acetyloximes

The selective radical/radical cross‐coupling of two different organic radicals is a great challenge due to the inherent activity of radicals. In this paper, a copper‐catalyzed radical/radical C? H/P? H cross‐coupling has been developed. It provides a radical/radical cross‐coupling in a selective manner. This work offers a simple way toward β‐ketophosphonates by oxidative coupling of aryl ketone o‐acetyloximes with phosphine oxides using CuCl as catalyst and PCy₃ as ligand in dioxane under N₂ atmosphere at 130 °C for 5 h, and yields ranging from 47 % to 86 %. The preliminary mechanistic studies by electron paramagnetic resonance (EPR) showed that, 1) the reduction of ketone o‐acetyloximes generates iminium radicals, which could isomerize to α‐sp³‐carbon radical species; 2) phosphorus radicals were generated from the oxidation of phosphine oxides. Various aryl ketone o‐acetyloximes and phosphine oxides were suitable for this transformation.     

New Radical Borylation Pathways for Organoboron Synthesis Enabled by Photoredox Catalysis

Radical borylation using N‐heterocyclic carbene (NHC)‐BH₃ complexes as boryl radical precursors has emerged as an important synthetic tool for organoboron assembly. However, the majority of reported methods are limited to reaction modes involving carbo‐ and/or hydroboration of specific alkenes and alkynes. Moreover, the generation of NHC‐boryl radicals relies principally on hydrogen atom abstraction with the aid of radical initiators. A distinct radical generation method is reported, as well as the reaction pathways of NHC‐boryl radicals enabled by photoredox catalysis. NHC‐boryl radicals are generated via a single‐electron oxidation and subsequently undergo cross‐coupling with the in‐situ‐generated radical anions to yield gem‐difluoroallylboronates. A photoredox‐catalyzed radical arylboration reaction of alkenes was achieved using cyanoarenes as arylating components from which elaborated organoborons were accessed. Mechanistic studies verified the oxidative formation of NHC‐boryl radicals through a single‐electron‐transfer pathway.     

Silver‐Catalyzed Nitration/Annulation of α‐Alkynyl Arylols toward 3‐Nitrated Benzofurans

A silver‐catalyzed nitration/annulation of α‐alkynyl arylols is reported by using tert‐butyl nitrite (TBN) as a NO₂ radical precursor, from which a set of 3‐nitrated benzofurans were synthesized with moderate to good yields. This transformation initiated by an in situ generated NO₂ radical proceeds efficiently under mild and neutral redox conditions, which provides a new pathway toward the 3‐nitrobenzofuran framework via catalytic difunctionalization of internal alkynes.     

Site‐Selective Tertiary Alkyl–Fluorine Bond Formation from α‐Bromoamides Using a Copper/CsF Catalyst System

A copper‐catalyzed site‐selective fluorination of α‐bromoamides possessing multiple reaction sites, such as primary and secondary alkyl?Br bonds, using inexpensive CsF is reported. Tertiary alkyl?F bonds, which are very difficult to synthesize, can be formed by this fluorination reaction with the aid of an amide group. Control experiments revealed that in situ generated CuF₂ is a key fluorinating reagent that reacts with the tertiary alkyl radicals generated by the reaction between an α‐bromocarbonyl compound and a copper(I) salt.     

Benzyl tert‐but­oxy­carbonyl‐α‐amino­isobutyrate

The small synthetic peptide, benzyl 2‐(tert‐but­oxy­carbonyl‐amino)­isobutyrate, C₁₆H₂₃NO₄, has the α‐helical conformation [|?| = 55.8 (2)° and |ψ| = 37.9 (2)°] observed in peptide fragments of peptaibols containing the α‐amino­isobutyric acid (Aib) residue. The structure shows no intramolecular hydrogen bonding, which would disrupt the limited conformational freedom associated with this amino acid. Two weak intermolecular hydrogen contacts are observed.     

Polarity‐Reversed Allylations of Aldehydes,Ketones, and Imines Enabled by Hantzsch Ester in Photoredox Catalysis

The polarity reversal (umpolung) reaction is an invaluable tool for reversing the chemical reactivity of carbonyl and iminyl groups, which subsequent cross‐coupling reactions to form C?C bonds offers a unique perspective in synthetic planning and implementation. Reported herein is the first visible‐light‐induced polarity‐reversed allylation and intermolecular Michael addition reaction of aldehydes, ketones, and imines. This chemoselective reaction has broad substrate scope and the engagement of alkyl imines is reported for the first time. The mechanistic investigations indicate the formation of ketyl (or α‐aminoalkyl) radicals from single‐electron reduction, where the Hantzsch ester is crucial as the electron/proton donor and the activator.     

Polarity‐Reversed Allylations of Aldehydes,Ketones, and Imines Enabled by Hantzsch Ester in Photoredox Catalysis

The polarity reversal (umpolung) reaction is an invaluable tool for reversing the chemical reactivity of carbonyl and iminyl groups, which subsequent cross‐coupling reactions to form C−C bonds offers a unique perspective in synthetic planning and implementation. Reported herein is the first visible‐light‐induced polarity‐reversed allylation and intermolecular Michael addition reaction of aldehydes, ketones, and imines. This chemoselective reaction has broad substrate scope and the engagement of alkyl imines is reported for the first time. The mechanistic investigations indicate the formation of ketyl (or α‐aminoalkyl) radicals from single‐electron reduction, where the Hantzsch ester is crucial as the electron/proton donor and the activator.