Direct Synthesis of Benzofuro[2,3‐b]pyrroles through a Radical Addition/[3,3]‐Sigmatropic Rearrangement/Cyclization/Lactamization Cascade

A straightforward synthetic method for the construction of benzofuro[2,3‐b]pyrrol‐2‐ones by a novel domino reaction through a radical addition/[3,3]‐sigmatropic rearrangement/cyclization/lactamization cascade has been developed. The domino reaction of O‐phenyl‐conjugated oxime ether with an alkyl radical allows the construction of two heterocycles with three stereogenic centers as a result of the formation of two C?C bonds, a C?O bond, and a C?N bond in a single operation, leading to pyrrolidine‐fused dihydrobenzofurans, which are not easily accessible by existing synthetic methods. Furthermore, asymmetric synthesis of benzofuro[2,3‐b]pyrrol‐2‐one derivatives through a diastereoselective radical addition reaction to a chiral oxime ether was also developed.     

Pd/Light‐Accelerated Atom‐Transfer Carbonylation of Alkyl Iodides: Applications in Multicomponent Coupling Processes Leading to Functionalized Carboxylic Acid Derivatives

The atom‐transfer carbonylation reaction of various alkyl iodides thereby leading to carboxylic acid esters was effectively accelerated by the addition of transition‐metal catalysts under photoirradiation conditions. By using a combined Pd/hν reaction system, vicinal C‐functionalization of alkenes was attained in which α‐substituted iodoalkanes, alkenes, carbon monoxide, and alcohols were coupled to give functionalized esters. When alkenyl alcohols were used as acceptor alkenes, three‐component coupling reactions, which were accompanied by intramolecular esterification, proceeded to give lactones. Pd‐dimer complex [Pd₂(CNMe)₆][PF₆]₂, which is known to undergo homolysis under photoirradiation conditions, worked quite well as a catalyst in these three‐ or four‐component coupling reactions. In this metal/radical hybrid system, both Pd radicals and acyl radicals are key players and a stereochemical study confirmed the carbonylation step proceeded through a radical carbonylation mechanism.     

Synthesis of Polysubstituted γ‐Butenolides via a Radical Pathway: Cyclization of α‐Bromo Aluminium Acetals and Comparison with the Cyclization of α‐Bromoesters at High Temperature

Polysubstituted butenolides were obtained in good to high yields from α‐bromoesters derived from propargyl alcohols by a one‐pot reaction involving the radical cyclization of α‐bromo aluminium acetals, followed by the oxidation of the resulting cyclic aluminium acetals in an Oppenauer‐type process and migration of the exocyclic C?C bond into the α,β‐position. Comparison with the direct cyclization of α‐bromoesters at high temperature and under high dilution conditions is described. Deuterium‐labelling experiments allowed us to uncover “invisible” 1,5‐hydrogen atom transfers (1,5‐HATs) that occur during these cyclization processes, together with the consequences of the latter in the epimerization of stereogenic centres. Compared to the classical approach, the cyclization of aluminium acetals proved to be highly chemoselective and its efficiency was illustrated by the short total syntheses of optically enriched γ‐butenolides isolated from Plagiomnium undulatum and from Kyrtuhrix maculans.     

Highly Functionalized and Potent Antiviral Cyclopentane Derivatives Formed by a Tandem Process Consisting of Organometallic,Transition‐Metal‐Catalyzed,and Radical Reaction Steps

A simple modular tandem approach to multiply substituted cyclopentane derivatives is reported, which succeeds by joining organometallic addition, conjugate addition, radical cyclization, and oxygenation steps. The key steps enabling this tandem process are the thus far rarely used isomerization of allylic alkoxides to enolates and single‐electron transfer to merge the organometallic step with the radical and oxygenation chemistry. This controlled lineup of multiple electronically contrasting reactive intermediates provides versatile access to highly functionalized cyclopentane derivatives from very simple and readily available commodity precursors. The antiviral activity of the synthesized compounds was screened and a number of compounds showed potent activity against hepatitis C and dengue viruses.     

Selective 1,2‐Aryl‐Aminoalkylation of Alkenes Enabled by Metallaphotoredox Catalysis

A highly chemo‐ and regioselective intermolecular 1,2‐aryl‐aminoalkylation of alkenes by photoredox/nickel dual catalysis is described here. This three‐component conjunctive cross‐coupling is highlighted by its first application of primary alkyl radicals, which were not compatible in previous reports. The readily prepared α‐silyl amines could be transferred to α‐amino radicals by photo‐induced single electron transfer step. The radical addition/cross‐coupling cascade reaction proceeds under mild, base‐free and redox‐neutral conditions with good functional group tolerance, and importantly, provides an efficient and concise method for the synthesis of structurally valuable α‐aryl substituted γ‐amino acid derivatives motifs.     

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.     

Photoredox‐Coupled F‐Nucleophilic Addition: Allylation of gem‐Difluoroalkenes

A novel strategy for the expedient construction of CF₃‐embeded tertiary/quarternary carbon centers was developed by taking advantage of photoredox catalysis. Thanks to a key step of single‐electron oxidation, electron‐rich gem‐difluoroalkenes, which otherwise are essentially reluctant towards F‐nucleoplilic addition, now readily participate in this fluoroallylation reaction. Furthermore, this strategy provides an elegant example for the generation, as well as functionalization, of α‐CF₃‐substituted benzylic radical intermediates using cheap and readily available starting materials.     

Tandem Anionic oxy‐Cope Rearrangement/Oxygenation Reactions as a Versatile Method for Approaching Diverse Scaffolds

Tandem anionic oxy‐Cope rearrangement/radical oxygenation reactions provide δ,?‐unsaturated α‐(aminoxy) carbonyl compounds, which serve as convenient precursors to diverse compound classes. Functionalized carbocycles are accessible by very rare all‐carbon 5‐endo‐trig cyclizations, but also common 5‐exo‐trig radical cyclizations, based on the persistent radical effect. The tandem reactions can be further extended by highly diastereoselective allylation or reduction steps to give complex scaffolds.     

Total Synthesis of Leuconoxine,Melodinine E,and Mersicarpine through a Radical Translocation–Cyclization Cascade

The Aspidosperma alkaloids leuconoxine, melodinine E, and mersicarpine were synthesized. The approach features a key cascade radical reaction. A 1,5‐hydrogen atom transfer is followed by spontaneous 5‐exo‐trig cyclization to construct the central indoline architecture. Late‐stage differentiation of the radical cyclization product by chemoselective oxidation allows production of either the leuconoxine/melodinine E or mersicarpine structure.     

A Photoredox‐Induced Stereoselective Dearomative Radical (4+2)‐Cyclization/1,4‐Addition Cascade for the Synthesis of Highly Functionalized Hexahydro‐1H‐carbazoles

A stereoselective synthesis of functionalized hexahydrocarbazoles was developed based on an unprecedented photoredox‐induced dearomative radical (4+2)‐cyclization/1,4‐addition cascade between 3‐(2‐iodoethyl)indoles and acceptor‐substituted alkenes. The title reaction simultaneously generates three C−C bonds and one C−H bond, along with three contiguous stereogenic centers. The hexahydro‐1H ‐carbazole products are highly valuable intermediates for the synthesis of novel antibiotics, as well as unnatural ring homologues of polycyclic indoline alkaloids.     

Oxidative Catalysis Using the Stoichiometric Oxidant as a Reagent: An Efficient Strategy for Single‐Electron‐Transfer‐Induced Tandem Anion–Radical Reactions

Oxidative single‐electron transfer‐catalyzed tandem reactions consisting of a conjugate addition and a radical cyclization are reported, which incorporate the mandatory terminal oxidant as a functionality into the product.     

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.     

Hypervalent Iodine(III)‐Mediated Benzannulation of Enamines with Alkynes: an Efficient Synthesis of Substituted Aminonaphthoic Acid Derivatives

An intermolecular two C? C bond formation procedure for the synthesis of carbocycles mediated by hypervalent iodine(III) reagents was developed. This metal free protocol provided a new approach for the synthesis of useful substituted 1‐amino‐2‐naphthoic acid derivatives via benzannulation reactions. Various N‐unsubstituted and N‐alkyl substituted aromatic enamines with terminal alkynes and non‐terminal alkynes can be converted into corresponding 1‐amino‐2‐naphthoic acid derivatives under mild reaction conditions. When meta‐substituted phenyl enamines were employed in the reaction, two cyclization paths were detected in the reaction and ortho‐cyclization products were the only or major products. Good functional group tolerance, readily available material and high atom utilization efficiency make this method a potential procedure which may find broad application in organic synthesis.     

Lanthanide‐Catalyst‐Mediated Tandem Double Intramolecular Hydroalkoxylation/Cyclization of Dialkynyl Dialcohols: Scope and Mechanism

Lanthanide‐organic complexes of the general type [Ln{N(SiMe₃)₂}₃] (Ln=La, Sm, Y, Lu) serve as effective precatalysts for the rapid, exo‐selective, and highly regioselective tandem double intramolecular hydroalkoxylation/cyclization of primary and secondary dialkynyl dialcohols to yield the corresponding bi‐exocyclic enol ethers. Conversions are highly selective with products distinctly different from those generally produced by conventional transition metal or other catalysts, and the turnover frequencies with some substrates are too large to determine accurately. The rates of terminal alkynl alcohol hydroalkoxylation/cyclization are significantly more rapid than those of internal alkynyl alcohols, arguing that steric demands dominate the cyclization transition state. The hydroalkoxylation/cyclizations of internal dialkynyl dialcohols afford excellent E selectivity. The rate law for dialkynyl dialcohol hydroalkoxylation/cyclization is first‐order in [catalyst] and zero‐order in [alkynyl alcohol], as is observed for the organolanthanide‐catalyzed hydroamination/cyclization of aminoalkenes, aminoalkynes, and aminoallenes, and the intramolecular single‐step hydroalkoxylation/cyclization of alkynyl alcohols. An ROH/ROD kinetic isotope effect of 0.82(0.02) is observed for the tandem double hydroalkoxylation/cyclization. These mechanistic data implicate turnover‐limiting insertion of C? C unsaturation into the Ln? O bond, involving a highly organized transition state, with subsequent, rapid Ln–C protonolysis.     

Copper‐Catalyzed Decarboxylative Radical Silylation of Redox‐Active Aliphatic Carboxylic Acid Derivatives

A decarboxylative silylation of aliphatic N ‐hydroxyphthalimide (NHPI) esters using Si−B reagents as silicon pronucleophiles is reported. This C(sp³)−Si cross‐coupling is catalyzed by copper(I) and follows a radical mechanism, even with exclusion of light. Both primary and secondary alkyl groups couple effectively, whereas tertiary alkyl groups are probably too sterically hindered. The functional‐group tolerance is generally excellent, and α‐heteroatom‐substituted substrates also participate well. This enables, for example, the synthesis of α‐silylated amines starting from NHPI esters derived from α‐amino acids. The new method extends the still limited number of C(sp³)−Si cross‐couplings of unactivated alkyl electrophiles.     

Reaction of Nitrogen‐Radicals with Organometallics Under Ni‐Catalysis: N‐Arylations and Amino‐Functionalization Cascades

Herein, we report a strategy for the generation of nitrogen‐radicals by ground‐state single electron transfer with organyl–Ni^I species. Depending on the philicity of the N‐radical, two types of processes have been developed. In the case of nucleophilic aminyl radicals direct N‐arylation with aryl organozinc, organoboron, and organosilicon reagents was achieved. In the case of electrophilic amidyl radicals, cascade processes involving intramolecular cyclization, followed by reaction with both aryl and alkyl organometallics have been developed. The N‐cyclization–alkylation cascade introduces a novel retrosynthetic disconnection for the assembly of substituted lactams and pyrrolidines with its potential demonstrated in the short total synthesis of four venom alkaloids.     

meso–meso‐Linked Diarylamine‐Fused Porphyrin Dimers

A meso–meso‐linked diphenylamine‐fused porphyrin dimer and its methoxy‐substituted analogue were synthesized from a meso–meso‐linked porphyrin dimer by a reaction sequence involving Ir‐catalyzed β‐selective borylation, iodination, meso‐chlorination, and S_NAr reactions with diarylamines followed by electron‐transfer‐mediated intramolecular double C?H/C?I coupling. While these dimers commonly display characteristic split Soret bands and small oxidation potentials, they produced different products upon oxidation with tris(4‐bromophenyl)aminium hexachloroantimonate. Namely, the diphenylamine‐fused porphyrin dimer was converted into a dicationic closed‐shell quinonoidal dimer, while the methoxy‐substituted dimer gave a meso–meso, β‐β doubly linked porphyrin dimer.     

Photoredox‐Catalyzed Cyclobutane Synthesis by a Deboronative Radical Addition–Polar Cyclization Cascade

Photoredox‐catalyzed methylcyclobutanations of alkylboronic esters are described. The reactions proceed through single‐electron transfer induced deboronative radical addition to an electron‐deficient alkene followed by single‐electron reduction and polar 4‐exo‐tet cyclization with a pendant alkyl halide. Key to the success of the methodology was the use of easily oxidizable arylboronate complexes. Structurally diverse cyclobutanes are shown to be conveniently prepared from readily available alkylboronic esters and a range of haloalkyl alkenes. The mild reactions display excellent functional group tolerance, and the radical addition‐polar cyclization cascade also enables the synthesis of 3‐, 5‐, 6‐, and 7‐membered rings.     

The Tris(trimethylsilyl)silane/Thiol Reducing System: A Tool for Measuring Rate Constants for Reactions of Carbon‐Centered Radicals with Thiols

An extension of the well‐known ‘free‐radical‐clock’ methodology is described that allows one to determine the rate constants of carbon‐centered radicals with a variety of thiols by using the tris(trimethylsilyl)silane/thiol couple as a reducing system. A total of 20 rate constants for the hydrogen abstraction from a variety of alkyl‐, silyl‐, and aryl‐substituted thiols by the primary‐alkyl radical 2 in toluene at 80° were determined with the aid of the 5‐exo‐trig cyclization as a timing device. Further, seven rate constants for the hydrogen abstraction from a variety of alkyl‐ and silyl‐substituted thiols by the acyl radical 9 in benzene at 80° were measured using the decarbonylation process as a timing device. The rate constants varied over two orders of magnitude from 10⁶ to 10⁸ M ^?1 s^?1. Substituent effects were rationalized. The radical‐trapping abilities of these reducing systems and those of other common hydrogen donors were compared.     

Copper‐Catalyzed 8‐Amido Chelation‐Induced Remote C−H Amination of Quinolines

A copper‐catalyzed 8‐amide chelation‐induced remote C?H amination of quinolines has been developed. This direct amination with readily available azodicarboxylates proceeded with perfect C5‐regioselectivity offering amino‐substituted 8‐aminoquinolines, important bioactive molecular scaffolds, in very high yields (up to 96 %). A single‐electron transfer (SET)‐mediated mechanism with k_H/k_D=1.1 was proposed after trapping of the radical intermediate.