Visible-Light-Induced Three-Component 1,2-Alkylpyridylation of Alkenes via a Halogen-Atom Transfer Process.

Visible-light-induced three-component 1,2-alkylpyridylation of alkenes with unactivated alkyl iodides and aryl cyanides is reported via a photocatalytic halogen-atom transfer (XAT) strategy. This metal-free protocol utilizes readily available tertiary alkylamine as the terminal reductant to smoothly convert alkyl iodides into the corresponding carbon radical species. The reaction features a broad substrate scope, excellent functional group tolerance, high efficiency, and mild reaction conditions. The practicability of this methodology is further demonstrated in the late-stage difunctionalization of bioactive molecules.

Copper-Catalyzed Oxidative Coupling of Quinazoline-3-Oxides: Synthesis of O-Quinazolinic Carbamates.

Organic carbamates represent a kind of privileged structures in both organic chemistry and industry. Despite the fact that the synthesis of alcohol-based carbamates has been well studied, an efficient access to hydroxamic acid-based carbamates is less explored due to the nucleophilicity of both O and N atoms in hydroxamic acids. Herein, we report a copper-catalyzed oxidative coupling of quinazoline-3-oxides and formamides for the synthesis of O-quinazolinic carbamates. This protocol is featured with practicability, simple starting materials, and operational simplicity.

Directed Copper-Catalyzed Intermolecular Aminative Difunctionalization of Unactivated Alkenes.

A diverse collection of copper-catalyzed intermolecular aminative difunctionalizations of unactivated alkenes with N-halodialkylamines as the terminal dialkylamino source is reported. A bidentate auxiliary tethered on the alkene substrates is crucial, which can promote the migratory insertion of nonactivated alkenes into the aminyl radical-metal complex and stabilize the resultant high-valent copper intermediate to allow for further transformations. By employing this strategy, the intermolecular aminohalogenation reactions and a three-component aminoazidation reaction of unactivated alkenes with dialkylamino source were successively achieved in a remarkable regio- and stereoselective manner. These reactions were performed under neutral conditions and maintained excellent functional group tolerance toward a wide range of N-halodialkylamines and unactivated alkenes. Further mechanistic studies and DFT calculations supported a concerted migratory insertion of the C-C double bond into the aminyl radical-metal complex to form a Cu(III) intermediate.

Directed Copper-Catalyzed Intermolecular Heck-Type Reaction of Unactivated Olefins and Alkyl Halides.

A new type of intermolecular alkylative olefination of unactivated olefins and alkyl halides has been realized for the first time. This copper-promoted Heck-type reaction employs a directing-group strategy to efficiently produce the coupled alkyl olefin products with excellent regio- and stereoselectivity. A broad substrate scope including 1°, 2°, and 3° alkyl bromides and various nonactivated alkenes could be well tolerated. DFT calculations disclosed a dimethyl sulfoxide assisted concerted H-Br elimination process of a conformationally strained Cu(III) cyclic transition state.

Palladium-catalyzed carbonylation of benzylic ammonium salts to amides and esters via C-N bond activation.

An efficient palladium-catalyzed carbonylation reaction of readily available quaternary ammonium salts with CO is reported for the first time to afford arylacetamides and arylacetic acid esters via benzylic C-N bond cleavage. This protocol features mild reaction conditions under atmospheric pressure of CO, a redox-neutral process without an additional oxidant, and a broad substrate scope for various kinds of amines, alcohols and phenols.

α-Substituted vinyl azides: an emerging functionalized alkene.

Vinyl azides are highly versatile synthons that provide access to numerous N-heterocycles and other functional groups. α-Substituted vinyl azides (azido vinylidenes) are a special class that display unique reactivity, able to react not only as azides, but also as radical acceptors, enamine-type nucleophiles, and even electrophiles, thus delivering a wide range of nitrogen-containing compounds and their derivatives. An impressive variety of intermediates - such as iminodiazonium ions, nitrilium ions, iminyl radicals, and metal enaminyl radicals - can be generated from vinyl azides and exploited in cycloadditions, C-H functionalizations, hydrolysis processes, and cascade reactions under transition metal/photoredox catalysis. In addition to presenting synthetic protocols to access vinyl azides, this Review offers a comprehensive coverage of the development of their multifaceted reactivity, and highlights their potential as versatile precursors for synthetic applications.

Synthesis of 2,3-Disubstituted Indoles and Benzofurans by the Tandem Reaction of Rhodium(II)-Catalyzed Intramolecular C-H Insertion and Oxygen-Mediated Oxidation.

A highly effective and straightforward method to construct a wide range of functionalized 2,3-disubstituted indoles has been developed. The method involves the tandem reaction of rhodium(II)-catalyzed denitrogenative annulation of triazole-based benzyl anilines and oxygen-mediated oxidative aromatization. The developed method can also be used to synthesize 2,3-disubstituted benzofurans by replacing the benzyl anilines with benzyl phenols.

Concise stereoselective synthesis of oxaspirocycles with 1-tosyl-1,2,3-triazoles: application to the total syntheses of (±)-Tuberostemospiroline and (±)-stemona-lactam†R.

A 4-substituted-1-tosyl-1,2,3-triazole-based stereoselective synthesis of structurally diverse oxaspirocycles is reported. The synthesis involves Rh-catalyzed loss of nitrogen from 4-substituted-1-tosyl-1,2,3-triazoles, Grignard reaction, and a ring-closing metathesis reaction as key steps. By employing readily available and stable 4-substituted-1-tosyl-1,2,3-triazoles as surrogates of diazo compounds and nitrogen sources, two types of oxaspirocycles were obtained. The latter compounds, which contain adjacent nitrogen stereocenters, could serve as the core structures of many natural products. This chemistry has been successfully applied to the total syntheses of (±)-tuberostemospiroline and (±)-stemona-lactam R.

A Catalytic Three-Component Aminofluorination of Unactivated Alkenes with Electron-Rich Amino Sources.

We present herein a copper-catalyzed three-component aminofluorination of unactivated alkenes with N-bromodialkylamines and readily available nucleophilic fluoride under the assistance of a bidentate auxiliary. This protocol exhibits excellent functional group tolerance toward a wide range of unactivated alkenes and N-bromodialkylamines to furnish the corresponding ß-fluoroalkylamines in a highly regio- and diastereoselective manner. The appropriate choice of nucleophilic fluoro source is essential to make this reaction a reality. Further DFT calculations show that the exothermic ion exchange between external fluoride ion and Cu(II) intermediate provides additional driving force to the irreversible migratory insertion, which offsets the unfavorable reaction energetics associated with the subsequent C(sp3)-F reductive elimination. This finding offers a new avenue to catalytic intermolecular aminofluorination of unactivated alkenes with electron-rich amino sources via a remarkable reductive elimination of Cu(III) species to forge the C(sp3)-F bonds.

A facile synthesis of α,ß-unsaturated imines via palladium-catalyzed dehydrogenation.

The dehydrogenation adjacent to an electron-withdrawing group provides an efficient access to α,ß-unsaturated compounds that serving as versatile synthons in organic chemistry. However, the α,ß-desaturation of aliphatic imines has hitherto proven to be challenging due to easy hydrolysis and preferential dimerization. Herein, by employing a pre-fluorination and palladium-catalyzed dehydrogenation reaction sequence, the abundant simple aliphatic amides are amendable to the rapid construction of complex molecular architectures to produce α,ß-unsaturated imines. Mechanistic investigations reveal a Pd(0)/Pd(II) catalytic cycle involving oxidative H-F elimination of N-fluoroamide followed by a smooth α,ß-desaturation of the in-situ generated aliphatic imine intermediate. This protocol exhibits excellent functional group tolerance, and even the carbonyl groups are compatible without any competing dehydrogenation, allowing for late-stage functionalization of complex bioactive molecules. The synthetic utility of this transformation has been further demonstrated by a diversity-oriented derivatization and a concise formal synthesis of (±)-alloyohimbane.

Organocatalytic 1,4-conjugate addition of ascorbic acid to α,ß-unsaturated aldehydes: bio-inspired total syntheses of leucodrin, leudrin and proposed structure of dilaspirolactone.

The organocatalytic additions of ascorbic acid to various α,ß-unsaturated aldehydes via tandem 1,4-conjugate addition/hemiacetalization/hemiketalization were developed, which provided a rapid entry into the 5-5-5 spirodilactone cores of a family of ascorbylated natural products. Based on the described chemistry, total syntheses of leucodrin, leudrin and the proposed structure of dilaspirolactone were achieved.

Synthesizing the tetracyclic core of nanolobatolide.

A concise synthetic pathway that enables the stereoselective construction of the tetracyclic core of nanolobatolide has been developed by applying a tandem ring-closing metathesis (RCM) reaction of dienynes, a Eu(fod)(3)-catalyzed intermolecular Diels-Alder reaction, and a biomimetic epoxide opening reaction as key steps.

Divergent regioselective Heck-type reaction of unactivated alkenes and N-fluoro-sulfonamides.

The control of regioselectivity in Heck-type reaction of unactivated alkenes represents a longstanding challenge due to several detachable hydrogens in ß-H elimination step, which generally afford either one specific regioisomer or a mixture. Herein, a copper-catalyzed intermolecular Heck-type reaction of unactivated alkenes and N-fluoro-sulfonamides with divergent regioselectivities is reported. The complete switch of regioselectivity mainly depends on the choice of different additives. Employment of alcohol solvent gives access to vinyl products, while the addition of carboxylate leads to the formation of allylic products. In addition, exclusion of these two promoting factors results in ß-lactams via a C-N reductive elimination. This protocol shows a broad substrate scope for both alkenes and structurally diverse N-fluoro-sulfonamides, producing the corresponding products with excellent regio- and stereoselectivities. Further control experiments and DFT calculations provide in-depth insights into the reaction mechanism, highlighting the distinct effect of the additives on a bidentate auxiliary-stabilized Cu(III) intermediate.

A Synthetic Route to The Core Structure of (-)-Retigeranic Acid A.

Retigeranic acid A is a uniquely structured pentacyclic sesterterpene bearing eight stereogenic centers. We report a concise route to the core structure of (-)-retigeranic acid A. The stereochemistry of its six chiral centers and three quaternary carbon centers was well-controlled. This route features two intramolecular Pauson-Khand reactions (IMPKRs): the first forged the D and E rings to deliver the triquinane subunit, and the second constructed the A and B rings and diastereoselectively installed the quaternary C6a center.

Copper-Catalyzed Diamination of Unactivated Alkenes With Electron-Rich Amino Sources.

The catalytic intermolecular diamination of unactivated alkenes with electron-rich amino sources is a challenge. Herein, by employing a directing-group strategy, a copper-catalyzed diamination of unactivated alkenes was realized. Symmetrical diamines were efficiently produced in a highly diastereoselective manner with readily available dialkylamines as amino sources, while a one-pot and two-step operation was necessary to produce the unsymmetrical diamines. These reactions were proposed to proceed through aziridinium intermediates.

Directing-Group-Based Strategy Enabling Intermolecular Heck-Type Reaction of Cycloketone Oxime Esters and Unactivated Alkenes.

A new type of coupling between unactivated olefins and nonstabilized alkyl radicals was achieved, which enabled the first intermolecular Heck-type reaction of cycloketone oxime esters and unactivated alkenes. This directing-group-based strategy was compatible with various unactivated alkenes and cyclobutanone-, cyclopentanone-, and cyclohexanone-derived oxime esters. Density functional theory calculations showed that both excellent regioselectivities and good diastereoselectivities could be ascribed to the 2-butanol-assisted concerted H-OBz elimination of the conformationally strained metallacyclic transition state.

Dual nickel- and photoredox-catalyzed reductive cross-coupling of aryl vinyl halides and unactivated tertiary alkyl bromides.

A novel reductive cross-coupling of aryl vinyl halides and unactivated tertiary alkyl bromides has been realized via photoredox/nickel dual catalysis to produce vinyl arene derivatives bearing all-carbon quaternary centers with excellent E-selectivity. A stoichiometric metal reductant could be avoided by employing commercially available N,N,N',N'-tetramethylethylenediamine (TMEDA) as the terminal reductant.

Copper-catalyzed ring-opening C(sp3)-N coupling of cycloketone oxime esters: access to 1°, 2° and 3° alkyl amines.

A novel copper-catalyzed C(sp3)-N coupling of cycloketone oxime esters with nitrogen nucleophiles has been realized. All of the N-aryl/alkylanilines, anilines and benzophenone imine could be employed in this protocol to produce a variety of 1°, 2° and 3° alkyl amines in one or two steps. These resultant cyano-containing alkyl amines were proven to be versatile synthetic building blocks in a variety of chemical transformations.

Multifunctionalization of Unactivated Cyclic Ketones via Synergistic Catalysis of Copper and Diarylamine: Access to Cyclic α-Enaminone.

A multifunctionalization of unactivated cyclic ketones via synergistic catalysis of copper and diarylamine for the direct synthesis of cyclic α-enaminone is reported for the first time. This reaction goes through oxidative α-amination, followed by a desaturation, and features mild reaction conditions, a broad substrate scope, and great functional group tolerance.