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.     

Visible‐Light‐Induced Photoredox Catalysis with a Tetracerium‐Containing Silicotungstate

The development of visible‐light‐induced photocatalysts for chemoselective functional group transformations has received considerable attention. Polyoxometalates (POMs) are potential materials for efficient photocatalysts because their properties can be precisely tuned by changing their constituent elements and structures and by the introduction of additional metal cations. Furthermore, they are thermally and oxidatively more stable than the frequently utilized organometallic complexes. The visible‐light‐responsive tetranuclear cerium(III)‐containing silicotungstate TBA₆[{Ce(H₂O)}₂{Ce(CH₃CN)}₂(μ₄‐O)(γ‐SiW₁₀O₃₆)₂] (CePOM; TBA=tetra‐n‐butylammonium) has now been synthesized; when CePOM was irradiated with visible light (λ>400 nm), a unique intramolecular Ce^III‐to‐POM(W^VI) charge transfer was observed. With CePOM, the photocatalytic oxidative dehydrogenation of primary and secondary amines as well as the α‐cyanation of tertiary amines smoothly proceeded in the presence of O₂ (1 atm) as the sole oxidant.     

Highly Efficient CH Hydroxylation of Carbonyl Compounds with Oxygen under Mild Conditions

A transition‐metal‐free Cs₂CO₃‐catalyzed α‐hydroxylation of carbonyl compounds with O₂ as the oxygen source is described. This reaction provides an efficient approach to tertiary α‐hydroxycarbonyl compounds, which are highly valued chemicals and widely used in the chemical and pharmaceutical industry. The simple conditions and the use of molecular oxygen as both the oxidant and the oxygen source make this protocol very environmentally friendly and practical. This transformation is highly efficient and highly selective for tertiary C(sp³)? H bond cleavage.     

Copper‐Catalyzed Aerobic Oxidative Inert CC and CN Bond Cleavage: A New Strategy for the Synthesis of Tertiary Amides

A copper‐catalyzed aerobic oxidative amidation reaction of inert C?C bonds with tertiary amines has been developed for the synthesis of tertiary amides, which are significant units in many natural products, pharmaceuticals, and fine chemicals. This method combines C?C bond activation, C?N bond cleavage, and C?H bond oxygenation in a one‐pot protocol, using molecular oxygen as the sole oxidant without any additional ligands.     

Long‐Lived Excited States of Zwitterionic Copper(I) Complexes for Photoinduced Cross‐Dehydrogenative Coupling Reactions

Four heteroleptic copper(I) complexes containing phenanthroline and monoanionic nido‐carborane‐diphosphine ligands have been prepared and structurally characterized by various spectroscopic techniques and X‐ray diffraction. These complexes exhibit intense absorptions in the visible range and excited‐state lifetimes on the microsecond scale. Their application in visible‐light‐induced cross‐dehydrogenative coupling reactions was investigated. Preliminary studies showed that one of the four copper(I) complexes is an efficient catalyst for photoinduced oxidative C?H functionalization using oxygen as oxidant. Furthermore, α‐functionalized tertiary amines were obtained in good‐to‐excellent yields by light irradiation (λ>420 nm) of a mixture of our Cu^I complex, tertiary amines, and a variety of nucleophiles (nitroalkane, acetone, or indoles) under aerobic conditions. Electron paramagnetic resonance measurements provided evidence for the formation of superoxide radical anions (O₂^??) rather than singlet oxygen (¹O₂) during these photocatalytic reactions.     

A unique combination of KI/ZnFe2O4 as a catalyst for oxidative Strecker reaction

α‐Aminonitriles as key intermediates for the preparation of α‐amino acid derivatives, amides, diamines, peptides, proteins and heterocycles were synthesized through methylarene oxidation in the Strecker reaction using a unique combination of KI/ZnFe₂O₄ as the best catalyst and aqueous tert‐butyl hydroperoxide as oxidant. A wide range of amines and methylarenes were converted to the corresponding products. Operational simplicity, short reaction time and recyclability of the catalyst are advantages of this protocol.     

Highly Efficient C?H Hydroxylation of Carbonyl Compounds with Oxygen under Mild Conditions

A transition‐metal‐free Cs₂CO₃‐catalyzed α‐hydroxylation of carbonyl compounds with O₂ as the oxygen source is described. This reaction provides an efficient approach to tertiary α‐hydroxycarbonyl compounds, which are highly valued chemicals and widely used in the chemical and pharmaceutical industry. The simple conditions and the use of molecular oxygen as both the oxidant and the oxygen source make this protocol very environmentally friendly and practical. This transformation is highly efficient and highly selective for tertiary C(sp³) H bond cleavage.     

Direct Borylation of Primary CH Bonds in Functionalized Molecules by Palladium Catalysis

Organoborane compounds are among the most commonly employed intermediates in organic synthesis and serve as crucial precursors to alcohols, amines, and various functionalized molecules. A simple palladium‐based system catalyzes the conversion of primary C(sp³)? H bonds in functionalized complex organic molecules into alkyl boronate esters. Amino acids, amino alcohols, alkyl amines, and a series of bioactive molecules can be functionalized with the use of readily available and removable directing groups in the presence of commercially available additives, simple ligands, and oxygen (O₂) as the terminal oxidant. This approach represents an economic and environmentally friendly method that could find broad applications.     

Novel Synthesis of Optically Active 2‐Ethylhexanoic Acid, 2‐Ethylhexanol,and 2‐Ethylhexylamine via the Asymmetric Favorskii Rearrangement

The asymmetric Favorskii rearrangement of optically active α‐haloketones, which are easily prepared from chiral menthyl‐4‐toluenesulfoxide in several steps using primary or secondary amines, yields their corresponding secondary or tertiary chiral amides. The secondary chiral amides were converted to acids or amines using acylation followed by hydrolysis or reduction. In addition, the tertiary amides were directly reduced to alcohol with Super‐Hydride^®.     

Utilizing Carbonyl Coordination of Native Amides for Palladium‐Catalyzed C(sp3)−H Olefination

Pd^II‐catalyzed C(sp³)?H olefination of weakly coordinating native amides is reported. Three major drawbacks of previous C(sp³)?H olefination protocols, 1) in situ cyclization of products, 2) incompatibility with α‐H‐containing substrates, and 3) installation of exogenous directing groups, are addressed by harnessing the carbonyl coordination ability of amides to direct C(sp³)?H activation. The method enables direct C(sp³)?H functionalization of a wide range of native amide substrates, including secondary, tertiary, and cyclic amides, for the first time. The utility of this process is demonstrated by diverse transformations of the olefination products.     

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.     

Simple and Efficient Ruthenium‐Catalyzed Oxidation of Primary Alcohols with Molecular Oxygen

Oxidative transformations utilizing molecular oxygen (O₂) as the stoichiometric oxidant are of paramount importance in organic synthesis from ecological and economical perspectives. Alcohol oxidation reactions that employ O₂ are scarce in homogeneous catalysis and the efficacy of such systems has been constrained by limited substrate scope (most involve secondary alcohol oxidation) or practical factors, such as the need for an excess of base or an additive. Catalytic systems employing O₂ as the “primary” oxidant, in the absence of any additive, are rare. A solution to this longstanding issue is offered by the development of an efficient ruthenium‐catalyzed oxidation protocol, which enables smooth oxidation of a wide variety of primary, as well as secondary benzylic, allylic, heterocyclic, and aliphatic, alcohols with molecular oxygen as the primary oxidant and without any base or hydrogen‐ or electron‐transfer agents. Most importantly, a high degree of selectivity during alcohol oxidation has been predicted for complex settings. Preliminary mechanistic studies including ¹⁸O labeling established the in situ formation of an oxo–ruthenium intermediate as the active catalytic species in the cycle and involvement of a two‐electron hydride transfer in the rate‐limiting step.     

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.     

2,4‐Dinitrophenol‐Catalyzed α‐C(sp3)−H and C(sp)−H Bond Functionalization of Cyclic Amines and Alkynes: Highly Regio‐/Diastereoselective Synthesis of α‐Alkynyl‐3‐Amino‐2‐Oxindoles

A transition‐metal‐ and oxidant‐free DNP (2,4‐dinitrophenol)‐catalyzed atom‐economical regio‐ and diastereoselective synthesis of monofunctionalized α‐alkynyl‐3‐amino‐2‐oxindole derivatives by C?H bond functionalization of cyclic amines and alkynes with indoline‐2,3‐diones has been developed. This cascade event sequentially involves the reductive amination of indoline‐2,3‐dione by imine formation and cross coupling between C(sp³)?H and C(sp)?H of the cyclic amines and alkynes. This reaction offers an efficient and attractive pathway to different types of α‐alkynyl‐3‐amino‐2‐oxindole derivatives in good yields with a wide tolerance of functional groups. The salient feature of this methodology is that it completely suppresses the homocoupling of alkynes. To the best of our knowledge, this is the first example of a DNP‐catalyzed metal‐free direct C(sp³)?H and C(sp)?H bond functionalization providing biologically active α‐alkynyl‐3‐amino‐2‐oxindole scaffolds.     

Highly efficient Cu-catalyzed oxidative coupling of tertiary amines and siloxyfurans

A mild, selective, and efficient protocol for the synthesis of γ-aminoalkyl butenolides via the oxidative coupling between tertiary amines and siloxyfurans catalyzed by simple copper salts was developed. Compared with the reported method, our method employs copper catalyst instead of the expensive rhodium catalyst. Besides TBHP, both O₂ and H₂O₂ can also be utilized as oxidant to effect the coupling.     

Design of New Ligands for the Palladium‐Catalyzed Arylation of α‐Branched Secondary Amines

In Pd‐catalyzed C? N cross‐coupling reactions, α‐branched secondary amines are difficult coupling partners and the desired products are often produced in low yields. In order to provide a robust method for accessing N‐aryl α‐branched tertiary amines, new catalysts have been designed to suppress undesired side reactions often encountered when these amine nucleophiles are used. These advances enabled the arylation of a wide array of sterically encumbered amines, highlighting the importance of rational ligand design in facilitating challenging Pd‐catalyzed cross‐coupling reactions.     

Direct Borylation of Primary C?H Bonds in Functionalized Molecules by Palladium Catalysis

Organoborane compounds are among the most commonly employed intermediates in organic synthesis and serve as crucial precursors to alcohols, amines, and various functionalized molecules. A simple palladium‐based system catalyzes the conversion of primary C(sp³) H bonds in functionalized complex organic molecules into alkyl boronate esters. Amino acids, amino alcohols, alkyl amines, and a series of bioactive molecules can be functionalized with the use of readily available and removable directing groups in the presence of commercially available additives, simple ligands, and oxygen (O₂) as the terminal oxidant. This approach represents an economic and environmentally friendly method that could find broad applications.     

Palladium‐Catalyzed Oxidative Difunctionalization of Alkenes with α‐Carbonyl Alkyl Bromides Initiated through a Heck‐type Insertion: A Route to Indolin‐2‐ones

The oxidative interception of various σ‐alkyl palladium(II) intermediates with additional reagents for the difunctionalization of alkenes is an important research area. A new palladium‐catalyzed oxidative difunctionalization reaction of alkenes with α‐carbonyl alkyl bromides is described, in which the σ‐alkyl palladium(II) intermediate is generated through a Heck insertion and trapped using an aryl C(sp²)? H bond. This method can be applied to various α‐carbonyl alkyl bromides, including primary, secondary, and tertiary α‐bromoalkyl esters, ketones, and amides.     

NiH‐Catalyzed Remote Asymmetric Hydroalkylation of Alkenes with Racemic α‐Bromo Amides

Reported here is a terminal‐selective, remote asymmetric hydroalkylation of olefins with racemic α‐bromo amides. The reaction proceeds by NiH‐catalyzed alkene isomerization and subsequent alkylation reaction, and can enantioconvergently introduce an unsymmetrical secondary alkyl group from a racemic α‐bromo amide onto a terminal C(sp³)?H position along the hydrocarbon chain of the alkene. This mild process affords a range of structurally diverse chiral α‐alkylalkanoic amides in excellent yields, and high regio‐ and enantioselectivities. In addition, the synthetic utility of this protocol is further highlighted by the regioconvergent conversion of industrial raw materials of isomeric olefin mixtures into enantioriched α‐alkylalkanoic amides on large scale.     

Enantioselective Synthesis of α‐Hydroxy Amides and β‐Amino Alcohols from α‐Keto Amides

Synthesis of enantiomerically enriched α‐hydroxy amides and β‐amino alcohols has been accomplished by enantioselective reduction of α‐keto amides with hydrosilanes. A series of α‐keto amides were reduced in the presence of chiral Cu^II/(S)‐DTBM‐SEGPHOS catalyst to give the corresponding optically active α‐hydroxy amides with excellent enantioselectivities by using (EtO)₃SiH as a reducing agent. Furthermore, a one‐pot complete reduction of both ketone and amide groups of α‐keto amides has been achieved using the same chiral copper catalyst followed by tetra‐n‐butylammonium fluoride (TBAF) catalyst in presence of (EtO)₃SiH to afford the corresponding chiral β‐amino alcohol derivatives.