Enantioselective Copper‐Catalyzed Intermolecular Amino‐ and Azidocyanation of Alkenes in a Radical Process

Asymmetric copper‐catalyzed intermolecular amino‐ and azidocyanation reactions of alkenes have been developed that proceed via a radical process in which a key benzylic radical intermediate is enantioselectively trapped by a chiral Box/Cu^II cyanide complex. A variety of enantiomerically enriched β‐amino/azido alkylnitriles were efficiently synthesized. The β‐azido alkylnitriles could be converted into a series of highly valuable optically active amine‐based building blocks and bioactive compounds.     

Transforming Olefins into γ,δ‐Unsaturated Nitriles through Copper Catalysis

We have developed a strategy to transform olefins into homoallylic nitriles through a mechanism that combines copper catalysis with alkyl nitrile radicals. The radicals are easily generated from alkyl nitriles in the presence of the mild oxidant di‐tert ‐butyl peroxide. This cross‐dehydrogenative coupling between simple olefins and alkylnitriles bears advantages over the conventional use of halides and toxic cyanide reagents. With this method, we showcase the facile synthesis of a flavoring agent, a natural product, and a polymer precursor from simple olefins.     

Quantum chemical studies of the oxidative alkylamination of diazinones

The B3LYP/6-31G** quantum chemical method was used to study the mechanism of the oxidative alkylamination of diazinones taking 1,3,6-trimethylpyrimido[4,5-d]pyrimidine-2,4,7(1H,3H,6H)-trione (lumazinone) as an example. The first limiting step of this reaction included a nucleophilic addition of alkylamine with the formation of the σ^H-adduct, which was oxidized by potassium permanganate in the second step. The alkylamination step proceeded in the associates formed by the lumazinone dimer and several alkylamine molecules involved in both the nucleophilic attack and the bifunctional catalysis of the process. The correlation of the Parr indices with the experimental data was studied for a number of diazinones.     

Copper‐Mediated/Catalyzed Oxyalkylation of Alkenes with Alkylnitriles

A copper‐promoted oxyalkylation of alkenes with alkylnitriles has been developed. The protocol provides rapid access to phthalides (γ‐lactones) or isochromanones (δ‐lactones) via the formation of a C(sp³)?C(sp³) and a C(sp³)?O bond with the generation of up to two quaternary carbon atoms. Mechanistic studies suggest that this reaction is initiated by the formation of the C(sp³)?C(sp³) bond rather than the C(sp³)?O bond. Catalytic conditions were subsequently developed using carboxylic acid as an internal nucleophile.     

NaBArF4‐Catalyzed Oxidative Cyclization of 1,5‐ and 1,6‐Diynes: Efficient and Divergent Synthesis of Functionalized γ‐ and δ‐Lactams

An efficient NaBAr^F₄‐catalyzed oxidative cyclization of readily available 1,5‐ and 1,6‐diynes has been developed. Importantly, this transition metal‐free oxidative catalysis proceeds via a presumable Lewis acid‐catalyzed S_N2’ pathway, which is distinct from the relevant oxidative rhodium and gold catalysis. This method leads to the facile and practical construction of a diverse range of synthetically useful γ‐ and δ‐lactams in mostly good to excellent yields with broad substrate scope.     

Chemo- and Enantioselective Oxidative α-Azidation of Carbonyl Compounds

We report high-performance I⁺/H₂O₂ catalysis for the oxidative or decarboxylative oxidative α-azidation of carbonyl compounds by using sodium azide under biphasic neutral phase-transfer conditions. To induce higher reactivity especially for the α-azidation of 1,3-dicarbonyl compounds, we designed a structurally compact isoindoline-derived quaternary ammonium iodide catalyst bearing electron-withdrawing groups. The nonproductive decomposition pathways of I⁺/H₂O₂ catalysis could be suppressed by the use of a catalytic amount of a radical-trapping agent. This oxidative coupling tolerates a variety of functional groups and could be readily applied to the late-stage α-azidation of structurally diverse complex molecules. Moreover, we achieved the enantioselective α-azidation of 1,3-dicarbonyl compounds as the first successful example of enantioselective intermolecular oxidative coupling with a chiral hypoiodite catalyst.     

2-(o-Hydroxyanilido)alkylnitriles vs. 2-[1-(o-hydroxyanilido)alkyl]-benzoxazoles as products from o-aminophenol and cyanohydrins

The reaction of o-aminophenol with cyanohydrins leads to the formation of novel benzoxazoles 2 or the expected 2-(o-hydroxyanilido)alkylnitriles 3 or mixtures of these two, depending on the alkyl substituents on the cyanohydrin. The formation of benzoxazoles 2 was found to be due to the intrinsic instability of the corresponding 2-(o-hydroxyanilido)alkylnitriles, such as 4 .     

Exploring the pivotal role of silver(I) additives in palladium-catalyzed NH2-directed C(sp3)–H arylation reactions

Combined theoretical and experimental studies have explained the mechanism of Pd-catalyzed δ-C(sp³)−H arylation of primary amines. Instead of the monomeric Pd mechanism, our research unveils that all steps including C–H activation, oxidative addition, and reductive elimination take place via the heterodimeric Pd–Ag intermediates and transition states. Experimentally, the active heterodimeric Pd–Ag species were detected by mass spectrometry, which further confirms the proposed heterodimeric mechanism. Insight gained through this study reveals the synergistic manner of palladium catalysis and silver(I) additives in native NH₂-directed C‒H activation and C–C coupling reactions.     

Palladium Catalysis for Aerobic Oxidation Systems Using Robust Metal–Organic Framework

Described here is a new and viable approach to achieve Pd catalysis for aerobic oxidation systems (AOSs) by circumventing problems associated with both the oxidation and the catalysis through an all‐in‐one strategy, employing a robust metal–organic framework (MOF). The rational assembly of a Pd^II catalyst, phenanthroline ligand, and Cu^II species (electron‐transfer mediator) into a MOF facilitates the fast regeneration of the Pd^II active species, through an enhanced electron transfer from in situ generated Pd⁰ to Cu^II, and then Cu^I to O₂, trapped in the framework, thus leading to a 10 times higher turnover number than that of the homogeneous counterpart for Pd‐catalyzed desulfitative oxidative coupling reactions. Moreover, the MOF catalyst can be reused five times without losing activity. This work provides the first exploration of using a MOF as a promising platform for the development of Pd catalysis for AOSs with high efficiency, low catalyst loading, and reusability.     

Supported palladium catalysis using a heteroleptic 2-methylthiomethylpyridine-N,S-donor motif for Mizoroki-Heck and Suzuki-Miyaura coupling, including continuous organic monolith in capillary microscale flow-through mode

Flow-through catalysis utilising (2-methylthiomethylpyridine)palladium(II) chloride species covalently attached to a macroporous continuous organic polymer monolith synthesised within fused silica capillaries of internal diameter 250 μm is described, together with related studies of ground bulk monolith compared with supported catalysis on Merrifield and Wang beads and homogeneous catalysis under identical conditions to bulk supported catalysis. The monolith substrate, poly(chloromethylstyrene-co-divinylbenzene), has a backbone directly related to Merrifield and Wang resins. The homogeneous precatalyst PdCl₂(L²) (L²=4-(4-benzyloxyphenyl)-2-methylthiomethylpyridine) contains the benzyloxyphenyl group on its periphery as a model for the spacer between the ‘PdCl₂(N∼S)’ centre and the polymer substituent of the resins and monolith. Suzuki-Miyaura and Mizoroki-Heck catalysis exhibit anticipated trends in reactivity with variation of aryl halide reagents for each system, and show that supported catalysis on beads and monolith gives higher yields than for homogeneous catalysis. The synthesis of 2-methylthiomethylpyridines is presented, together with crystal structures of 4-bromo-2-bromomethylpyridine hydrobromide, 4-(4-hydroxyphenyl)-2-methylthiomethylpyridine (L¹), PdCl₂(L¹) and PdCl₂(L²). Hydrogen bonding occurs in 4-bromo-2-bromomethylpyridine hydrobromide as N-H?Br interactions, in 4-(4-hydroxyphenyl)-2-methylthiomethylpyridine as O-H?N to form chains, and in PdCl₂(L¹) as O-H?Cl interactions leading to adjacent π-stacked chains oriented in an antiparallel fashion.     

Chemo‐ and Enantioselective Oxidative α‐Azidation of Carbonyl Compounds

We report high‐performance I⁺/H₂O₂ catalysis for the oxidative or decarboxylative oxidative α‐azidation of carbonyl compounds by using sodium azide under biphasic neutral phase‐transfer conditions. To induce higher reactivity especially for the α‐azidation of 1,3‐dicarbonyl compounds, we designed a structurally compact isoindoline‐derived quaternary ammonium iodide catalyst bearing electron‐withdrawing groups. The nonproductive decomposition pathways of I⁺/H₂O₂ catalysis could be suppressed by the use of a catalytic amount of a radical‐trapping agent. This oxidative coupling tolerates a variety of functional groups and could be readily applied to the late‐stage α‐azidation of structurally diverse complex molecules. Moreover, we achieved the enantioselective α‐azidation of 1,3‐dicarbonyl compounds as the first successful example of enantioselective intermolecular oxidative coupling with a chiral hypoiodite catalyst.     

Visible‐Light‐Mediated Decarboxylation/Oxidative Amidation of α‐Keto Acids with Amines under Mild Reaction Conditions Using O2

Photochemistry has ushered in a new era in the development of chemistry, and photoredox catalysis has become a hot topic, especially over the last five years, with the combination of visible‐light photoredox catalysis and radical reactions. A novel, simple, and efficient radical oxidative decarboxylative coupling with the assistant of the photocatalyst [Ru(phen)₃]Cl₂ is described. Various functional groups are well‐tolerated in this reaction and thus provides a new approach to developing advanced methods for aerobic oxidative decarboxylation. The preliminary mechanistic studies revealed that: 1) an SET process between [Ru(phen)₃]²⁺* and aniline play an important role; 2) O₂ activation might be the rate‐determining step; and 3) the decarboxylation step is an irreversible and fast process.     

Iron(II)‐Catalyzed Direct Cyanation of Arenes with Aryl(cyano)iodonium Triflates

A direct oxidative cyanation of arenes under Fe^II catalysis with 3,5‐di(trifluoromethyl)phenyl(cyano)iodonium triflate (DFCT) as the cyanating agent has been developed. The reaction is applicable to wide range of aromatic substrates, including polycyclic structures and heteroaromatic compounds.     

Direct Catalytic Addition of Alkylnitriles to Aldehydes by Transition‐Metal/NHC Complexes

Direct catalytic addition of alkylnitriles to aldehydes allows for an atom‐economical access to β‐hydroxynitriles under proton transfer conditions. Direct use of alkylnitriles as pronucleophiles has been hampered due to their low acidity resulting in an inability to generate α‐cyano carbanions in a catalytic manner. A transition metal/N‐heterocyclic carbene (NHC) complex prepared from [{Rh(OMe)(cod)}₂] and an imidazolium‐based carbene was identified as an effective catalyst to promote the reaction with as little as 1.25 mol % of catalyst loading. The corresponding Rh complex, derived from chiral triazolium salt, rendered the reaction enantioselective, albeit with moderate enantioselectivity.     

L-Shaped Heterobidentate Imidazo[1,5-a]pyridin-3-ylidene (N,C)-Ligands for Oxidant-Free AuI/AuIII Catalysis

In the last decade, major advances have been made in homogeneous gold catalysis. However, Au^I/Au^III catalytic cycle remains much less explored due to the reluctance of Au^I to undergo oxidative addition and the stability of the Au^III intermediate. Herein, we report activation of aryl halides at gold(I) enabled by NHC (NHC=N-heterocyclic carbene) ligands through the development of a new class of L-shaped heterobidentate ImPy (ImPy=imidazo[1,5-a]pyridin-3-ylidene) N,C ligands that feature hemilabile character of the amino group in combination with strong σ-donation of the carbene center in a rigid conformation, imposed by the ligand architecture. Detailed characterization and control studies reveal key ligand features for Au^I/Au^III redox cycle, wherein the hemilabile nitrogen is placed at the coordinating position of a rigid framework. Given the tremendous significance of homogeneous gold catalysis, we anticipate that this ligand platform will find widespread application.     

Predicting the R/S absolute configuration in asymmetric bifunctional catalysis (ABC)

A predictive model for assigning the R/S absolute configuration in chiral Lewis base-dependent asymmetric bifunctional catalysis (ABC) has been developed. Chiral Lewis base (LB^∗)-dependent ABC abolishes the chiral Lewis acid (LA^∗) component as the stereochemical determining factor in asymmetric catalysis. By correlating the constant LB^∗ chirality to the facial preference for the LA^∗-bound carbonyl group for nucleophile delivery, the R/S absolute configuration of the products can be predicted a priori.     

Mechanistic Insights into the Oxidative Coupling of N‐Heterocyclic Carbenes within the Coordination Sphere of Copper Complexes

The behavior of N‐heterocyclic carbene (NHC) ligands in organometallic chemistry is hugely important for catalysis, due to the effect of these ligands on catalytic pathways and their involvement in catalyst decomposition. In this report, a combined experimental and computational study is presented, which provides mechanistic understanding of the unprecedented oxidative coupling of NHCs at Cu. The presence of Cu^I–, Cu^II–, and Cu^III–NHC complexes during the process is postulated, with the unusual C_carbene–C_carbene oxidative coupling reaction occurring under extremely mild reaction conditions. This process may represent a novel pathway for the decomposition of Cu–NHC complexes.     

Development of aqueous oxidative Ugi-type reactions by copper-catalyzed surfactant-promoted C(sp)–H direct functionalization in water

Direct assembly of α-amino amides from N-alkyl amines and isocyanides through oxidative Ugi-type reactions in aqueous conditions, has been achieved in a Cu(I)–TBHP–surfactant catalysis system. Various N-alkyl amines and isocyanides could be tolerated in this reaction and furnish α-amino amides in moderate yields.     

Gold(I)/Gold(III) Catalysis that Merges Oxidative Addition and π-Alkene Activation

Heteroarylation of alkenes with aryl iodides was efficiently achieved with a (MeDalphos)AuCl complex through Au^I/Au^III catalysis. The possibility to combine oxidative addition of aryl iodides and π-activation of alkenes at gold is demonstrated for the first time. The reaction is robust and general (>30 examples including internal alkenes, 5-, 6-, and 7-membered rings). It is regioselective and leads exclusively to trans addition products. The (P,N) gold complex is most efficient with electron-rich aryl substrates, which are troublesome with alternative photoredox/oxidative approaches. In addition, it provides a very unusual switch in regioselectivity from 5-exo to 6-endo cyclization between the Z and E isomers of internal alkenols.     

Paired Oxidative and Reductive Catalysis: Breaking the Potential Barrier of Electrochemical C(sp3)−H Alkenylation**

Due to the intrinsic inertness of alkanes, strong oxidative conditions are typically required to enable their C(sp³)−H functionalization. Herein, a paired electrocatalysis strategy was developed by integrating oxidative catalysis with reductive catalysis in one cell without interference, in which earth-abundant iron and nickel are employed as the anodic and cathodic catalysts, respectively. This approach lowers the previously high oxidation potential required for alkane activation, enabling electrochemical alkane functionalization at the ultra-low oxidation potential of ≈0.25 V vs. Ag/AgCl under mild conditions. Structurally diverse alkenes, including challenging all-carbon tetrasubstituted olefins, can be accessed using readily available alkenyl electrophiles.