Electrophilic Amination Research Articles

Domino Sequence of Ketimization and Electrophilic Amination for an Inverse Aza Intramolecular Morita-Baylis-Hillman Adduct.

Morita-Baylis-Hillman (MBH) reaction, typically catalyzed by a Lewis base, is a popular and useful method for C-C bond formation. Unfortunately, it is limited by a slow reaction rate and has sensitivity toward steric and electronic parameters. Despite tremendous efforts, the versatility of the reaction keeps the quest open for new mechanistic and catalytic pathways. Here, we have reported a Bro̷nsted acid-catalyzed, electrophilic amination (Umpolung of imine) as a method for an inverse Aza Intramolecular MBH adduct in the form of 2-acylindole. Umpolung of imine with nitrogen acting as an electrophilic center has been achieved. Interestingly, the reaction was also shown to occur under catalyst-free conditions also. The expected products of ketimine formation, 6π electrocyclization, or quinoline formation were least/not observed. A large number of examples have demonstrated the reaction strength. β-aryl-substituted acrylate and acrylamide (cinnamates and cinnamides), which are extremely sluggish in conventional MBH chemistry, are the highlights of the developed methodology. The annulated product exhibited keto-enol tautomerism, which was proven by 1H NMR integrals. As an application, another tandem reaction in the form of Michael addition on a highly complex amine was carried out to provide spiro-annulated indole.

Enantioselective Electrophilic Amination of Active Methine Compounds Using Chiral COFs

Enantioselective Electrophilic Amination of Active Methine Compounds Using Chiral COFs

Synthesis of Carbazolylamines through Brønsted Acid‐Catalyzed Direct Electrophilic Aminations

AbstractA Brønsted acid catalyzed direct and dual C−H amination of carbazoles and indolocarbazoles with N‐Ts iminoquinone acetal is reported. It is characterized that the mentioned C−H amination was determined by the selection of catalysts and the molar ratio of the starting materials. The efficiency of this protocol was showcased by diverse carbazolylamine and indolocarbazolylamine assemblies. The late‐stage functionalization of a series of natural products fully illustrates the synthetic value of this methodology.

Crystalline Olefin-Linked Chiral Covalent Organic Frameworks as a Platform for Asymmetric Catalysis.

The construction of olefin-linked chiral covalent organic frameworks (COFs) with high crystallinity is highly desirable while remains great challenge due to the poor reversibility of the formation reaction for the olefin linkages during the in situ structural self-healing process. Herein, we successfully synthesized two sets of enantiomeric olefin-linked COFs. The chiral catalytic groups are uniformly distributed on the pore walls of COFs, resulting in the full exposure of catalytic sites to the reactants in asymmetric catalysis. The as-prepared (R)/(S)-CCOF8 exhibits excellent catalytic performance with exceeding 99 % enantiomeric excess in the enantioselective electrophilic amination reaction. Moreover, the heterogeneous chiral catalysts are conveniently recycled and could maintain the performance after ten catalytic cycles. Our findings expand the scope to construct stable and crystalline chiral COFs for the asymmetric catalysis.

Crystalline Olefin‐Linked Chiral Covalent Organic Frameworks as a Platform for Asymmetric Catalysis

AbstractThe construction of olefin‐linked chiral covalent organic frameworks (COFs) with high crystallinity is highly desirable while remains great challenge due to the poor reversibility of the formation reaction for the olefin linkages during the in situ structural self‐healing process. Herein, we successfully synthesized two sets of enantiomeric olefin‐linked COFs. The chiral catalytic groups are uniformly distributed on the pore walls of COFs, resulting in the full exposure of catalytic sites to the reactants in asymmetric catalysis. The as‐prepared (R)/(S)‐CCOF8 exhibits excellent catalytic performance with exceeding 99 % enantiomeric excess in the enantioselective electrophilic amination reaction. Moreover, the heterogeneous chiral catalysts are conveniently recycled and could maintain the performance after ten catalytic cycles. Our findings expand the scope to construct stable and crystalline chiral COFs for the asymmetric catalysis.

Enantioselective Synthesis of Sulfinamidines via Asymmetric Nitrogen Transfer from N‐H Oxaziridines to Sulfenamides

Sulfinamidines are promising aza‐SIV chiral building blocks in asymmetric synthesis and drug discovery. However, no report has documented their enantioselective synthesis. Here we present an enantioselective synthesis of sulfinamidines via electrophilic amination of sulfenamides using an enantiopure N‐H oxaziridine. The resulting enantiomerically enriched primary sulfinamidines are configurationally stable at 90 oC in solution and show remarkable stability against organic acids and bases under non‐aqueous conditions. We also demonstrate a one‐pot, three‐component, enantioselective synthesis of sulfinamides using N‐H oxaziridine reagents.

Enantioselective Synthesis of Sulfinamidines via Asymmetric Nitrogen Transfer from N-H Oxaziridines to Sulfenamides.

Sulfinamidines are promising aza-SIV chiral building blocks in asymmetric synthesis and drug discovery. However, no report has documented their enantioselective synthesis. Here we present an enantioselective synthesis of sulfinamidines via electrophilic amination of sulfenamides using an enantiopure N-H oxaziridine. The resulting enantiomerically enriched primary sulfinamidines are configurationally stable at 90 °C in solution and show remarkable stability against organic acids and bases under non-aqueous conditions. We also demonstrate a one-pot, three-component, enantioselective synthesis of sulfinamides using N-H oxaziridine reagents.

Pd(II)-Catalyzed 1,2-Oxyarylation of Alkenes with O-Acylhydroxylamines as the Oxygen Source.

O-Acylhydroxylamine has been widely employed as an electrophilic amination reagent in transition-metal-catalyzed C-N coupling reactions, but its use as an electrophilic oxygen source has not been disclosed. Here, we report a Pd-catalyzed 1,2-oxyarylation of alkenes with O-acylhydroxylamines as an oxidant and an oxygen source for the first time. With simple amide as the monodentate directing group, this method features a broad substrate scope, good functional group tolerance, and mild conditions.

Synthesis of Heteroaromatic-Fused Cyclic β-Amino Acids by Rhodium-Catalyzed Electrophilic Amination

AbstractA series of cyclic β-amino acids fused with heteroaromatic moieties was prepared by Rh-catalyzed electrophilic amination. The transformation involves a rhodium alkyl nitrene generated from substituted isoxazolidin-5-ones upon the N–O bond cleavage. These products contain an underexplored class of cyclic structures that may have specific applications in various chemistry disciplines.

Catalytic Synthesis of Atropoisomers via Non‐Canonical Friedel‐Crafts Reactions

AbstractThe Friedel‐Crafts reaction stands as a powerful synthetic tool for C−H functionalization of aromatic feedstocks, which is conventionally realized through electrophilic alkylation and acylation. The burgeoning interests in axially chiral compounds across diverse fields have spurred extensive exploration of this classic transformation for catalytic atroposelective synthesis. Consequently, the past decade has witnessed the rapid expansion of various non‐canonical Friedel‐Crafts reactions, including electrophilic arylation, alkenylation, halogenation, sulfenylation, and amination of aryl C−H bonds, thereby delving into new chemical spaces. A range of catalytic atroposelective synthetic methods have been devised for these significant arene C−H functionalization. This review provides a comprehensive overview of the cutting‐edge catalytic synthesis of atropoisomers through non‐canonical Friedel‐Crafts reactions, categorized into three parts based on the type of bond formation on the aromatics: C(sp2)−C(sp3) bond formations, C(sp2)−C(sp2) bond formations and C(sp2)−heteroatom bond formations. The richness of electrophiles and the modulation of atroposelectivity by diverse chiral organocatalysts, particularly chiral Brønsted acids, are elucidated. We anticipate that the repertoire of asymmetric Friedel‐Crafts reaction will continue to flourish and to be demonstrated in not only scientific researches but also industrial organic synthesis.

Atroposelective Synthesis of Diarylamines via Organocatalyzed Electrophilic Amination

Atroposelective Synthesis of Diarylamines via Organocatalyzed Electrophilic Amination

Electrochemical Ni‐Catalyzed Decarboxylative C(sp3)−N Cross‐Electrophile Coupling

AbstractA new electrochemical transformation is presented that enables chemists to couple simple alkyl carboxylic acid derivatives with an electrophilic amine reagent to construct C(sp3)−N bond. The success of this reaction hinges on the merging of cooperative electrochemical reduction with nickel catalysis. The chemistry exhibits a high degree of practicality, showcasing its wide applicability with 1°, 2°, 3° carboxylic acids and remarkable compatibility with diverse functional groups, even in the realm of late‐stage functionalization. Furthermore, extensive mechanistic studies have unveiled the engagement of alkyl radicals and iminyl radicals; and elucidated the multifaceted roles played by iPr2O, Ni catalyst, and electricity.

Electrochemical Ni-Catalyzed Decarboxylative C(sp3 )-N Cross-Electrophile Coupling.

A new electrochemical transformation is presented that enables chemists to couple simple alkyl carboxylic acid derivatives with an electrophilic amine reagent to construct C(sp3 )-N bond. The success of this reaction hinges on the merging of cooperative electrochemical reduction with nickel catalysis. The chemistry exhibits a high degree of practicality, showcasing its wide applicability with 1°, 2°, 3° carboxylic acids and remarkable compatibility with diverse functional groups, even in the realm of late-stage functionalization. Furthermore, extensive mechanistic studies have unveiled the engagement of alkyl radicals and iminyl radicals; and elucidated the multifaceted roles played by i Pr2 O, Ni catalyst, and electricity.

Amino-λ3 -iodane-Enabled Electrophilic Amination of Arylboronic Acid Derivatives.

In this report, we describe the use of amino-λ3 -iodanes in the electrophilic amination of arylboronic acids and boronates. Iodine(III) reagents with transferable amino groups, including one with an NH2 group, were synthesized and used in the amination, allowing the synthesis of a wide range of primary and secondary (hetero)arylamines. Mechanistic studies by DFT calculations indicate that the reaction proceeds through an electrophilic amination process from a tetravalent borate complex with a B-N dative bond.

Amino‐λ3‐iodane‐Enabled Electrophilic Amination of Arylboronic Acid Derivatives

AbstractIn this report, we describe the use of amino‐λ3‐iodanes in the electrophilic amination of arylboronic acids and boronates. Iodine(III) reagents with transferable amino groups, including one with an NH2 group, were synthesized and used in the amination, allowing the synthesis of a wide range of primary and secondary (hetero)arylamines. Mechanistic studies by DFT calculations indicate that the reaction proceeds through an electrophilic amination process from a tetravalent borate complex with a B−N dative bond.

Preparation of Aromatic and Heterocyclic Amines by the Electrophilic Amination of Functionalized Diorganozincs with Polyfunctional O-2,6-Dichlorobenzoyl Hydroxylamines.

We report a catalyst-free electrophilic amination, which enables the synthesis of aromatic and heterocyclic amines. By subjecting diarylzinc or diheteroarylzinc compounds to readily accessible O-2,6-dichlorobenzoyl hydroxylamines in the presence of MgCl2 in dioxane at a temperature of 60 °C (8-16 h). This new electrophilic amination allowed an expedited synthesis of two pharmaceutically significant compounds: vortioxetine is a key intermediate of delamanid. This approach offers opportunities for the streamlined synthesis of amine-based molecules in the pharmaceutical industry.

Catalytic Atroposelective Electrophilic Amination of Diaryl Anilines and Diaryl Phenols for the Synthesis of Axially Chiral Diaryl Compounds

Disclosed here is a chiral phosphoric acid catalyzed atroposelective electrophilic amination reaction, which provides access to a series of axially chiral diaryl compounds through the desymmetric amination reactions of diaryl...

Copper-catalysed electrophilic carboamination of terminal alkynes with benzyne looked at through the computational lens.

A detailed computational mechanistic study of the copper-catalysed three-component-type electrophilic carboamination of terminal alkynes with benzyne and an archetypal O-benzoylhydroxylamine electrophile is presented. Probing various plausible pathways for relevant elementary steps and scrutinising performance degradation pathways, with the aid of a reliable computational protocol applied to a realistic catalyst model combined with kinetic analysis, identified the pathways preferably traversed in productive catalysis. It entails rapid alkynylcupration of in situ generated benzyne to deliver the arylcopper nucleophile that undergoes amination with the O-benzoylhydroxylamine electrophile to afford copper benzoate. Umpolung-enabled electrophilic amination favours a multistep SN2-type oxidative addition/N-C bond-forming reductive elimination sequence involving a short-lived formal {P^P}CuIII carboxylate amido aryl intermediate. SN2-type displacement of the benzoate leaving group at the arylcopper nucleophile, which represents the catalyst resting state, is predicted to be the turnover limiting step. Alkynolysis transforms copper benzoate back to catalytically competent alkynylcopper. The computational probe of a wider range of substrates reveals that only severely ring-strained C6-arynes, C6-cycloalkynes and electron-deficient cyclopropenes featuring a highly reactive C≡C linkage could replace benzyne. Moreover, strict control of stationary benzyne concentration is indispensable for electrophilic carboamination to ever become achievable.

Copper-Mediated N-Trifluoromethylation of O-Benzoylhydroxylamines.

The use of trifluoromethyl containing compounds is well established within medicinal chemistry, with a range of approved drugs containing C-CF3 and O-CF3 moieties. However, the utilisation of the N-CF3 functional group remains relatively unexplored. This may be attributed to the challenging synthesis of this unit, with many current methods employing harsh conditions or less accessible reagents. A robust methodology for the N-trifluoromethylation of secondary amines has been developed, which employs an umpolung strategy in the form of a copper-catalysed electrophilic amination. The method is operationally simple, uses mild, inexpensive reagents, and has been used to synthesise a range of novel, structurally complex N-CF3 containing compounds.

Azodicarboxylate as a comonomer for radical polymerization to incorporate nitrogen–nitrogen single bonds into the polymer chain

AbstractIn organic synthesis, azodicarboxylates are frequently used as an aza‐dienophile and electrophilic amination agent. To create carbon–nitrogen bonds, azodicarboxylates typically react with nucleophiles or radicals. This report explores its reactivity as a co‐monomer towards radical polymerization to introduce nitrogen–nitrogen single bonds into the polymer chain. Azodicarboxylates are capable of copolymerizing with styrenic monomers to achieve linear polymers with 40% feed.