Regioselective Insertion of o‐Carborynes into the α‐C?H Bond of Tertiary Amines: Synthesis of α‐Carboranylated Amines

o‐Carboryne can undergo α‐C H bond insertion with tertiary amines, thus affording α‐carboranylated amines in very good regioselectivity and isolated yields. In this process, the nucleophilic addition of tertiary amines to the multiple bond of o‐carboryne generates a zwitterionic intermediate. An intramolecular proton transfer, followed by a nucleophilic attack leads to the formation of the final product. Thus, regioselectivity is highly dependent upon the acidity of α‐C H proton of tertiary amines. This approach serves as an efficient methodology for the preparation of a series of 1‐aminoalkyl‐o‐carboranes.     

A Highly Efficient Gold‐Catalyzed Photoredox α‐C(sp3)H Alkynylation of Tertiary Aliphatic Amines with Sunlight

A new α‐C(sp³)? H alkynylation of unactivated tertiary aliphatic amines with 1‐iodoalkynes as radical alkynylating reagents in the presence of [Au₂(μ‐dppm)₂]²⁺ in sunlight provides propargylic amines. Based on mechanistic studies, a C? C coupling of an α‐aminoalkyl radical and an alkynyl radical is proposed for the C(sp³)? C(sp) bond formation. The mild, convenient, efficient, and highly selective C(sp³)? H alkynylation reaction shows excellent regioselectivity and good functional‐group compatibility. A scale‐up to gram quantities is possible with sunlight used as a clean and sustainable energy source.     

Asymmetric Synthesis of Less Accessible α‐Tertiary Amines from Alkynyl Z‐Ketimines

A highly stereoselective synthesis of hitherto less accessible chiral α‐tertiary amines with multiple structurally similar linear carbon chains was achieved through chiral auxiliary mediated addition of organolithium reagents to the geometrically well‐controlled alkynyl Z ‐ketimines. This stereoselective nucleophilic addition offers a general approach to the asymmetric synthesis of nitrogen‐containing chiral materials.     

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.     

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.     

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.     

α‐Halogenoacetanilides as Hydrogen‐Bonding Organocatalysts that Activate Carbonyl Bonds: Fluorine versus Chlorine and Bromine

α‐Halogenoacetanilides (X=F, Cl, Br) were examined as H‐bonding organocatalysts designed for the double activation of C?O bonds through NH and CH donor groups. Depending on the halide substituents, the double H‐bond involved a nonconventional C?H???O interaction with either a H?CX_n (n=1–2, X=Cl, Br) or a H?C_Ar bond (X=F), as shown in the solid‐state crystal structures and by molecular modeling. In addition, the catalytic properties of α‐halogenoacetanilides were evaluated in the ring‐opening polymerization of lactide, in the presence of a tertiary amine as cocatalyst. The α‐dichloro‐ and α‐dibromoacetanilides containing electron‐deficient aromatic groups afforded the most attractive double H‐bonding properties towards C?O bonds, with a N?H???O???H?CX₂ interaction.     

Synthesis and Structural Analysis of Aspergillus fumigatus Galactosaminogalactans Featuring α‐Galactose, α‐Galactosamine and α‐N‐Acetyl Galactosamine Linkages

Galactosaminogalactan (GAG) is a prominent cell wall component of the opportunistic fungal pathogen Aspergillus fumigatus. GAG is a heteropolysaccharide composed of α‐1,4‐linked galactose, galactosamine and N‐acetylgalactosamine residues. To enable biochemical studies, a library of GAG‐fragments was constructed featuring specimens containing α‐galactose‐, α‐galactosamine and α‐N‐acetyl galactosamine linkages. Key features of the synthetic strategy include the use of di‐tert‐butylsilylidene directed α‐galactosylation methodology and regioselective benzoylation reactions using benzoyl‐hydroxybenzotriazole (Bz‐OBt). Structural analysis of the Gal, GalN and GalNAc oligomers by a combination of NMR and MD approaches revealed that the oligomers adopt an elongated, almost straight, structure, stabilized by inter‐residue H‐bonds, one of which is a non‐conventional C?H???O hydrogen bond between H5 of the residue (i+1) and O3 of the residue (i). The structures position the C‐2 substituents almost perpendicular to the oligosaccharide main chain axis, pointing to the bulk solvent and available for interactions with antibodies or other binding partners.     

Copper‐Catalyzed α‐Amination of Phosphonates and Phosphine Oxides: A Direct Approach to α‐Amino Phosphonic Acids and Derivatives

A direct approach to important α‐amino phosphonic acids and its derivatives has been developed by using copper‐catalyzed electrophilic amination of α‐phosphonate zincates with O‐acyl hydroxylamines. This amination provides the first example of C? N bond formation which directly introduces acyclic and cyclic amines to the α‐position of phosphonates in one step. The reaction is readily promoted at room temperature with as little as 0.5 mol % of catalyst, and demonstrates high efficiency on a broad substrate scope.     

Amine‐Catalyzed Highly Regioselective and Stereoselective C(sp2)–C(sp2) Cross‐Coupling of Naphthols with trans‐α,β‐Unsaturated Aldehydes

A metal‐free C(sp²)–C(sp²) cross‐coupling approach to highly congested (E)‐α‐naphtholylenals from simple naphthols and enals is described. The mild reaction conditions with pyridine hydrobromideperbromide (PHBP) as the bromination reagent in the presence of piperidine or diphenylprolinol trimethylsilyl (TMS) ether as promoters enable the process in good yields and with high chemoselectivity, regioselectivity, and stereoselectivity. The process involves an unprecedented pathway of in situ regioselective 4‐bromination of 1‐naphthols and the subsequent unusual aromatic nucleophilic substitution of the resulting 4‐bromo‐1‐naphthols with the α‐C(sp²) of enals through a Michael‐type Friedel–Crafts alkylation–dearomatization followed by a cyclopropanation ring‐opening cascade process. The noteworthy features of this strategy are highlighted by the highly efficient creation of a C(sp²)–C(sp²) bond from readily available unfunctionalized naphthols and enals catalyzed by non‐metal, readily available cyclic secondary amines under mild reaction conditions.     

Ligand‐Controlled α‐ and β‐Arylation of Acyclic N‐Boc Amines

The palladium‐catalyzed ligand‐controlled arylation of α‐zincated acyclic amines, obtained by directed α‐lithiation and transmetalation, is described. Whereas PtBu₃ gave rise to α‐arylated Boc‐protected amines, more flexible N‐phenylazole‐based phosphine ligands induced major β‐arylation through migrative cross‐coupling.     

Highly para‐Selective C−H Alkylation of Benzene Derivatives with 2,2,2‐Trifluoroethyl α‐Aryl‐α‐Diazoesters

Compared to the most popular directing‐group‐assisted strategy, the “undirected” strategy for C−H bond functionalization represents a more flexible but more challenging approach. Reported herein is a gold‐catalyzed highly site‐selective C(sp²)−H alkylation of unactivated arenes with 2,2,2‐trifluoroethyl α‐aryl‐α‐diazoesters. This protocol demonstrates that high site‐selective C−H bond functionalization can be achieved without the assistance of a directing group. In this transformation, both the gold catalyst and trifluoroethyl group on the ester of the diazo compound play vital roles for achieving the chemo‐ and regioselectivity.     

Effects of introduction of α‐carboxylate,N‐methyl,and N‐formyl groups on intramolecular cyclization of o‐quinone amines: Density functional theory‐based study

o‐Quinone amines, which are relevant to various biological processes, can undergo spontaneous intramolecular cyclization (ring closure reaction by amino‐terminated hydrocarbon side chain) that deactivates them toward another possible reactions, that is, thiol binding. Density functional theory‐based calculation is employed for obtaining the potential energy curves along the C? N bond formation in the intramolecular cyclization of various o‐quinone amines, viz., dopaminequinone, dopaquinone, N‐methyl‐dopaminequinone, N‐formyl‐dopaminequinone, and the corresponding methylene‐inserted analogues. The activation barrier is decreased by introduction of α‐carboxylate and N‐methyl group whereas increased by introduction of N‐formyl group. A negative correlation between the activation barriers and the level of highest occupied molecular orbital is pointed out. Furthermore, the methylene‐inserted analogues show decreased activation barriers. This is explained by reduction of steric repulsion in the transition state.     

Conformational analysis of the disaccharide methyl α‐d‐mannopyranosyl‐(1→3)‐2‐O‐acetyl‐β‐d‐mannopyranoside monohydrate

The crystal structure of methyl α‐d ‐mannopyranosyl‐(1→3)‐2‐O‐acetyl‐β‐d ‐mannopyranoside monohydrate, C₁₅H₂₆O₁₂·H₂O, ( II ), has been determined and the structural parameters for its constituent α‐d ‐mannopyranosyl residue compared with those for methyl α‐d ‐mannopyranoside. Mono‐O‐acetylation appears to promote the crystallization of ( II ), inferred from the difficulty in crystallizing methyl α‐d ‐mannopyranosyl‐(1→3)‐β‐d ‐mannopyranoside despite repeated attempts. The conformational properties of the O‐acetyl side chain in ( II ) are similar to those observed in recent studies of peracetylated mannose‐containing oligosaccharides, having a preferred geometry in which the C2—H2 bond eclipses the C=O bond of the acetyl group. The C2—O2 bond in ( II ) elongates by ～0.02 Å upon O‐acetylation. The phi (?) and psi (ψ) torsion angles that dictate the conformation of the internal O‐glycosidic linkage in ( II ) are similar to those determined recently in aqueous solution by NMR spectroscopy for unacetylated ( II ) using the statistical program MA′AT, with a greater disparity found for ψ (Δ = ～16°) than for ? (Δ = ～6°).     

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.     

Palladium(II)‐Catalyzed ortho‐CH Arylation/Alkylation of N‐Benzoyl α‐Amino Ester Derivatives

The palladium‐catalyzed arylation/alkylation of ortho‐C?H bonds in N‐benzoyl α‐amino ester derivatives is described. In such a system both the NH‐amido and the CO₂R groups in the α‐amino ester moieties play a role in successful C?H activation/C?C bond formation using iodoaryl coupling partners. A wide variety of functional groups and electron‐rich/deficient iodoarenes are tolerated. The yields obtained range from 20 to 95 %.     

N‐Heterocyclic Carbene Iron(III) Porphyrin‐Catalyzed Intramolecular C(sp3)–H Amination of Alkyl Azides

Metal‐catalyzed intramolecular C?H amination of alkyl azides constitutes an appealing approach to alicyclic amines; challenges remain in broadening substrate scope, enhancing regioselectivity, and applying the method to natural product synthesis. Herein we report an iron(III) porphyrin bearing axial N‐heterocyclic carbene ligands which catalyzes the intramolecular C(sp³)–H amination of a wide variety of alkyl azides under microwave‐assisted and thermal conditions, resulting in selective amination of tertiary, benzylic, allylic, secondary, and primary C?H bonds with up to 95 % yield. 14 out of 17 substrates were cyclized selectively at C4 to give pyrrolidines. The regioselectivity at C4 or C5 could be tuned by modifying the reactivity of the C5–H bond. Mechanistic studies revealed a concerted or a fast re‐bound mechanism for the amination reaction. The reaction has been applied to the syntheses of tropane, nicotine, cis‐octahydroindole, and leelamine derivatives.     

Gold‐catalyzed Reactions of 3‐Alkynyloxireno[2, 3‐b]chromenones to Form 3(2H)‐Furanones via a Domino Pathway

3(2H)‐Furanones are efficiently generated from 3‐alkynyl oxireno[2,3‐b]chromenones by an Au/DDQ‐catalyzed domino reaction through a pathway composed of cyclization, C? C cleavage, nucleophilic addition, oxidation, and nucleophilic addition. It was found that stoichiometric AuCl₃ or catalytic Au with stoichiometric DDQ can oxidize the benzylic sp³ C? H bond to facilitate nucleophilic addition.     

Transformation of schiff bases derived from alpha‐naphthaldehyde. Synthesis,spectral data and biological activity of new‐3‐aryl‐2‐(α‐naphtyl)‐4‐thiazolidinones and N‐aryl‐N‐[1‐(α‐naphthyl)but‐3‐enyl]amines

New N‐aryl substituted 2‐(α‐naphthyl)‐4‐thiazolidinones were prepared by the cyclocondensation of α‐mercaptoacetic acid and corresponding N‐(α‐naphthyliden)anilines. The same starting materials were utilized to obtain a new series of N‐aryl‐N‐[1‐(α‐naphthyl)but‐3‐enyl]amines, which was synthesized through an addition of the Grignard reagent (allylmagnesium bromide) to the double bond C?N of the aldimines. The antichagasic and trichomonacidal in vitro activity, as well as, the antifungal and cytotoxic properties of some of these compounds were evaluated.     

Isolation of a Reactive Tricoordinate α‐Oxo Gold Carbene Complex

The [(P,P)Au=C(Ph)CO₂Et]⁺ complex 3 [where (P,P) is an o‐carboranyl diphosphine ligand] was prepared by diazo decomposition at ?40 °C. It is the first α‐oxo gold carbene complex to be characterized. Its crystallographic structure was determined and DFT calculations have been performed, unraveling the key influence of the chelating (P,P) ligand. The gold center is tricoordinate and the electrophilicity of the carbene center is decreased. Complex 3 mimics transient α‐oxo gold carbenes in a series of catalytic transformations, and provides support for the critical role of electrophilicity in the chemoselectivity of phenol functionalization (O?H vs. C?H insertion).