Hydroamination of Triisopropylsilyl Acetylene Sulfur Pentafluoride - a Bench-top Route to Pentafluorosulfanylated Enamines.

Synthetic access to a variety of aliphatic and vinylic pentafluorosulfanylated building blocks remains a major challenge in contemporary organofluorine chemistry hampering its investigation in the context of medicinal chemistry, agrochemistry and functional materials. Herein, we report a bench-top protocol to access the virtually unknown class of α-SF5 -enamines under mild reaction conditions in good to excellent yields (up to 95 %). This reaction combines the protodesilylation of the commercially available precursor TASP with the in situ hydroamination of HC≡C-SF5 . The on-site use of highly toxic gases or corrosive reagents is avoided, making access to this motif applicable to a wide chemical audience. The excellent E-diastereoselectivity of this two-step cascade reaction is suggested to be the result of the convergence of the fast Z-/E- isomerization of a vinyl anion as well as the isomerization of the iminium ion. The remarkable thermal stability of these SF5 -enamines encourages further studies of their synthetic utility.

Synthesis of Indole-Fused Pyrazino[1,2-a]quinazolinones by Copper(I)-Catalyzed Selective Hydroamination-Cyclization of Alkynyl-tethered Quinazolinones.

We described a copper(I)-catalyzed atom economic and selective hydroamination-cyclization of alkynyl-tethered quinazolinones to prepare a variety of indole-fused pyrazino[1,2-a]quinazolinones in good to excellent yields ranging from 39 %-99 % under mild reaction conditions. Control experiments revealed that coordination-directed method of quinazolinone moiety with copper(I) was important for the selective hydroamination-cyclization of alkynes at the N1-atom instead of N3-atom of quinazolinone. The reaction could be easily performed at gram scales and some prepared indole-fused pyrazino[1,2-a]quinazolinones with donating groups on the indole moiety showed a distinct fluorescence emission wavelength with blue shift under the acid conditions.

Enantioselective Hydroaminations Catalyzed by Yttrium(III)-Bis(sulfoximine) Complexes.

Bis(sulfoximine) yttrium complexes as catalysts for enantioselective intramolecular hydroaminations were prepared for the first time and characterized by a multinuclear NMR study including the nuclei 1H, 13C, 15N and 89Y. The stoichiometries of the complexes were confirmed by a Job plot. In addition to the experimental results, the 89Y NMR shifts and the complex structures were elucidated by DFT calculations.

Regio- and Enantioselective Synthesis of 1,2-Diamines by Formal Hydroamination of Enamines: Scope, Mechanism, and Asymmetric Synthesis of Orthogonally Protected Bis-Piperazines as a Privileged Scaffold.

We have previously reported the first formal hydroamination of enamines for the synthesis of chiral 1,2-diamines. Here, we describe: (i) the discovery, optimization, and substrate expansion of this reaction; (ii) a novel and straightforward protocol for the "click-type" synthesis of enamines in quantitative yield utilizing sodium sulfate in a dual role as an ancillary and dehydrating agent without the need for workup or purification; (iii) the application of this methodology to the first enantioselective synthesis of orthogonally protected 1,1'-(1-(4-fluorophenyl)ethane-1,2-diyl) piperazines, a scaffold for rapid lead optimization in drug discovery; (iv) a computational investigation into the mechanism and rationalization of the enantioselectivities of the reaction.

Chiral Acetal-Based Stereo-Controlled Degradable Polymer Synthesis.

The precise synthesis of chiral polymers remains a significant challenge in polymer chemistry, particularly for applications in advanced biomedical and electronic materials. The development of degradable polymers is important for eco-friendly and advanced materials. Here, we introduce a stereo-controlled degradable polymer via cascade enyne metathesis polymerization and enantioselective acetal synthesis through Pd-catalyzed asymmetric hydroamination. This approach allows for the creation of chiral acetal-based polymers with controlled stereochemistry and degradability, highlighting their potential for use in drug delivery and electronic applications. This concept article reviews the background, development, and potential applications of these stereo-controlled degradable polymers.

Synthesis of phenanthridine derivatives by a water-compatible gold-catalyzed hydroamination.

Since transition-metal-catalyzed reactions are one of the most powerful and direct approaches for the synthesis of organic molecules, translating them to biological systems for biomedical applications is an emerging field. The manipulation of transition metal reactions in biological settings for uncaging prodrugs and synthesizing bioactive drugs has been widely studied. To expand the toolbox of transition-metal-mediated prodrug strategy, this work introduces the 2'-alkynl-biphenylamine precursors for the synthesis of phenanthridine derivatives using a water-compatible gold-catalyzed hydroamination under mild conditions. Moreover, the structure-reactivity relationship revealed that the nucleophilicity of the amine group in the precursor was critical for facilitating the gold-catalyzed synthesis of phenanthridine derivatives. The research shows the potential to be used for phenanthridine-based prodrug designs in an aqueous solution.

Metal-Free, PPA-Mediated Fisher Indole Synthesis via Tandem Hydroamination-Cyclization Reaction between Simple Alkynes and Arylhydrazines.

A new variant of Fisher indole synthesis involving Bronsted acid-catalyzed hydrohydrazination of unactivated terminal and internal acetylenes with arylhydrazines is reported. The use of polyphosphoric acid alone either as the reaction medium or in the presence of a co-solvent appears to provide the required balance for activating the C-C triple bond towards the nucleophilic attack of the hydrazine moiety without unrepairable reactivity loss of the latter due to competing amino group protonation. Additionally, the formal hydration of acetylenes to the corresponding ketones occurs under the same conditions, making it an alternative approach for generating carbonyl groups from alkynes.

Copper-Catalyzed Dearomative 1,2-Hydroamination.

Catalytic olefin hydroamination reactions are some of the most atom-economical transformations that bridge readily available starting materials-olefins and high-value-added amines. Despite significant advances in this field over the last two decades, the formal hydroamination of nonactivated aromatic compounds remains an unsolved challenge. Herein, we report the extension of olefin hydroamination to aromatic π-systems by using arenophile-mediated dearomatization and Cu-catalysis to perform 1,2-hydroamination on nonactivated arenes. This strategy was applied to a variety of substituted arenes and heteroarenes to provide general access to structurally complex amines. We conducted DFT calculations to inform mechanistic understanding and rationalize unexpected selectivity trends. Furthermore, we developed a practical, scalable desymmetrization to deliver enantioenriched dearomatized products and enable downstream synthetic applications. We ultimately used this dearomative strategy to efficiently synthesize a collection of densely functionalized small molecules.

A Covalent Triazine Framework for Photocatalytic Anti-Markovnikov Hydrofunctionalizations.

Porous materials-based heterogeneous photocatalysts, performing selective organic transformations, are increasing the applicability of photocatalytic reactions due to their ability to merge traditional photocatalysis with structured pores densely decorated with catalytic moiety for efficient mass and charge transfer, as well as added recyclability. We herein disclose a porous crystalline covalent triazine framework (CTF)-based heterogeneous photocatalyst that exhibits excellent photoredox properties for different hydrofunctionalization reactions such as hydrocarboxylations, hydroamination and hydroazidations. The high oxidizing property of this CTF enables the activation of styrenes, followed by regioselective C-N and C-O bond formation at ambient conditions. A change in the physicochemical and optoelectronic properties of the CTF, upon protonation during catalysis, lies at the basis of its photocatalytic properties. This allows us to obtain hydrocarboxylations, hydroamination, and hydroazidations from a myriad of electron-donating and -withdrawing aromatic and aliphatic substrates. This catalytic approach is further extended to late-stage functionalization of bio-active molecules. Finally, detailed characterizations of the CTF and further mechanistic investigations provides mechanistic insights in these reactions.

Ni-Catalyzed Enantioselective Reductive Cyclization/Amidation and Amination of 1,6-Enynes and 1,7-Enynes.

Transition-metal-catalyzed hydroamination of unsaturated hydrocarbons is an appealing synthetic tool for the construction of high value-added chiral amines. Despite significant progress in the asymmetric hydroamination of alkenes, allenes, and 1,3-dienes, asymmetric hydroamination of 1,6-enynes or 1,7-enynes remains rather limited due to the enormous challenges in controlling the chemoselectivity and stereoselectivity of the reaction. Herein, we report a Ni-catalyzed chemo- and enantioselective reductive cyclization/amidation and amination of 1,6-enynes and 1,7-enynes using dioxazolones or anthranils as nitrene-transfer reagents. This mild, modular, and practical protocol provides rapid access to a variety of enantioenriched 2-pyrrolidone and 2-piperidone derivatives bearing an aminomethylene group at the 4-position in good yields (up to 83%) with excellent enantioselectivities (40 examples, up to 99% ee). Mechanistic experiments and density functional theory calculations indicate that the reaction is initiated by hydronickelation of alkynes followed by migratory insertion into alkenes, rather than by a [2+2+1] oxidative addition process of nickel to alkenes and alkynes.

Additive-controlled chemoselective inter-/intramolecular hydroamination via electrochemical PCET process.

Electrochemically generated amidyl radical species produced distinct inter- or intramolecular hydroamination reaction products via a proton-coupled electron transfer (PCET) mechanism. Cyclic voltammetry (CV) analysis indicated that the chemoselectivity was derived from the size of the hydrogen bond complex, which consisted of the carbamate substrate and phosphate base, and could be controlled using 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as an additive. These results provide fundamental insights for the design of PCET-based redox reaction systems under electrochemical conditions.

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination.

Kinetic studies on the intramolecular hydroamination of protected variants of 2,2-diphenylpent-4-en-1-amine were carried out under a variety of conditions with cationic gold catalysts supported by phosphine ligands. The impact of ligand on gold, protecting group on nitrogen, and solvent and additive on reaction rates was determined. The most effective reactions utilized more Lewis basic ureas, and more electron-withdrawing phosphines. A DCM/alcohol cooperative effect was quantified, and a continuum of isotope effects was measured with low KIE's in the absence of deuterated alcoholic solvent, increasing to large solvent KIE's when comparing reactions in pure MeOH to those in pure MeOH-d4. The effects are interpreted both within the context of a classic gold π-activation/protodeauration mechanism and a general acid-catalyzed mechanism without intermediate gold alkyls.

Synthesis and Cytotoxicity Evaluation of Dehydroepiandrosterone Derivatives by Iron-Catalyzed Stereoselective Hydroamination.

The direct modification of structurally complex natural product dehydroepiandrosterone (DHEA) through iron-catalyzed direct hydroamination of DHEA with various nitro(hetero)arenes was carried out to afford 5α-arylamino-DHEAs (1-25) in good yields (53-72%). Though as a radical reaction, it features high stereoselectivity, and only the 5α-substituted derivatives were produced. The in vitro antiproliferative activity of these synthesized compounds against the human breast cancer MCF-7 cell was evaluated, showing that most of DHEA analogues possessed the moderate cytotoxic activity. The preliminary structure-activity relationship analysis revealed that the electron-withdrawing groups installed at the para-position of arylamine ring had a great contribution to the improvement of the DHEA's cytotoxic potency. Among them, (4-trifluoromethylaniline)-DHEA (4) displayed the most potent cytotoxicity, with an IC50 value of 19.3 µM, which was 2.3-fold more active than DHEA.

Synthesis of Functionalized 3H-pyrrolo-[1,2,3-de] Quinoxalines via Gold-Catalyzed Intramolecular Hydroamination of Alkynes.

A gold-catalyzed protocol to obtain functionalized 3H-pyrrolo [1,2,3-de] quinoxalines from suitable substituted N-alkynyl indoles has been proposed. The mild reaction conditions were revealed to be compatible with different functional groups, including halogen, alkoxyl, cyano, ketone, and ester, allowing the isolation of title compounds with yields from good to high. A reaction mechanism has been proposed, and theoretical calculations have been provided to rationalize the final step of the hypothesized reaction mechanism. As quinoxaline-containing polycyclic compounds, this class of molecules may represent a valuable template in medicinal chemistry and material science.

Jumping in the Chiral Pool: Asymmetric Hydroaminations with Early Metals.

The application of early-metal-based catalysts featuring natural chiral pool motifs, such as amino acids, terpenes and alkaloids, in hydroamination reactions is discussed and compared to those beyond the chiral pool. In particular, alkaline (Li), alkaline earth (Mg, Ca), rare earth (Y, La, Nd, Sm, Lu), group IV (Ti, Zr, Hf) metal-, and tantalum-based catalytic systems are described, which in recent years improved considerably and have become more practical in their usability. Additional emphasis is directed towards their catalytic performance including yields and regio- as well as stereoselectivity in comparison with the group IV and V transition metals and more widely used rare earth metal-based catalysts.

Metal-Free Aerobic C-N Bond Formation of Styrene and Arylamines via Photoactivated Electron Donor-Acceptor Complexation.

This study processes a facile and green approach for the Markovnikov-selective hydroamination of styrene with naphthylamine through irradiation with UV LED light (365 nm) via an electron donor-acceptor complexation between naphthylamines and oxygen in situ. This protocol showcases the synthetic potential for aerobic C-N bond formation without using a metal catalyst and photosensitizer. Three naphthylamines were examined and afforded desired C-N bond formation product in moderate yield.

Catalyst-Controlled Regiodivergent and Enantioselective Formal Hydroamination of N,N-Disubstituted Acrylamides to α-Tertiary-α-Aminolactam and ß-Aminoamide Derivatives.

Enantioenriched α-tertiary-α-aminoacid and α-chiral-ß-aminoacid derivatives play an important role in biological science and pharmaceutical chemistry. Thus, the development of methods for their synthesis is highly valuable and yet remains challenging. Herein, an unprecedented catalyst-controlled regiodivergent and enantioselective formal hydroamination of N,N-disubstituted acrylamides with aminating agents has been developed, accessing enantioenriched α-tertiary-α-aminolactam and α-chiral-ß-aminoamide derivatives. Sterically-disfavored and electronically-disfavored enantioselective hydroamination of electron-deficient alkenes have been successfully tuned using different transition metals and chiral ligands. Notably, extremely hindered aliphatic α-tertiary-α-aminolactam derivatives were synthesized by Cu-H catalyzed asymmetric C-N bond forming with tertiary alkyl species. Enantioenriched α-chiral-ß-aminoamide derivatives have been accessed by Ni-H catalyzed anti-Markovnikov-selective formal hydroaminations of alkenes. This set of reactions tolerates a wide range of functional groups to deliver diverse α-tertiary-α-aminolactam and α-chiral-ß-aminoamide derivatives in good yields with high levels of enantioselectivity.

Generation of Aromatic N-Heterocyclic Radicals for Functionalization of Unactivated Alkenes.

Nitrogen-centered radicals (NCRs) have been widely recognized as versatile synthetic intermediates for the construction of nitrogen containing molecules of high value. As such, there has been a long-standing interest in the field of organic synthesis to develop novel nitrogen-based radicals and explore their inherent reactivity. In this study, we present the generation of aromatic N-heterocyclic radicals and their application in a novel and diverse functionalization of unactivated alkenes. Bench-stable aromatic N-heterocyclic pyridinium salts were employed as crucial NCR precursors, which enabled the efficient conversion of various unactivated alkenes into medicinally relevant alkylated N-heterocyclic amines. This approach offers an unexplored retrosynthetic disconnection for the synthesis of related molecules that commonly possess therapeutic value. Furthermore, this platform can be extended to the synthesis of densely functionalized heterocyclic amines by utilizing disulfides and diethyl bromomalonate as radical quenchers. Mechanistic investigations indicate an energy transfer (EnT) pathway involving the formation of a transient aromatic N-heterocyclic radical, radical addition to unactivated alkenes, and subsequent generation of the amination product through either hydrogen atom transfer (HAT) or radical addition processes.

Skeleton-Reorganizing Coupling Reactions of Cycloheptatriene and Cycloalkenones with Amines.

Skeletal reorganization reactions have emerged as an intriguing tool for converting readily available compounds into complicated molecules inaccessible by traditional methods. Herein, we report a unique skeleton-reorganizing coupling reaction of cycloheptatriene and cycloalkenones with amines. In the presence of Rh/acid catalysis, cycloheptatriene can selectively couple with anilines to deliver fused 1,2-dihydroquinoline products. Mechanistic studies indicate that the retro-Mannich type ring-opening and subsequent intramolecular Povarov reaction account for the ring reorganization. Our mechanistic studies also revealed that skeleton-reorganizing amination between anilines and cycloalkenones can be achieved with acid. The synthetic utilization of this skeleton-reorganizing coupling reaction was showcased with a gram-scale reaction, synthetic derivatizations, and the late-stage modification of commercial drugs.

Nickel-Catalyzed Kinetic Resolution of Racemic Unactivated Alkenes via Enantio-, Diastereo-, and Regioselective Hydroamination.

Kinetic resolution is a powerful strategy for the isolation of enantioenriched compounds from racemic mixtures, and the development of selective catalytic processes is an active area of research. Here, we present a nickel-catalyzed kinetic resolution of racemic α-substituted unconjugated carbonyl alkenes via the enantio-, diastereo-, and regioselective hydroamination. This protocol affords both chiral α-substituted butenamides and syn-ß2,3 -amino acid derivatives with high enantiomeric purity (up to 99 % ee) and selectivity factor up to >684. The key to the excellent kinetic resolution efficiency is the distinctive architecture of the chiral nickel complex, which enables successful resolution and enantioselective C-N bond construction. Mechanistic investigations reveal that the unique structure of the chiral ligand facilitates a rapid migratory insertion step with one enantiomer. This strategy provides a practical and versatile approach to prepare a wide range of chiral compounds.