Multicomponent Reductive Coupling for Selective Access to Functional γ-Lactams by a Single-Atom Cobalt Catalyst.

Despite their significant importance to numerous fields, the difficulties in direct and diverse synthesis of α-hydroxy-γ-lactams pose substantial obstacles to their practical applications. Here, we designed a nitrogen and TiO2 co-doped graphitic carbon-supported material with atomically dispersed cobalt sites (CoSA-N/NC-TiO2), which was successfully applied as a multifunctional catalyst to establish a general method for direct construction of α-hydroxy-γ-lactams from cheap and abundant nitro(hetero)arenes, aldehydes, and H2O with alkynoates. The striking features of operational simplicity, broad substrate and functionality compatibility (>100 examples), high step and atom efficiency, good selectivity, and exceptional catalyst reusability highlight the practicality of this new catalytic transformation. Mechanistic studies reveal that the active CoN4 species and the dopants exhibit a synergistic effect on the formation of key acid-masked nitrones; their subsequent nucleophilic addition to the alkynoates followed by successive reduction, alkenyl hydration, and intramolecular ester ammonolysis delivers the desired products. In this work, the concept of reduction interruption leading to new reaction route will open a door to further develop useful transformations by rational catalyst design.

Selective Access to Functional Fluoroenones via Palladium-Catalyzed Selenofluoroalkylacylation of Terminal Alkynes.

The trifluoromethylacyl group (-COCF3) is an important motif and widely studied in catalysis, medicinal chemistry, and materials science. Herein, a novel palladium-catalyzed selenofluoroalkylacylation of terminal alkynes with commercially available fluoroalkyl anhydride and diorganyl diselenides to afford ß-seleno and aryl/alkyl disubstituted enones under mild conditions is disclosed. In addition, selenodifluoroacetylations and selenoperfluoroacetylations are also suitable for this reaction. Mechanistic studies reveal that this reaction proceeds via an oxidative radical-polar crossover process.

Reductive Coupling of Nitroarenes and HCHO for General Synthesis of Functional Ethane-1,2-diamines by a Cobalt Single-Atom Catalyst.

Despite the extensive applications, selective and diverse access to N,N'-diarylethane-1,2-diamines remains, to date, a challenge. Here, by developing a bifunctional cobalt single-atom catalyst (CoSA-N/NC), we present a general method for direct synthesis of such compounds via selective reductive coupling of cheap and abundant nitroarenes and formaldehyde, featuring good substrate and functionality compatibility, an easily accessible base metal catalyst with excellent reusability, and high step and atom efficiency. Mechanistic studies reveal that the N-anchored cobalt single atoms (CoN4) serve as the catalytically active sites for the reduction processes, the N-doped carbon support enriches the HCHO to timely trap the in situ formed hydroxyamines and affords the requisite nitrones under weak alkaline conditions, and the subsequent inverse electron demand 1,3-dipolar cycloaddition of the nitrones and imines followed by hydrodeoxygenation of the cycloadducts furnishes the products. In this work, the concept of catalyst-controlled nitroarene reduction to in situ create specific building blocks is anticipated to develop more useful chemical transformations.

A sustainable metal and base-free direct amidation of esters using water as a green solvent.

Herein, we report a simple and efficient synthetic approach for direct amidation of esters via C(acyl)-O bond cleavage without any additional reagents or catalysts, using only water as a green solvent. Subsequently, the reaction byproduct is recovered and utilized for the next phase of ester synthesis. This method emphasized metal-free, additive-free, and base-free characteristics making it a new, sustainable, and eco-friendly way to realize direct amide bond formation. In addition, the synthesis of the drug molecule diethyltoluamide and the Gram-scale synthesis of a representative amide are demonstrated.

Room Temperature Construction of Vicinal Amino Alcohols via Electroreductive Cross-Coupling of N-Heteroarenes and Carbonyls.

Despite the widespread applications of α-hydroxyalkyl cyclic amines, direct and diverse access to such a class of unique vicinal amino alcohols still remains, to date, a challenge. Here, through a strategy of electroreductive α-hydroxyalkylation of inactive N-heteroarenes with ketones or electron-rich arylaldehydes, we describe a room temperature approach for the direct construction of α-hydroxyalkyl cyclic amines, which features a broad substrate scope, operational simplicity, high chemoselectivity, and no need for pressurized H2 gas and transition metal catalysts. The zinc ion generated from anode oxidation plays a crucial role in the activation of both reactants by decreasing their reduction potentials. The strategy of electroreduction in combination with substrate activation by Lewis acids in this work is anticipated to develop more useful transformations.

Utilizing Nitroarenes and HCHO to Directly Construct Functional N-Heterocycles by Supported Cobalt/Amino Acid Relay Catalysis.

Due to the generation of multiple intermediates during the nitroarene reduction, precise interception of single one to develop tandem reactions involving both C-C and C-N bond formations still remains a significant challenge. Herein, the relay catalysis of a supported bifunctional cobalt catalyst with l-proline has been successfully applied to establish a bran-new reductive annulation reaction of nitroarenes and formaldehyde, which enables direct and diverse construction of both symmetrical and unsymmetrical 1,3-diaryl imidazolines. It proceeds with operational simplicity, good substrate and functionality compatibility, and excellent step and atom-efficiency. Mechanistic studies reveal that the Co-catalyst exhibits a synergistic effect on the formation of key N-hydroxy imine, and the l-proline subsequently facilitates the key C-C bond formation. The current work opens a door to develop useful transformations with nitroarenes by reduction-interrupted strategy.

Ruthenium-Catalyzed Regioselective Hydrohalogenation of Alkynes Mediated by Trimethylsilyl Triflate.

Here we describe a ruthenium-catalyzed regioselective hydrohalogenation reaction of alkynes under mild conditions. Commercially simple halogen sources such as KI, ZnBr2, and ZnCl2 were employed to achieve this transformation. Alkynes derived from bioactive molecules such as l-(-)-borneol, l-menthol, and estrone were also suitable for the transformation, demonstrating the potential synthetic value of this new reaction in organic synthesis.

Intermolecular diastereoselective annulation of azaarenes into fused N-heterocycles by Ru(II) reductive catalysis.

Derivatization of azaarenes can create molecules of biological importance, but reductive functionalization of weakly reactive azaarenes remains a challenge. Here the authors show a dearomative, diastereoselective annulation of azaarenes, via ruthenium(II) reductive catalysis, proceeding with excellent selectivity, mild conditions, and broad substrate and functional group compatibility. Mechanistic studies reveal that the products are formed via hydride transfer-initiated ß-aminomethylation and α-arylation of the pyridyl core in the azaarenes, and that paraformaldehyde serves as both the C1-building block and reductant precursor, and the use of Mg(OMe)2 base plays a critical role in determining the reaction chemo-selectivity by lowering the hydrogen transfer rate. The present work opens a door to further develop valuable reductive functionalization of unsaturated systems by taking profit of formaldehyde-endowed two functions.

Practical iridium-catalyzed direct α-arylation of N-heteroarenes with (hetero)arylboronic acids by H2O-mediated H2 evolution.

Despite the widespread applications of 2-(hetero)aryl N-heteroarenes in numerous fields of science and technology, universal access to such compounds is hampered due to the lack of a general method for their synthesis. Herein, by a H2O-mediated H2-evolution cross-coupling strategy, we report an iridium(III)-catalyzed facile method to direct α-arylation of N-heteroarenes with both aryl and heteroaryl boronic acids, proceeding with broad substrate scope and excellent functional compatibility, oxidant and reductant-free conditions, operational simplicity, easy scalability, and no need for prefunctionalization of N-heteroarenes. This method is applicable for structural modification of biomedical molecules, and offers a practical route for direct access to 2-(hetero)aryl N-heteroarenes, a class of potential cyclometalated C^N ligands and N^N bidentate ligands that are difficult to prepare with the existing α-C-H arylation methods, thus filling an important gap in the capabilities of synthetic organic chemistry.

Metal-catalyzed silylation of sp3C-H bonds.

Metal-catalyzed activations of inert sp2C-H and sp3C-H bonds have recently brought about a revolution in the synthesis of useful molecules and molecular materials. Among them, the catalytic silylation of sp3C-H bonds has been developed due to the interest in the formed sp3C-SiR3 silanes, a stable organometallic species, for carrying out further functionalizations that cannot be directly achieved using sp3C-H bonds. Besides many examples of sp2C-H bond catalytic silylations, metal-catalyzed silylations of sp3C-H bonds have been mostly discovered during the last decade in spite of the high reactivity of the sp3C-SiR3 group. This review will present all the methods of metal-catalyzed silylations of sp3C-H bonds into sp3C-SiR3 functions, discuss the catalytic mechanisms according to various metal-catalysts, and illustrate their applications in synthesis. The review describes successively the intermolecular sp3C-H bond silylations directed first by N-containing heterocycles with silanes using various Ru, Rh, and Ir catalysts and then directed by an amide type function using a Pd(ii) catalyst and R3Si-SiR3 reagent. The catalytic intramolecular silylations of sp3C-H bonds can be performed after the catalytic formation of CH-OSiR2H or CH-N(R)SiR2H groups from alcohols, ketones, esters, or amine NH bonds by catalytic hydrosilylation with R2SiH2. Both catalytic processes can be performed using Ir(i) and Rh(i) catalysts with an alkene to capture the formed H2. This reaction with Rh(i) and Ir(i) catalysts can be applied to the formation of 5-membered cyclic silanes from aryl silanes and from alkyl silanes arising from hydrosilylated terminal C[double bond, length as m-dash]C bonds of alkenes. Oxidation of the cyclic silane derivatives easily leads to 1,3- and 1,4-diols, from alcohol or ketone precursors and to 1,2-amino alcohols from amines. Several methods show how to transform various heteroatom-methyl groups X-CH3: B-CH3, O-CH3, Si-CH3, N-CH3, Ge-CH3 and S-CH3 into their reactive functionalized X-CH2SiR3 group, using various Ru(0), Ir(i), pincer-Ru(ii), or Y catalysts. Examples are shown of catalytic transformations of the allylic moiety CH3-C(R)[double bond, length as m-dash]CH2 into its silylated CH2[double bond, length as m-dash]C(R)-CH2SiR'3 form via (i) Pd(ii) allyl activation, (ii) silyl radical generation with photocatalyst and (iii) dual Ir(i) and Fe(ii) catalysts for hydrosilylation of alkanes, via alkene formation, isomerization and hydrosilylation. Finally, a Ru(ii)-catalyzed sp3C-H silylation of a methyl group of arylphosphine, directed by a P(iii) atom, will be presented.

Late-Stage Diversification of Biarylphosphines through Rhodium(I)-Catalyzed C-H Bond Alkenylation with Internal Alkynes.

We report herein P(III)-directed C-H bond alkenylation of (dialkyl)- and (diaryl)biarylphosphines using internal alkynes. Chloride-free [Rh(OAc)(COD)]2 acts as a better catalyst than commercially available [RhCl(COD)]2. Conditions were developed to control the mono- and difunctionalization depending on the alkyne stoichiometry. One of these novel bisalkenylated (dialkyl)biarylphosphines was employed for the preparation of a palladium(II) complex, and some of these functionalized ligands outperformed their corresponding unfunctionalized phosphines in Pd-catalyzed amidation with sterically hindered aryl chlorides.

Identification of novel antifungal agents: antimicrobial evaluation, SAR, ADME-Tox and molecular docking studies of a series of imidazole derivatives.

Thirty-four imidazole-based compounds synthesized by one-pot catalytic method were evaluated for their antifungal and antibacterial activities against several fungal and bacterial strains. None of the compounds had antibacterial activity. Interestingly, compounds 1, 2, 3, 10 and 15 displayed a strong antifungal activity against all the tested fungal species, while compounds 5, 7, 9, 11, 21 and 27 showed a moderate antifungal activity. To better understand the biological activity of the most active compounds ADME-Tox and molecular docking studies were carried out. Interestingly, compounds 1, 2, 3, 7, 10 and 15 showed excellent bioavailability. In addition, compounds 1, 2 and 3, exhibited good toxicity profiles. Docking studies of the two most active compounds 2 (IC50 of 95 ± 7.07 µM) and 10 (IC50 of 235 ± 7.07 µM) suggested that they might act by inhibiting the fungal lanosterol 14α-demethylase. Therefore, these novel antifungal agents merit further characterization for the development of new antifungal therapeutics.

RhI -Catalyzed PIII -Directed C-H Bond Alkylation: Design of Multifunctional Phosphines for Carboxylation of Aryl Bromides with Carbon Dioxide.

We report the C-H alkylation of biarylphosphines at the ortho' position(s) with alkenes by using rhodium(I) catalysis, which provides straightforward access to a large library of multifunctionalized phosphines. Some of these modified ligands outperformed commercially available phosphines in the Pd-catalyzed carboxylation of aryl bromides with carbon dioxide in the presence of a photoredox catalyst.

Carbonylation of tertiary carbon radicals: synthesis of lactams.

Herein, we disclose an interesting iron-catalyzed approach for the carbonylation of a tertiary carbon radical. The tertiary carbon radical generated from a 1,5-hydrogen atom transfer can be captured by CO gas smoothly. Various six-membered lactams were constructed chemo-selectively in high yields.

Photoredox Catalysis for Building C-C Bonds from C(sp2)-H Bonds.

Transition metal-catalyzed C-H bond functionalizations have been the focus of intensive research over the last decades for the formation of C-C bonds from unfunctionalized arenes, heteroarenes, alkenes. These direct transformations provide new approaches in synthesis with high atom- and step-economy compared to the traditional catalytic cross-coupling reactions. However, such methods still suffer from several limitations including functional group tolerance and the lack of regioselectivity. In addition, they often require harsh reaction conditions and some of them need the use of strong oxidant, in a stoichiometric amount, avoiding these processes to be truly eco-friendly. The use of photoredox catalysis has contributed to a significant expansion of the scope of C(sp2)-H bond functionalizations which include the direct arylations, (perfluoro)alkylations, acylations, and even cyanations. Most of these transformations involve the photochemical induced generation of a radical followed by its regioselective addition to arenes, heteroarenes, or alkenes, leading to the building of a new C(sp2)-C bond. The use of photoredox catalysis plays crucial roles in these reactions promoting electron transfer, enabling the generation of radical species and single electron either oxidation or reduction. Such reactions operating at room temperature allow the building of C-C bonds with high chemo-, regio-, or stereoselectivity. This review surveys the formation of C(sp2)-C bonds initiated by photoredox catalysis which involves a C(sp2)-H bond functionalization step, describes the advantages compared to traditional C(sp2)-H bond functionalizations, and presents mechanistic insights into the role played by the photoredox catalysts.

Metal-free C(sp3)-H bond sulfonyloxylation of 2-alkylpyridines and alkylnitrones.

Pyridin-2-ylmethyl tosylate derivatives are obtained in high yields from 2-alkylpyridine 1-oxides via a [3,3]-sigmatropic rearrangement of the adduct between 2-alkylpridine 1-oxides with benzenesulfonyl chlorides. Moreover, alkylnitrones also undergo [3,3]-sigmatropic rearrangement to give α-tosylated ketones after hydrolysis. Substitution reactions with nucleophiles then lead to diverse useful functionalizations for the synthesis of pincer ligands.

Late stage modifications of P-containing ligands using transition-metal-catalysed C-H bond functionalisation.

Phosphorus containing molecules have seen widespread applications in the development of innovative metal-ligand catalysts and materials. In recent years, the implementation of late-stage modifications of phosphorus derivatives via ortho-regioselective C-H bond functionalisation has led to faster and better ways for the synthesis of complex ligands by creating new reactions with low impact on the environment. This Feature article highlights transition-metal catalysed regioselective C-H bond functionalisation of phosphorus-containing molecules, in which the phosphorus containing unit plays the role of a directing group for C-H bond activation and the synthesis of new functional phosphorus derivatives.

Ruthenium(η6,η¹-arene-CH2-NHC) Catalysts for Direct Arylation of 2-Phenylpyridine with (Hetero)Aryl Chlorides in Water.

A series of new benzimidazolium halides were synthesized in good yields as unsymmetrical N-heterocyclic carbene (NHC) precursors containing the N-CH2-arene group. The benzimidazolium halides were readily converted into ruthenium(II)-NHC complexes with the general formula [RuCl2(η6,η¹-arene-CH2-NHC)]. The structures of all new compounds were characterized by ¹H NMR (Nuclear Magnetic Resonance), 13C NMR, FT-IR (Fourier Transform Infrared) spectroscopy and elemental analysis techniques. The single crystal structure of one benzimidazole ruthenium complex, 2b, was determined. The complex is best thought of as containing an octahedrally coordinated Ru center with the arene residue occupying three sites, the remaining sites being occupied by a (carbene)C-Ru bond and two Ru-Cl bonds. The catalytic activity of [RuCl2(η6,η¹-arene-CH2-NHC)] complexes was evaluated in the direct (hetero)arylation of 2-phenylpyridine with (hetero)aryl chlorides in water as the nontoxic reaction medium. These results show that catalysts 2a and 2b were the best for monoarylation with simple phenyl and tolyl chlorides. For functional aryl chlorides, 2d, 2e, and 2c appeared to be the most efficient.

Synthesis of 2-Pyridinemethyl Ester Derivatives from Aldehydes and 2-Alkylheterocycle N-Oxides via Copper-Catalyzed Tandem Oxidative Coupling-Rearrangement.

Successful benzylic C(sp3)-H acyloxylation of 2-alkylpyridine, 2-alkylpyrazine, and 2-alkylthiazole compounds was achieved using simple aldehydes. This was carried out via a copper-catalyzed tandem reaction, involving oxidative esterification followed by O-atom transfer of the resultant high yield formed Boekelheide intermediate. The method enables the preparation of functional heterocycles and the desymmetrization of 2,6-dialkylpyridines for efficient synthesis of dissymmetric pincer ligands, thus offering a new life for more practical Boekelheide rearrangement.

Selective synthesis of nitrogen bi-heteroarenes by a hydrogen transfer-mediated direct α,ß-coupling reaction.

By an external hydrogen transfer-mediated activation mode, we herein demonstrate a new palladium-catalyzed direct α,ß-coupling of different types of N-heteroarenes. Such a selective coupling reaction proceeds with the advantages of operational simplicity, high atom-economical efficiency, and use of safe and abundant i-propanol as the activating agent, offering a practical way to access nitrogen bi-heteroarenes. Preliminary exploration has revealed that the obtained bis-1,10-phenanthroline 2qq' as a ligand is capable of improving a copper catalyst for C-C bond formation. The work reported in this paper has built an important basis for the creation of extended π-conjugated systems that are of high significance in biological, medicinal, materials and synthetic organic chemistry as well as catalysis.