Halide Perovskite Induces Halogen/Hydrogen Atom Transfer (XAT/HAT) for Allylic C-H Amination.

Allylic C-H amination has emerged as a powerful tool to construct allylamines, common motifs in molecular therapeutics. Such reaction implies an oxidative path for C-H activation but furnishes reductive amines, inferring mild oxidants' inactivity for C-H oxidation but strong oxidants' detriment to products. Herein we report a heterogeneous catalytic approach that manipulates halogen-vacancies of perovskite photocatalyst and exploits halogenated-solvents (i.e. CH2Cl2, CH2Br2) as mild oxidants for selective C-H allyl amination with 19,376 turnover. CsPbBr3 nanocrystals induce cooperative hydrogen-atom-transfer (HAT, C-H oxidation, and halogen-vacancy CsPbBr3-x formation) and halogen-atom-transfer (XAT, CsPbBr3-x-induced solvent reduction) under a radical chain mechanism. Terminal/internal olefins are amenable to forge aromatic/aliphatic, cyclic/acyclic, secondary/tertiary allylamines (70 examples), including drugs or their derivatives.

Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA.

Isoquinolinone is an important heterocyclic framework in natural products and biologically active molecules, and the efficient synthesis of this structural motif has received much attention in recent years. Herein, we report a (phenyliodonio)sulfamate (PISA)-mediated, solvent-dependent synthesis of different isoquinolinone derivatives. The method provides highly chemoselective access to 3- or 4-substituted isoquinolinone derivatives by reacting o-alkenylbenzamide derivatives with PISA in either acetonitrile or wet hexafluoro-2-isopropanol.

From C-H to C-N Bonds: Three Challenges, Three Catalysts, Three Solutions.

N-heterocycles are key building blocks for many pharmaceutical products. An efficient and sustainable method for the synthesis of this class of compounds consists of the recently established intramolecular C-H amination reaction. Development of new iron-based catalysts for this transformation is of paramount importance. Herein, three major challenges in this field are addressed: the accessibility of the catalyst, the lack of mechanisticunderstanding, and the limited activity and robustness of the catalyst. These challenges are tackled by threedifferent catalysts. The first catalyst is the commercially available FeI2, that shows good activities, but is limitedto substrates with activated C-H bonds. The Fe(HMDS)2 catalyst is used to perfom in-depth mechanistic studies, revealing key intermediates of the C-H amination reaction. The third catalyst, featuring mesoionic carbene ligands, displays unprecedented activities and aminates various C-H bonds.

Metal-Free Synthesis of N-Heterocycles via Intramolecular Electrochemical C-H Aminations.

N-heterocycles are key structural units in many drugs, biologically interesting molecules and functional materials. To avoid the residues of metal catalysts, the construction of N-heterocycles under metal-free conditions has attracted much research attention in academia and industry. Among them, the intramolecular electrochemical C-H aminations arguably constitute environmentally friendly methodologies for the metal-free construction of N-heterocycles, mainly due to the direct use of clean electricity as the redox agents. With the recent renaissance of organic electrosynthesis, the intramolecular electrochemical C-H aminations have undergone much progress in recent years. In this article, we would like to summarize the advances in this research field since 2019. The emphasis is placed on the reaction design and mechanistic insight. The challenges and future developments in the intramolecular electrochemical C-H aminations are also discussed.

µ-Oxo-Hypervalent-Iodine-Catalyzed Oxidative C-H Amination for Synthesis of Benzolactam Derivatives.

Benzolactams have unique biological activity and high utility in the synthesis of valuable compounds with direct applicability to oxindole alkaloids and antibacterial agents. Despite recent advances in organic chemistry and the growing number of reported methods for synthesizing benzolactams, their preparation still requires a multistep process. C-H amination reactions can convert aromatic C(sp2)-H bonds directly to C(sp2)-N bonds, and this direct approach to C-N bond formation offers effective access to benzolactams. Hypervalent iodine reagents are promising tools for achieving oxidative C-H amination. Motivated by our ongoing research efforts toward the development of useful hypervalent-iodine-mediated oxidative transformations, we herein describe an effective intramolecular oxidative C-H amination reaction based on µ-oxo hypervalent iodine catalysis for the synthesis of benzolactams bearing various functional groups.

Regiospecific C-H amination of (-)-limonene into (-)-perillamine by multi-enzymatic cascade reactions.

BACKGROUND: (-)-Limonene, one of cyclic monoterpenes, is an important renewable compound used widely as a key building block for the synthesis of new biologically active molecules and fine chemicals. (-)-Perillamine, as derived from (-)-limonene, is a highly useful synthon for constructing more complicated and functionally relevant chemicals. AIM: We aimed to report a more sustainable and more efficient method for the regiospecific C-H amination of (-)-limonene into (-)-perillamine. RESULTS: Here, we report an artificial penta-enzymatic cascade system for the transformation of the cheap and easily available (-)-limonene into (-)-perillamine for the first time. This system is composed of cytochrome P450 monooxygenase, alcohol dehydrogenase and w-transaminase for the main reactions, as well as formate dehydrogenase and NADH oxidase for cofactor recycling. After optimization of the multi-enzymatic cascade system, 10 mM (-)-limonene was smoothly converted into 5.4 mM (-)-perillamine in a one-pot two-step biotransformation, indicating the feasibility of multi-enzymatic C7-regiospecific amination of the inert C-H bond of (-)-limonene. This method represents a concise and efficient route for the biocatalytic synthesis of derivatives from similar natural products.

Site-Selective Molecular Transformation: Acylation of Hydroxy Groups and C-H Amination.

Control of site selectivity is an exciting direction for synthetic organic chemistry owing to the possibility of selective modification of multifunctionalized molecules, ultimately including biomacromolecules. In this review, our recent research related to site selectivity in two types of transformation, namely, the acylation of hydroxy groups and C-H amination, is summarized. Regarding the acylation of hydroxy groups, catalyst-controlled site selectivity enables unconventional retrosynthetic analysis, leading to efficient syntheses of sugar-related natural and unnatural products. Regarding C-H amination, the discovery of unprecedented reaction sites in intermolecular amination mediated by dirhodium nitrenes is described. The findings of this research demonstrate the power of site-selective transformation in the synthesis of a particular class of compounds.

Regio- and stereoselective C-H functionalization of brassinosteroids.

Late stage CH functionalization is a powerful tool for modification of natural compounds. Herein we report that the rhodium-catalyzed reaction of brassinosteroids with aryloxysulfonamides proceeds regio- and stereoselectively at C15 position. The derivative obtained from 24-epibrassinolide was easily transformed to the conjugate with a BODIPY dye bearing unaffected functional groups of the native brassinosteroid.

Synthesis, molecular docking and inhibition studies of novel 3-N-aryl substituted-2-heteroarylchromones targeting microtubule affinity regulating kinase 4 inhibitors.

A series of 3-N-aryl substituted-2-heteroarylchromones was efficiently synthesized via Pd-mediated oxidative coupling under the influence of hetero-atoms neighboring group participation. Synthesized molecules were evaluated against human microtubule affinity regulating kinase 4 (MARK4) enzyme inhibitors, a recently identified anti-cancer drug target. Among 21 synthesized molecules, compounds 2, 3, and 14 exhibited excellent in vitro inhibitory effect against MARK4 with IC50 value (50% of ATPase activity) at 2.12 ±â€¯0.22 µM, 1.98 ±â€¯0.34 µM and 5.56 ±â€¯0.42 µM respectively. The fluorescence binding and dot blot assay of these compounds were found in µM range, indicating a better binding affinity. In vitro study of these compounds against cancerous cells (MCF-7 and HepG2) inhibited the cell viability, induced apoptosis and lowered the tau-phosphorylation. Cell viability studies of compounds 2, 3, and 14 showed inhibition of cancerous cells growth with IC50 values of 3.22 ±â€¯0.42, 4.32 ±â€¯0.23 µM and 16.22 ±â€¯1.33 µM for human breast cancer cells (MCF-7) and 6.45 ±â€¯1.12, 5.22 ±â€¯0.72 µM and 19.12 ±â€¯1.43 µM for human liver carcinoma cells (HepG2) respectively. ROS quantification of these compounds showed oxidative stress to cancerous cells and molecular docking study showed hydrogen bonding, charge or polar and van der Waals interactions with the active site residues of MARK4. Owning to high binding fit nicely in the active site, offering the possibilities to be used as novel therapeutic molecules in the drug discovery against MARK4-related diseases.

Bioamination of alkane with ammonium by an artificially designed multienzyme cascade.

Biocatalytic C-H amination is one of the most challenging tasks. C-H amination reaction can hardly be driven efficiently by solely one enzyme so far. Thus, enzymatic synergy represents an alternative strategy. Herein, we report an "Artificially Bioamination Pathway" for C-H amination of cyclohexane as a model substrate. Three enzymes, a monooxygenase P450BM3 mutant, an alcohol dehydrogenase ScCR from Streptomyces coelicolor and an amine dehydrogenase EsLeuDH from Exiguobacterium sibiricum, constituted a clean cascade reaction system with easy product isolation. Two independent cofactor regeneration systems were optimized to avoid interference from the endogenous NADH oxidases in the host E. coli cells. Based on a stepwise pH adjustment and ammonium supplement strategy, and using an in vitro mixture of cell-free extracts of the three enzymes, cyclohexylamine was produced in a titer of 14.9 mM, with a product content of up to 92.5%. Furthermore, designer cells coexpressing the three required enzymes were constructed and their capability of alkane bio-amination was examined. This artificially designed bioamination paves an attractive approach for enzymatic synthesis of amines from accessible and cheap alkanes.

P450-catalyzed intramolecular sp3 C-H amination with arylsulfonyl azide substrates.

The direct amination of aliphatic C-H bonds represents a most valuable transformation in organic chemistry. While a number of transition metal-based catalysts have been developed and investigated for this purpose, the possibility to execute this transformation with biological catalysts has remained largely unexplored. Here, we report that cytochrome P450 enzymes can serve as efficient catalysts for mediating intramolecular benzylic C-H amination reactions in a variety of arylsulfonyl azide compouds. Under optimized conditions, the P450 catalysts were found to support up to 390 total turnovers leading to the formation of the desired sultam products with excellent regioselectivity. In addition, the chiral environment provided by the enzyme active site allowed for the reaction to proceed in a stereo- and enantioselective manner. The C-H amination activity, substrate profile, and enantio/stereoselectivity of these catalysts could be modulated by utilizing enzyme variants with engineered active sites.