Chemoselective C-H Hydroxylation and Borylation of N-Phenylbenzamides using BBr3.

A novel metal-free chemoselective C-H hydroxylation and borylation of N-phenylbenzamides using BBr3 is described. The protocol generates the corresponding phenols and arylboronic esters in moderate to excellent yields under mild conditions with brilliant chemoselectivity. Additionally, this strategy can be realized in one pot, and several potential bioactive derivatives can be synthesized efficiently. Density functional theory calculations certify that the preferred pathway for this metal-free C-H hydroxylation process is the formation of a five-membered boracycle.

Ligand-controlled regiodivergent Ni-catalyzed trans-hydroboration/carboboration of internal alkynes with B2pin2.

Unprecedented regioselective trans-hydroboration and carboboration of unbiased electronically internal alkynes were realized via a nickel catalysis system with the aid of the directing group strategy. Furthermore, the excellent α- and ß-regioselectivity could be accurately switched by the nitrogen ligand (terpy) and phosphine ligand (Xantphos). Mechanistic studies provided an insight into the rational reaction process, that underwent the cis-to-trans isomerization of alkenyl nickel species. This transformation not only expands the scope of transition-metal-catalyzed boration of internal alkynes but also, more particularly, portrays the vast prospects of the directing group strategy in the selective functionalization of unactivated alkynes.

Recent advancements in the discovery of small-molecule non-nucleoside inhibitors targeting SARS-CoV-2 RdRp.

The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 plays a pivotal role in the life cycle of the novel coronavirus and stands as a significant and promising target for anti-SARS-CoV-2 drugs. Non-nucleoside inhibitors (NNIs), as a category of compounds directed against SARS-CoV-2 RdRp, exhibit a unique and highly effective mechanism, effectively overcoming various factors contributing to drug resistance against nucleoside inhibitors (NIs). This review investigates various NNIs, including both natural and synthetic inhibitors, that closely interacting with the SARS-CoV-2 RdRp with valid evidences from in vitro and in silico studies.

Rh(III)-catalyzed selective mono- and dual-functionalization/cyclization of 1-aryl-5-aminopyrazoles with iodonium ylides.

An efficient Rh(III)-catalyzed selective mono- and dual-C-H bond functionalization/cyclization with iodonium ylide as a single coupling partner was demonstrated, in which fused benzodiazepine skeletons were obtained in excellent yields. This method greatly improved an effective approach to dual C-H unsymmetrical functionalization.

Synthesis of Tetrahydro-indolones through Rh(III)-Catalyzed [3 + 2] Annulation of Enaminones with Iodonium Ylides.

An unprecedented protocol for a Rh(III)-catalyzed [3 + 2] annulation from simple and readily available enaminones and iodonium ylides has been developed. The novel strategy allows for access to a new class of structurally diverse tetrahydro-indolones with high efficiency and a broad substrate scope. In addition, this transformation represents the first example of the selective Rh(III)-catalyzed alkenyl C-H bond functionalization and annulation of enaminones. Finally, the potential applications of this protocol are demonstrated through gram-scale reaction and late-stage modification.

Mn(OAc)2-promoted [3+2] cyclization of enaminone with isocyanoacetate: Rapid access to pyrrole-2-carboxylic ester derivatives with potent anticancer activity.

The practical and facile Mn(OAc)2-promoted [3+2] cycloaddition reaction of enaminones with isocyanoacetate was developed, that delivered a diversity of 3-aroyl pyrrole-2-carboxylic esters with broad substrates scope. The most of the newly synthesized compounds exhibit moderate antiproliferative activity against four cancer cells. Notably, compound 2n demonstrate the most potent activity with average IC50 values of 5.61 µM against four distinct cancer cell lines. Moreover, 2n exhibit favorable anti-migration activity and drug-like properties. The further investigation suggests that compound 2n possesses the ability to inhibit ERK5 activity and exhibits effective binding with the ERK5 protein, making it a promising candidate as a lead compound for a new class of ERK5 inhibitors discovery.

Access to thiionized-, selenolized-, and alkylated 5-alkylidene 3-pyrrolin-2-one derivatives via a regioselective oxidative annulation reaction.

A metal-free regioselective oxidative annulation reaction of readily available 2,4-pentanediones with primary amines has been described. This protocol provides a divergent strategy for the incorporation of various radical donors into 5-alkylidene 3-pyrrolin-2-one skeletons, producing a variety of thiionized-, selenolized-, and alkylated 5-alkylidene 3-pyrrolin-2-one derivatives. Moreover, the diverse synthetic transformations of the 5-alkylidene 3-pyrrolin-2-one products were also investigated.

Small change for big improvement in the preparation of the key intermediate N 1, N 3-disubstituted 1,3,5-triazone of ensitrelvir.

In this study, the key intermediate N 1, N 3-disubstituted 1,3,5-triazone of ensitrelvir fumaric acid, approved in Japan for the treatment of SARS-CoV-2 infection under the emergency regulatory approval system, was produced from S-ethylisothiourea hydrobromide and aminomethyl triazole with CDI by four-step telescoped strategy including CDI-activated, condensation, CDI-cyclization, and N 1-alkylation. The strategy with simple conditions and operations had a total yield of 53% on a gram scale. The strategy for synthesizing the key N 1, N 3-disubstituted 1,3,5-triazone intermediate of ensitrelvir might provide a new avenue for further research and development of ensitrelvir analogs.

Cyclometalated iridium complexes-catalyzed acceptorless dehydrogenative coupling reaction: construction of quinoline derivatives and evaluation of their antimicrobial activities.

The acceptorless dehydrogenative coupling (ADC) reaction is an efficient method for synthesizing quinoline and its derivatives. In this paper, various substituted quinolines were synthesized from 2-aminobenzyl alcohols and aryl/heteroaryl/alkyl secondary alcohols in one pot via a cyclometalated iridium-catalyzed ADC reaction. This method has some advantages, such as easy availability of raw materials, mild reaction conditions, wide range of substrates, and environmental friendliness which conforms to the principles of green chemistry. Furthermore, a gram-scale experiment with low catalyst loading offers the potential to access the aryl/heteroaryl quinolones in suitable amounts. In addition, the antibacterial and antifungal activities of the synthesized quinolines were evaluated in vitro, and the experimental results showed that the antibacterial activities of compounds 3ab, 3ad, and 3ah against Gram-positive bacteria and compound 3ck against C. albicans were better than the reference drug norfloxacin.

Facile access to the 2,2-difluoro-2,3-dihydrofuran skeleton without extra additives: DMF-promoted difluorocarbene formation of ClCF2CO2Na.

A practical and facile difluorocarbene-triggered cycloaddition reaction of enaminones was developed, which delivered 2,2-difluoro-2,3-dihydrofurans with a broad substrate scope. Notably, the reaction proceeded smoothly without any extra additives. Readily available sodium chlorodifluoroacetate (ClCF2CO2Na, SCDA) served as a difluorocarbene precursor in this transformation through DMF-promotion. Moreover, it is proved that the 2,2-difluoro-2,3-dihydrofuran derivatives exhibit potential antiproliferative activity against human tumour cells HeLa, MCF7 and HepG2.

B2pin2-Mediated Cascade Cyclization/Aromatization Reaction: Facial Access to Functionalized Indolizines.

Herein, a B2pin2-mediated radical cascade cyclization/aromatization reaction of enaminone with pyridine is described. This strategy provides a practical way for the construction of valuable functionalized indolizines under metal-, external oxidant-, and base-free conditions, which could be compatible with various kinds of functional groups, such as halogen, π-system, heterocycle, ferrocenyl, etc. A preliminary mechanism investigation indicated that the pyridine-boryl radical formed in situ triggered the reaction to occur.

Nickel-Catalyzed Reductive Borylation of Enaminones via C(sp2)-N Bond Cleavage.

The cleavage and transformation of alkenyl C(sp2)-N bonds is a significant synthetic challenge. Herein we described an unprecedented nickel-catalyzed reductive borylation of enaminones to synthesize ß-ketone boronic esters. Notably, B2pin2 played the dual role in this process, and water served as a hydrogen source, which was transferred to target products. The air-stable nickel catalyst was applied to the cleavage of alkenyl C(sp2)-N bonds, concomitant with the reductive process of the alkenyl boronic ester intermediates, on the basis of the mechanism study.

Substrate-Controlled Cu(OAc)2-Catalyzed Stereoselective Semi-Reduction of Alkynes with MeOH as the Hydrogen Source.

A substrate-controlled stereoselective semi-reduction of alkynes with MeOH as the hydrogen source has been developed, and readily available Cu(OAc)2 (copper acetate) is utilized as an optimal catalyst. The detailed investigation of the mechanism revealed distinct catalytic processes for the (Z)- and (E)-alkenes, respectively. As a result, a diversity of alkynes (including terminal, internal alkynes etc.) were compatible under the mild reaction conditions. Furthermore, the high proportion of deuterium in Z-alkenes (up to 96%) was obtained using d 4-methanol as a solvent.

B2pin2-Mediated Palladium-Catalyzed Diacetoxylation of Aryl Alkenes with O2 as Oxygen Source and Sole Oxidant.

A novel palladium-catalyzed alkene diacetoxylation with dioxygen (O2) as both the sole oxidant and oxygen source is developed, which was identified by 18O-isotope labeling studies. Control experiments suggested that bis(pinacolato)diboron (B2pin2) played a dominant intermediary role in the formation of a C-O bond. This method performed good functional group tolerance with moderate to excellent yields, which could be successfully applied to the late-stage modification of natural products. Furthermore, an atmospheric pressure of dioxygen enhances the practicability of the protocol.

Palladium-catalyzed regioselective hydroboration of aryl alkenes with B2pin2.

A palladium(ii)-catalyzed hydroboration of aryl alkenes with stable and easy-to-handle (pinacolato)diboron (B2pin2) under mild conditions has been developed. Acetic acid acted as the solvent and the hydrogen source, which has been identified by deuterium experiments. Notably, isomerization-hydroboration of allyl benzene derivatives was observed. As a result, a series of benzyl boronic esters were obtained in moderate to excellent yields with exclusive regioselectivity.

Access to α-Amino Acid Esters through Palladium-Catalyzed Oxidative Amination of Vinyl Ethers with Hydrogen Peroxide as the Oxidant and Oxygen Source.

A novel and convenient palladium catalytic system for the synthesis of α-amino acid esters from simple starting materials is reported. Hydrogen peroxide not only acts as the green oxidant, but also as the oxygen source. This strategy for the conversion of amines and vinyl ethers into highly functionalized and structurally diverse α-amino acid esters is characterized by the simplicity of the experimental procedure, mild reaction conditions, high atom economy, scalability, and practicability.

Palladium-catalyzed oxidative amination of homoallylic alcohols: sequentially installing carbonyl and amino groups along an alkyl chain.

A novel Pd-catalyzed intermolecular cascade oxidative amination of homoallylic alcohols to yield ß-amino ketones has been developed by using TBHP as the terminal oxidant. The synthetic utility of the reaction can be performed by installing the carbonyl and amino groups along an alkyl chain in one step, offering several advantages such as simple starting materials and easy operation. The resultant ß-amino ketones should have potential applications in the fields of biopharmaceutical and functional materials.

Palladium-Catalyzed Intermolecular Oxidative Cyclization of Allyltosylamides with AcOH: Assembly of 3-Pyrrolin-2-ones.

The first example of Pd-catalyzed oxidative cyclization of allyltosylamides with acetic acid is reported. This transformation involved C-N/C-C bond formation and provided 3-pyrrolin-2-ones in a one-pot manner with easy-operation, excellent atom economy and good yields. Mechanistic studies indicate that the reaction proceeds through intermolecular aminopalladation, migratory insertion, reinsertion and ß-hydride elimination processes.

Dual Role of H2O2 in Palladium-Catalyzed Dioxygenation of Terminal Alkenes.

A palladium-catalyzed, environmentally friendly dioxygenation reaction of simple alkenes has been developed that enabled rapid assembly of valuable α-hydroxy ketones with high atom economy. Notably, control experiments and 18O isotope-labeling experiments established that H2O2 played a dominant dual role in this transformation.

Application of the Helquist annulation in Lycopodium alkaloid synthesis: unified total syntheses of (-)-8-deoxyserratinine, (+)-fawcettimine, and (+)-lycoflexine.

A unified strategy for total synthesis of the Lycopodium alkaloids (-)-8-deoxyserratinine (7), (+)-fawcettimine (1), and (+)-lycoflexine (4) is detailed. The key features include a highly efficient Helquist annulation to assemble the cis-fused 6/5 bicycle, facile construction of the aza nine-membered ring system employing double N-alkylation strategy, providing access to the common tricyclic skeleton, asymmetric Shi epoxidation, delivering the desired ß-epoxide stereospecifically to furnish (-)-8-deoxyserratinine (7), SmI(2) reduction of dihydroxylation derivative 35 to enable formation of (+)-fawcettimine (1), and a rapid biomimetic transformation of (+)-fawcettimine (1) into (+)-lycoflexine (4) via an intramolecular Mannich cyclization.