Copper-promoted C5-selective bromination of 8-aminoquinoline amides with alkyl bromides.

An efficient and practical method for the synthesis of C5-brominated 8-aminoquinoline amides via a copper-promoted selective bromination of 8-aminoquinoline amides with alkyl bromides was developed. The reaction proceeds smoothly in dimethyl sulfoxide (DMSO) under air, employing activated and unactivated alkyl bromides as the halogenation reagents without additional external oxidants. This method features outstanding site selectivity, broad substrate scope, and excellent yields.

Palladium-catalyzed C-H alkylation of 2-phenylpyridines with alkyl iodides.

Palladium-catalyzed C-H alkylation reaction of 2-phenylpyridines with alkyl iodides has been successfully developed. The palladacycles obtained from 2-phenylpyridines should act as the key intermediates in the alkylation reaction.

Oxalic acid as the in situ carbon monoxide generator in palladium-catalyzed hydroxycarbonylation of arylhalides.

An efficient palladium-catalyzed hydroxycarbonylation reaction of arylhalides using oxalic acid as a CO source has been developed. The reaction features high safety, low catalyst loading, and a broad substrate scope, and provides a safe and tractable approach to access a variety of aromatic carboxylic acid compounds. Mechanistic studies revealed the decomposition pattern of oxalic acid.

Ligand-promoted oxidative cross-coupling of aryl boronic acids and aryl silanes by palladium catalysis.

The first cross-coupling reaction between aryl silanes and aryl boronic acids is described. This transformation represents one of the very few examples of coupling reactions between two nucleophilic organometallic reagents and provides a new method for the formation of biaryl compounds. The successful development of this reaction was enabled by the use of commercially available 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) as the ligand. A small amount of BINAP (3 mol %) was sufficient to suppress the formation of the homocoupling products, and the reaction yielded the cross-coupling products with high selectivity under mild conditions, even when the ratio of the two coupling partners was 1:1.

Copper-catalyzed highly efficient ester formation from carboxylic acids/esters and formates.

A highly efficient copper-catalyzed protocol for the synthesis of esters has been developed from formates. This protocol is applicable to reactions with either esters or acids as the substrates, and shows broad substrate scopes and high yields.

Clinical Efficacy and Safety of an Immune Checkpoint Inhibitor in Combination with Regorafenib Therapy as Second-Line Regimen for Patients with Unresectable Hepatocellular Carcinoma.

Purpose: This study aimed to evaluate the safety and efficacy of a combination of programmed death-1 (PD-1) inhibitor and regorafenib as second-line treatment for advanced hepatocellular carcinoma (HCC). Patients and Methods: We retrospectively analyzed the data of 38 patients with unresectable HCC who were treated with PD-1 inhibitor in combination with regorafenib as a second⁃line therapy as well as the data of 32 patients treated with regorafenib only therapy as a control. The clinical data, previous treatment strategies, follow-up imaging results, and adverse events during follow-ups were recorded. The mRECIST Criteria were used to evaluate the treatment outcome of intrahepatic lesions, and the Kaplan-Meier method was used to evaluate survival time. Results: Up to the last follow-up, the rego-PD-1 group had higher objective response rate (39.5% vs 15.6%, P = 0.028), longer progression-free survival (median 5.9 vs 4.6 months; P = 0.044), and better overall survival (OS) (median 14.5 vs 9.5 months; P = 0.041) than the regorafenib only group. Among the 38 patients in rego-PD-1 group, 1 patient (2.7%) achieved complete response, 14 patients (36.8%) achieved partial response, 14 patients (36.8%) achieved stable disease, and 9 patients (23.7%) achieved progressive disease. Among the 32 patients in regorafenib alone, 5 (15.6%) achieved partial response, 12 (37.5%) achieved stable disease, and 15 (46.9%) achieved progressive disease. Regorafenib alone, Child-Pugh B, and tumors >3 were independent prognostic factors for poor OS. The difference in the incidence of grade 3/4 adverse events between the two groups was not statistically significant (36.8% vs 28.1%; P = 0.439). Grade ≥3 treatment-related adverse events included hypertension and diarrhea. Conclusion: PD-1 inhibitor combined with regorafenib is a promising regimen in treating patients with unresectable HCC owing to its safety and effectiveness as well as low incidence of serious adverse events with its use.

Copper-catalyzed selective C5-H bromination and difluoromethylation of 8-aminoquinoline amides using ethyl bromodifluoroacetate as the bifunctional reagent.

A simple and effective method for the copper-catalyzed selective C5-H bromination and difluoromethylation of 8-aminoquinoline amides with ethyl bromodifluoroacetate as the bifunctional reagent was developed. The combination of cupric catalyst and alkaline additive results in a C5-bromination reaction, whereas cuprous catalyst combined with silver additive results in the C5-difluoromethylation reaction. This method has a broad substrate scope and allows for easy and convenient access to desired C5-functionalized quinolones with good to excellent yields.

Directed Palladium(II)-Catalyzed Intermolecular Anti-Markovnikov Hydroarylation of Unactivated Alkenes with (Hetero)arylsilanes.

We describe herein a regioselective palladium(II)-catalyzed intermolecular hydroarylation of unactivated aliphatic alkenes with electronically and sterically diverse (hetero)arylsilanes under redox-neutral conditions. A removable bidentate 8-aminoquinoline auxiliary was readily employed to dictate the regioselectivity, prevent ß-hydride elimination, and facilitate protodepalladation. This silicon-based protocol features a broad substrate scope with excellent functional group compatibility and enables an expeditious route to a variety of γ-aryl butyric acid derivatives in good yields with exclusive anti-Markovnikov selectivity.

Direct Hiyama Cross-Coupling of (Hetero)arylsilanes with C(sp2)-H Bonds Enabled by Cobalt Catalysis.

We report a chelation-assisted C-H arylation of various indoles with sterically and electronically diverse (hetero)arylsilanes enabled by cost-effective Cp*-free cobalt catalysis. Key to the success of this strategy is the judicious choice of copper(II) fluoride as a bifunctional sliane activator and catalyst reoxidant. This methodology features a broad substrate scope and good functional group compatibility. The synthetic versatility of this protocol has been highlighted by the gram-scale synthesis and late-stage diversification of biologically active molecules.

Palladium-catalyzed sequential three-component reactions to access vinylsilanes.

A palladium-catalyzed sequential three-component reaction has been developed. The palladacycles, generated through cascade reactions of aryl halides and alkynes, are the key intermediates and react with hexamethyldisilane to form disilylated products. The reaction represents a useful preparative method for vinylsilanes, and the vinylsilanes can be transformed into tetrasubstituted alkenes.

An approach to spirooxindoles via palladium-catalyzed remote C-H activation and dual alkylation with CH2Br2.

A facile and efficient approach for the synthesis of spirooxindoles has been developed via the coupling of spirocyclic C,C-palladacycles with CH2Br2. The key spirocyclic palladacycles are generated catalytically via remote C-H activation. A range of spirooxindoles can be synthesized in good to excellent yields from readily available starting material.

Silver-catalyzed C-H trifluoromethylation of arenes using trifluoroacetic acid as the trifluoromethylating reagent.

Direct trifluoromethylation of arenes using TFA as the trifluoromethylating reagent was achieved with Ag as the catalyst. This reaction not only provides a new protocol for aryl C-H trifluoromethylation, but the generation of CF3· from TFA may prove useful in other contexts and could potentially be extended to other trifluoromethylation reactions.

Palladium-catalyzed C-H ethoxycarbonyldifluoromethylation of electron-rich heteroarenes.

The first Pd-catalyzed C-H ethoxycarbonyldifluoromethylation with BrCF2CO2Et has been developed. The use of a bidentate phosphine ligand (Xantphos) is critical for the reaction to occur. A variety of electron-rich heteroarenes, including indoles, furans, thiophenes, and pyrroles, can be ethoxycarbonyldifluoromethylated in moderate to excellent yields. The reactions take place at the C-H bonds adjacent to the heteroatoms with high regioselectivity. This method provides a new protocol for the introduction of difuoroalkyl groups into electron-rich heteroarenes.