Regio- and Diastereoselective Hydrophosphination and Hydroamidation of gem-Difluorocyclopropenes.

In this study, concise, efficient, and modular hydrophosphinylation and hydroamidation of gem-difluorocyclopropenes were disclosed in a mild and transition-metal-free pattern. Through this approach, phosphorus, and nitrogen-containing gem-difluorocyclopropanes were produced in moderate to good yields with excellent regio- and diastereoselectivity. Readily available gem-difluorocyclopropenes and nucleophilic reagents, along with inexpensive inorganic bases, were employed. Multiple synthetic applications, including gram-scale and derivatization reactions and modification of bioactive molecules, were subsequently elaborated.

Modular Synthesis of 1,2-Benzothiazines and 1,2-Benzothiazine 1-Imines via Palladium-Catalyzed C-H/C-C Activation Reactions.

In this study, a modular approach toward cyclic sulfoximines and sulfondiimines via palladium-catalyzed intramolecular C-H/C-C activation reactions was reported. Various 1,2-benzothiazines including bicyclic, tricyclic, highly fused ones, ones of the seven-membered ring, along with 1,2-benzothiazine 1-imines were accessed in good yields. KIE experiment demonstrated that the C-H bond cleavage at the position ortho to the sulfoximine group is not the rate-determining step in the coupling reaction.

Targeting AXL induces tumor-intrinsic immunogenic response in tyrosine kinase inhibitor-resistant liver cancer.

Hepatocellular carcinoma (HCC) is an aggressive malignancy without effective therapeutic approaches. Here, we evaluate the tumor-intrinsic mechanisms that attenuate the efficacy of immune checkpoint inhibitor (ICI) that is observed in patients with advanced HCC who progress on first-line tyrosine kinase inhibitor (TKI) therapy. Upregulation of AXL observed in sorafenib- and lenvatinib-resistant HCCs is correlated with poor response towards TKI and ICI treatments. AXL upregulation protects sorafenib-resistant HCC cells from oxidative stress, mitochondrial damage, and accompanying immunogenic cell death through suppressed tumor necrosis factor-α (TNF-α) and STING-type I interferon pathways. Pharmacological inhibition of AXL abrogates the protective effect and re-sensitizes TKI-resistant HCC tumors to anti-PD-1 treatment. We suggest that targeting AXL in combination with anti-PD-1 may provide an alternative treatment scheme for HCC patients who progress on TKI treatment.

Spectrum and size controllable synthesis of high-quality gold nanorods using 1,7-dihydroxynaphthalene as a reducing agent.

The spectrum and size controllable synthesis of gold nanorods is of great value for their widely applicable aspect ratio dependence of anisotropic surface plasmon resonance. Herein, 1,7-dihydroxynaphthalene with a relatively strong reducibility is proposed as a reducing agent for the controllable synthesis of gold nanorods. The result indicated that gold nanorods with high monodispersity, high shape yield, relatively small diameters, and maximum plasmon resonance wavelength of above 1000 nm can be acquired. More importantly, by virtue of the reducing agent used, fine and precise controls over the plasmon wavelength and diameter of the rod can be achieved via changes in experimental conditions. In particular, increases in the concentration of both silver ions and cetyltrimethylammonium bromide (CTAB) can increase the plasmon wavelength from around 600 nm to 1000 nm but respectively show a decreased diameter with the smallest value of around 14.3 nm and a mildly increased diameter from around 9.0 nm to 14.3 nm; moreover, increasing the concentration of reducing agents and gold seeds can simultaneously cause decreases in the plasmon wavelength from around 1000 nm to 800 nm and the diameters from around 14.3 nm to 9.0 and 7.3 nm, respectively. This powerful and efficient method of controllable synthesis of AuNRs could be valuable and attractive for the application of the as-obtained particles.

Palladium-Catalyzed Atroposelective Coupling-Cyclization of 2-Isocyanobenzamides to Construct Axially Chiral 2-Aryl- and 2,3-Diarylquinazolinones.

A palladium-catalyzed imidoylative cycloamidation of N-alkyl-2-isocyanobenzamides with 2,6-disubstituted aryl iodides, affording unprecedented axially chiral 2-arylquinazolinones, has been developed with good yields and atroposelectivities. In this coupling-cyclization process, the biaryl linkage and the heteroaromatic ring are formed sequentially in one step. When N-(2,4-dimethoxyphenyl)-2-isocyanobenzamide is applied as a substrate, 2,3-diarylquinazolinones containing two stereogenic axes are produced with moderate diastereoselectivity and good enantioselectivities.

Pd-Catalyzed Domino Imidoylation/Heck/C(sp2)-H Cyclization: Isocyanide Relay Strategy toward Tricyclic-Fused Heterocycles Containing an All-Carbon Quaternary Center.

A palladium-catalyzed domino process for the quick assembly of tricyclic-fused heterocycles starting from aryl iodides and functionalized isocyanides containing a disubstituted terminal alkene has been developed. The process is triggered by intermolecular isocyanide insertion, followed by Heck-type carbopalladation of the intramolecular alkene moiety and subsequent C(sp2)-H activation. Moreover, an asymmetric version of this reaction could also be realized in good yield with moderate enantioselectivity after preliminary exploration of chiral ligands.

Palladium-Catalyzed C-H Bond Functionalization Reactions Using Phosphate/Sulfonate Hypervalent Iodine Reagents.

A new and operationally simple approach for palladium-catalyzed C-H functionalization reactions utilizing an organophosphorus/sulfonate hypervalent iodine reagent as both an oxidant and the source of a functional group has been developed. Through this method, the oxidative phosphorylation-, sulfonation-, and hydroxylation of unactivated benzyl C(sp3)-H bonds, along with the hydroxylation and arylation of aryl C(sp2)-H bonds, are successfully realized under mild conditions and with excellent site-selectivity. The versatile C-OSO2R bond provides a platform for a wide array of subsequent diversification reactions.

Defluorinative C(sp3 )-P Bond Construction for the Synthesis of Phosphorylation gem-Difluoroalkenes under Catalyst- and Oxidant-Free Conditions.

Defluorinative C(sp3 )-P bond formation of α-trifluoromethyl alkenes with phosphine oxides or phosphonates have been achieved under catalyst- and oxidant-free conditions, giving phosphorylation gem-difluoroalkenes as products. α-Trifluoromethyl alkenes bearing various of aryl substituents such as halogen, cyano, ester and heterocyclic groups are available in this transformation. The results of control experiments demonstrated that the mechanism of dehydrogenative/defluorinative cross-coupling reactions was not a radical route, but might be an SN 2' process involving phosphine oxide anion.

I2-catalyzed intramolecular oxidative amination of C(sp3)-H bond: efficient access to 3-acylimidazo[1,2-a]pyridines under neat condition.

An efficient and "green" protocol for the synthesis of 3-acylimidazo[1,2-a]pyridines through intramolecular oxidative α-amination of carbonyl compounds has been developed. The reaction proceeds smoothly utilizing I2 as a catalyst and H2O2 as an oxidant under neat condition with broad substrate scope. Several complex nitrogen-containing fused rings are conveniently constructed, which are not easy to access by traditional methods.

Palladium-catalysed ring-opening [3 + 2]-annulation of spirovinylcyclopropyl oxindole to diastereoselectively access spirooxindoles.

A novel palladium-catalysed ring-opening [3 + 2]-annulation of spirovinylcyclopropyl oxindole with α,ß-unsaturated nitroalkenes is reported. A series of spirooxindole derivatives were synthesized in high yields and good to excellent diastereoselectivities. This developed protocol offers a new and efficient pathway for the assembly of spirooxindoles.

Metal-free oxidative isocyanides insertion with aromatic aldehydes to aroylated N-heterocycles.

A metal-free, mild and efficient protocol for the construction of aroylated N-heterocycles via radical cascade aroylation of phenyl or vinyl isocyanides with aromatic aldehydes has been developed. Both phenanthridine and isoquinoline derivatives are delivered quickly in moderate to good yields with high regioselectivity.

A metal-free synthesis of 2-aminobenzothiazoles through aminyl radical addition to aryl isothiocyanates.

A convenient synthesis of 2-aminobenzothiazoles, starting from aryl isothiocyanates and formamides under metal-free conditions, is described. Various secondary and tertiary amine- and even α-amino acid-derived formamides can be used as amino sources in this process. Mechanistic studies suggest that the reaction is initiated by decarbonylative aminyl radical formation in the presence of n-Bu4NI and TBHP, followed by aminyl radical addition to isothiocyanates and cyclization via sulfur centred radical intermediates.

Palladium-catalyzed intramolecular C(sp(2))-H imidoylation for the synthesis of six-membered N-heterocycles.

A new strategy for the construction of phenanthridine and isoquinoline scaffolds, starting from arenes containing a pending isocyanide moiety under palladium catalysis, has been developed. This process involves sequential intermolecular isocyanide insertion to an aryl palladium(II) intermediate and intramolecular aromatic C-H activation as key steps. Alkyl palladium(II) intermediate lacking ß-hydrogen is also applicable to this reaction, generating unique bisheterocyclic scaffolds with three C-C bonds being formed consecutively.

Palladium-catalyzed C(sp2)-H pyridocarbonylation of N-aryl-2-aminopyridines: dual function of the pyridyl moiety.

An efficient synthesis of 11H-pyrido[2,1-b]quinazolin-11-one through palladium-catalyzed C(sp(2))-H pyridocarbonylation of N-aryl-2-aminopyridines has been developed. The pyridyl group acts as an intramolecular nucleophile for the first time in C-H carbonylation reactions.

Arylative cyclization of 2-isocyanobiphenyls with anilines: one-pot synthesis of 6-arylphenanthridines via competitive reaction pathways.

A transition-metal-free method for the synthesis of C6 phenanthridine derivatives by arylative cyclization of 2-isocyanobiphenyls with arylamines in one pot was developed. Mechanistic studies suggest that electrophilic aromatic substitution (SEAr) of a nitrilium intermediate and homolytic aromatic substitution (HAS) of an imidoyl radical intermediate are two competitive reaction pathways involved in the annulation step.

C-H cycloamination of N-aryl-2-aminopyridines and N-arylamidines catalyzed by an in situ generated hypervalent iodine(III) reagent.

A metal-free synthesis of diversified pyrido[1,2-a]benzimidazoles and 1H-benzo[d]imidazoles from N-aryl-2-aminopyridines and N-arylamidines has been developed. The C-H cycloamination reaction was catalyzed by hypervalent iodine(III) species generated in situ from iodobenzene (catalytic) and peracetic acid (stoichiometric). The reaction proceeded smoothly at ambient temperature to provide the corresponding N-heterocycles in good to excellent yields.

A metal-free tandem demethylenation/C(sp2)-H cycloamination process of N-benzyl-2-aminopyridines via C-C and C-N bond cleavage.

A mild, metal-free synthesis of pyrido[1,2-a]benzimidazoles starting with N-benzyl-2-aminopyridines, which employs PhI(OPiv)2 as a stoichiometric oxidant, has been developed. The process is initiated by an unusual PhI(OPiv)2-mediated ipso S(E)Ar reaction, followed by solvent-assisted C-C and C-N bond cleavage.

CuI-mediated sequential iodination/cycloetherification of o-arylphenols: synthesis of 2- or 4-iododibenzofurans and mechanistic studies.

An efficient synthesis of 2- or 4-iododibenzofurans through CuI-mediated sequential iodination/cycloetherification of two aromatic C-H bonds in o-arylphenols has been developed. Both the preexisting electron-withdrawing groups (NO(2), CN, and CHO) and the newly introduced iodide are readily modified for a focused dibenzofuran library synthesis. Mechanistic studies and DFT calculations suggest that a Cu(III)-mediated rate-limiting C-H activation step is involved in cycloetherification.

Synthesis of benzimidazoles by PIDA-promoted direct C(sp2)-H imidation of N-arylamidines.

A metal-free synthesis of diversified benzimidazoles from N-arylamidines through a phenyliodine(III) diacetate (PIDA) promoted intramolecular direct C(sp(2))-H imidation has been developed. The reaction proceeds smoothly at 0 °C or ambient temperature to provide the desired products in good to excellent yields. The synthesis of 2-alkyl- or 2-alkyl-fused benzimidazoles, which are generally inaccessible by similar Pd- or Cu-catalyzed approaches, can also be achieved.

Cu-catalyzed oxidative C(sp2)-H cycloetherification of o-arylphenols for the preparation of dibenzofurans.

A new process involving copper-catalyzed aerobic C(sp(2))-H activation, followed by cycloetherification, has been developed. This reaction serves as a direct method for the preparation of multisubstituted dibenzofurans starting with o-arylphenols. The presence of a strong para-electron-withdrawing group (e.g., NO(2)) on the phenol is essential for the success of the reaction.