A new transition-metal-free route for the direct trifluoromethylthiolation and trifluoromethylsulfoxidation of electron-rich aromatics with CF3SO2Na in the presence of PCl3 was developed. Notably, PCl3 was used as a reducing and chlorination reagent. The transition-metal-free protocol utilized cheap and readily available reagents and exhibited good atom economy; therefore, it will serve as an alternative and practical strategy for the trifluoromethylthiolation and trifluoromethylsulfoxidation of electron-rich aromatics.

•Four ring-closing analogs of Desmethylxanthohumol were synthesized.•The catechol motif is critical for the antioxidant activity.•The dimers show better antioxidant activity than the corresponding monomers.•Compound 14d was identified as the most potent antioxidant activity.•Compound 14d decreased apoptosis in H2O2-treated PC12 cells.Four ring-closed analogs of natural prenylated chalcone desmethylxanthohumol (1) and their dimers were synthesized from the commercially available 1-(2,4,6-trihydroxyphenyl)ethan-1-one in five and six linear steps, respectively. The structures of the eight new derivatives were confirmed using1H NMR, 13C NMR and HRMS. The antioxidant activity of the new chalcone derivatives were evaluated in a PC12 cell model of H2O2-induced oxidative damage. The SAR studies suggested that the catechol motif was essential for the antioxidant activity. Moreover, the dimers showed better antioxidant activity than their corresponding monomers did. Among them, compound 14d was the most potent and increased PC12 cell viability from 25% to 85%. Flow cytometric analysis showed that compound 14d, the most potent compound, decreased the apoptotic PC12 cell percentage and significantly reduced the LDH release and 8-OHdG generation but increased the GSH levels in H2O2-treated PC12 cells. Furthermore, compound 14d had a higher FRAP value than that of gallic acid. It also reduced the stable ABTS+ free radical with a lower EC50 than that of gallic acid.Four ring-closing analogs of natural prenylated chalcone Desmethylxanthohumol (1) and their dimers were synthesized. The antioxidant activities of these new chalcone derivatives were evaluated in the PC12 cell model of hydrogen peroxide (H2O2)-induced oxidative damage.

A new method for phosphine-mediated difluoromethylthiolation of indole derivatives and other electron-rich aromatics including pyrroles, pyrazolones, indolizine, and 1,3,5-trimethoxybenzene was developed using difluoromethanesulfonyl chloride. The additive n-Bu4NI was demonstrated to facilitate this reaction by generating iodine in situ, which could promote this transformation. The use of a transition-metal-free protocol, readily available reagents, and mild reaction conditions makes this protocol more practical than traditional methods.

A novel triphenylphosphine-mediated direct trifluoromethylthiolation of indole derivatives using trifluoromethanesulfonyl chloride as the SCF3 source was developed. Sodium iodide facilitated this transformation by generating iodine in situ which was found to accelerate this transformation. The use of a transition metal-free protocol, readily available reagents, and mild reaction conditions allowed this protocol to be easily scaled up.

The first total synthesis of I3,II8-biapigenin and ridiculuflavone A via the key steps of regioselective iodination, Sonogashira reaction, and rhodium-catalyzed oxidative coupling with the overall yields of 31% and 22%, respectively, was reported. The structures of the key intermediates for the two natural products were confirmed by single-crystal X-ray analysis.

A series of 6-hydroxyaurones and their analogues have been synthesized and evaluated for their in vitro α-glucosidase inhibitory and glucose consumption-promoting activity. These compounds exhibited varying degrees of α-glucosidase inhibitory activity, 11 of them showing higher potency than that of the control standard acarbose (IC50 = 50.30 μM). Surprisingly, analogues devoid of a substituent at C-2 but having an aryl group at C-5 were found to be highly active (e.g., 7f, IC50 = 9.88 μM). Docking analysis substantiated these findings. The kinetic analysis of compound 7f, the most potent α-glucosidase inhibitor of this study, revealed that it inhibited α-glucosidase in an irreversible and mixed competitive mode. In addition, compounds 7f and 10c exhibited significant glucose consumption promoting activity at 1 μM.Download high-res image (221KB)Download full-size image

•Anastatins A and B as well as their analogs were synthesized.•Aurone derivatives showed better antioxidant activity than flavone counterparts.•Compound 24c was identified as the most potent antioxidant activity.•Compound 24c decreased apoptosis in H2O2-treated PC12 cells.Two novel flavonoids (±)-Anastatins A and B as well as 14 analogs, which containing a benzofuran moiety, were synthesized by using halogenation, Suzuki coupling reaction and an oxidation/Oxa-Michael reaction cascade as the key steps. The structures of the new flavonoids were confirmed by 1H NMR, 13C NMR and HRMS. The antioxidant activities of them as well as the key intermediates were evaluated by ferric reducing antioxidant power (FRAP) assay and the active compounds were evaluated in the PC12 cell model of hydrogen peroxide (H2O2)-induced oxidative damage. SAR studies suggested that, for in vitro antioxidant activity, aurone derivatives showed better bioactivity than flavone counterparts. However, cyclization to benzofuran and connecting the two conjugated parts as a whole conjugated system by a double bond diminished the in vitro antioxidant activity. Among them, the most potent compound 24c was significantly decreased H2O2-caused cell injury. The apoptotic rate (Annexin V+) of H2O2-damaged PC12 cells was 60.7% while that of the compound 24c-treated cells decreased to 5.9% and 4.1% at 10 μM and 100 μM respectively.Two novel flavonoids Anastatins A and B as well as their analogs were synthesized. The antioxidant activities of these flavonoids and the key intermediates were evaluated by ferric reducing antioxidant power (FRAP) assay and PC12 cell-based antioxidant assay.Download high-res image (167KB)Download full-size image

Triphenylphosphine-mediated metal-free trifluoromethylthiolation and difluoromethylthiolation of thiols by CF3SO2Cl and CHF2SO2Cl to synthesize trifluoromethyl disulfides and difluoromethyl disulfides, respectively, was achieved at room temperature. Iodine generated in situ from iodide facilitated this reaction via the formation of iodotriphenylphosphonium iodide which could serve as a reducing agent in this transformation. Readily available reagents and mild reaction conditions without transition-metals allow this protocol to be more practical than traditional methods.Download high-res image (133KB)Download full-size image

A novel transition metal-free route for the direct trifluoromethylthiolation of electron-rich aromatics using CF3SO2Na in the presence of PhPCl2 was developed. More specifically, PhPCl2 was used as both a reducing and a chlorinating reagent for the first time in this CF3SO2Na-based trifluoromethylthiolation reaction. The absence of transition metals and the use of cheap and readily available reagents render this method an alternative and practical strategy for the trifluoromethylthiolation of electron-rich aromatics.Download high-res image (153KB)Download full-size image

A four-component, 1,4-addition Ugi reaction using cyclic α,β-unsaturated ketones, carboxylic acids, amines, and isocyanides was developed for the first time. By combining this reaction with Michael addition, nucleophilic substitution, and C–N bond formation reactions, bicyclic and tricyclic scaffolds with pyridinone and quinolinone moieties, two basic units among a variety of natural products and pharmaceuticals, were constructed.

•A novel flavone 8-(6″-umbelliferyl)apigenin were synthesized for the first time.•Regio-selective iodination and Suzuki coupling reactions were used as key steps.•Analogues with different flavonoids cores were synthesized.•Effects of these compounds on glucose disposal were investigated in adipocytes.•The most potent could promote glucose consumption by 57% in 10 μΜ.The naturally occurring flavone 8-(6″-umbelliferyl)apigenin, a hybrid structure of apigenin and coumarin, as well as seven of its analogues were synthesized for the first time by using iodination and Suzuki coupling reactions as key steps. The synthesis of 8-(6″-umbelliferyl)-apigenin was achieved in seven linear steps from the commercially available 1-(2,4,6-trihydroxyphenyl)ethan-1-one and 7-hydroxyl coumarine with 31% overall yield. Effects of these compounds on glucose disposal were investigated in adipocytes. All of the flavonoid and coumarin hydrids were found to have better bioactivities than their corresponding flavonoid cores. The most potent compound 15 (10 μΜ) could promote glucose consumption by 57% which exhibited similar effect as the positive control metformin at 1 mM. Moreover, fluorescence microscopy showed that four 8-(6″-umbelliferyl)apigenin analogues 2, 15, 30 and 31 could promote the 2-NBDG uptake into 3T3-L1 cells, which consist with those observed in the regulation of glucose.A novel flavone 8-(6″-umbelliferyl)apigenin and its analogues were synthesized for the first time. The anti-diabetic activity evaluation results revealed these compounds could promote glucose consumption in adipocytes.

Iodine-catalysed regioselective sulfenylation of flavonoid derivatives with sulfonyl hydrazides was developed. Various flavonoid thioethers were obtained in moderate to good yield. The thiolation could be conveniently directed to C-8 for flavone, flavonol, dihydroflavone, and isoflavone derivatives or to C-7 for aurone derivatives by employing the isopropyl ethers of flavonoids bearing free OH groups at the C-5 or C-4 positions.

Iodine-catalyzed thiolation of electron-rich aromatics, including substituted anisole, thioanisole, phenol, toluene, and naphthalene, using sulfonyl hydrazides as sulfenylation reagents was carried out. Sulfonothioates, the products of decomposition of sulfonyl hydrazides in the presence of iodine, are proposed as the major sulfenylation species in this transformation.

•Transition-metal-free thiolation of pyrazolones and benzofurans was achieved.•Aryl sulfonyl chlorides were used as sulfenylation reagents.•Triphenylphosphine was used as a reducing agent.•Potassium iodide was found to facilitate the transformation.An efficient, transition-metal-free method to synthesize pyrazolone thioethers as well as 2-aryl and 3-aryl benzofuran thioethers by employing aryl sulfonyl chlorides as sulfenylation reagents in the presence of triphenylphosphine was developed. Potassium iodide was found to facilitate the transformation for the first time by generating more reactive sulfenyl iodide in situ from sulfenyl chloride.

Two novel flavones (±)-Anastatins A and B, each containing a benzofuran moiety, were synthesized for the first time by using bromination, Suzuki coupling reaction, and an oxidation/Oxa-Michael reaction cascade as the key steps. The syntheses of (±)-Anastatins A and B were achieved in eight steps from the commercially available phloroglucinol with 9% and 10% overall yield, respectively.

An efficient, metal-free protocol used to synthesize aryl benzo[b]furan thioethers based on the I2-catalyzed cross-coupling of benzo[b]furans as well as the electrophilic cyclization of 2-alkynylphenol derivatives with aryl sulfonyl hydrazides was developed. Various 2-aryl and 3-aryl benzo[b]furan thioethers were obtained in moderate to good yields.

Aryl pyrazolone thioethers were synthesized via the I2-catalysed cross-coupling of pyrazolones with aryl sulphonyl hydrazides in the presence of p-toluenesulphonic acid, which has been proposed to promote the reaction by facilitating the decomposition of sulphonyl hydrazides.

Highlights•First total synthesis of isoxanthoangelol was reported in 36% overall yield.•The improved syntheses of three natural C-alkyl chalcones were reported.•Regio-selective iodination and Suzuki coupling reaction were used as key steps.Four natural chalcones bearing prenyl or geranyl groups, i.e., isobavachalcone (1), bavachalcone (2), xanthoangelol (3), and 2′,4′,4-trihydroxy-5′-geranylchalcone (isoxanthoangelol, 4) were synthesized by using a regio-selective iodination and the Suzuki coupling reaction as key steps. Among them, the first total synthesis of 2′,4′,4-trihydroxy-5′-geranylchalcone was achieved in 36% overall yield. Comparing with the reported methods based on C-alkylation or O-alkylation followed by Claisen rearrangement to introduce the side chain, this new strategy capitalizes on a precious regiochemical control during iodination. The overall yields for the synthesis of the first three chalcones were improved from 17% to 53%, 12% to 35%, and 28% to 50%, respectively.

Iodine-catalysed regioselective sulfenylation of flavonoid derivatives with sulfonyl hydrazides was developed. Various flavonoid thioethers were obtained in moderate to good yield. The thiolation could be conveniently directed to C-8 for flavone, flavonol, dihydroflavone, and isoflavone derivatives or to C-7 for aurone derivatives by employing the isopropyl ethers of flavonoids bearing free OH groups at the C-5 or C-4 positions.

Aryl pyrazolone thioethers were synthesized via the I2-catalysed cross-coupling of pyrazolones with aryl sulphonyl hydrazides in the presence of p-toluenesulphonic acid, which has been proposed to promote the reaction by facilitating the decomposition of sulphonyl hydrazides.

Iodine-catalyzed thiolation of electron-rich aromatics, including substituted anisole, thioanisole, phenol, toluene, and naphthalene, using sulfonyl hydrazides as sulfenylation reagents was carried out. Sulfonothioates, the products of decomposition of sulfonyl hydrazides in the presence of iodine, are proposed as the major sulfenylation species in this transformation.

A new method for phosphine-mediated difluoromethylthiolation of indole derivatives and other electron-rich aromatics including pyrroles, pyrazolones, indolizine, and 1,3,5-trimethoxybenzene was developed using difluoromethanesulfonyl chloride. The additive n-Bu4NI was demonstrated to facilitate this reaction by generating iodine in situ, which could promote this transformation. The use of a transition-metal-free protocol, readily available reagents, and mild reaction conditions makes this protocol more practical than traditional methods.

A novel triphenylphosphine-mediated direct trifluoromethylthiolation of indole derivatives using trifluoromethanesulfonyl chloride as the SCF3 source was developed. Sodium iodide facilitated this transformation by generating iodine in situ which was found to accelerate this transformation. The use of a transition metal-free protocol, readily available reagents, and mild reaction conditions allowed this protocol to be easily scaled up.