Palladium-Catalyzed Enantioselective Intramolecular Heck Dearomative Annulation of Indoles with N-Tosylhydrazones.

An elegant Pd(dba)2-catalyzed enantioselective Heck dearomative annulation of indoles and N-tosylhydrazones for the straightforward assembly of structurally diverse optically active indoline scaffolds containing the quaternary carbon centers at the C2 position has been developed. The tandem protocol, which utilized a Pd(dba)2/BINOL-based phosphoramidite ligand as the catalytic system, proceeded smoothly through successive oxidative addition, intramolecular carbon palladation, migratory insertion, and ß-elimination sequences, leading to the chiral indoline derivatives in moderate to excellent yields, with excellent enantioselectivities and diastereoselectivities. In addition, the synthetic practicability of the catalytic system was underlined by a scaled-up experiment and the late-stage derivatization of the products, thus highlighting the potential applications in synthetic chemistry, medicinal chemistry, and material science.

Lewis Acid Catalyzed [4 + 2] Annulation of Propargylic Alcohols with 2-Vinylanilines.

An elegant Lewis acid catalyzed, protection-free, and straightforward synthetic strategy for the assembly of a series of sophisticated polycyclic quinoline skeletons employing propargylic alcohols and 2-vinylanilines as the substrates in the presence of Yb(OTf)3 (10 mol %) and AgOTf (10 mol %) in tetrahydrofuran has been described. This annulation protocol, which proceeds through a sequential Meyer-Schuster rearrangement/nucleophilic substitution/deprotonation sequence, provides a versatile, practical, and atom-economical approach for accessing quinoline derivatives in moderate-to-good yields.

New synthetic approaches toward OCF3-containing compounds.

Fluorinated organic compounds are an important class of organic molecules and play a key role in both academic and industrial communities due to the unique nature of fluorine. Among the fluorine-containing functional groups, the OCF3 group is of vital importance because of its favorable physicochemical properties, so it frequently acts as the pivotal skeletal motif in a broad spectrum of pharmaceutical molecules, agrochemicals, natural products, and materials. Over the past few decades, a wider range of strategies for the efficient, versatile, and practical synthesis of trifluoromethoxylated compounds have been the focus of a number of research initiatives. These synthesis approaches are especially fascinating in the context of the design of agrochemicals and new drugs as established pathways for installing the OCF3 moiety. In this review, the state of the art of the synthesis of OCF3-containing compounds is summarized. It can be segmented into six categories: (1) de novo formation of the OCF3 group; (2) construction of trifluoromethoxylated compounds via trifluoromethylation of the corresponding alcohol or phenol; (3) construction of trifluoromethoxylated compounds via installing the entire OCF3 group straightaway onto a complex molecule; (4) visible-light-induced trifluoromethoxylation; (5) transition metal-catalyzed trifluoromethoxylation; and (6) construction of the trifluoromethoxylated compounds via rearrangement reactions.

Visible-Light-Induced Oxyalkylation of 1,2,4-Triazine-3,5(2H, 4H)-diones with Ethers via Oxidative Cross-Dehydrogenative Coupling.

An efficient and convenient method to synthesize 6-oxyalkylated 1,2,4-triazine-3,5(2H, 4H)-diones has been developed via visible-light-induced cross-dehydrogenative coupling reaction between 1,2,4-triazine-3,5(2H, 4H)-diones and ethers with a wide range of functional group tolerance. The present transformation employs the cheap and low-toxic 2-tert-butylanthraquinone as a metal-free photocatalyst and air as a green oxidant at room temperature. Moreover, this reaction can also be driven by sunlight as a clean energy resource. The synthetic utility of this method is further demonstrated by gram-scale reaction and application in the preparation of key intermediates of bioactive molecules.

Primary Amination of Ar2P(O)-H with (NH4)2CO3 as an Ammonia Source under Simple and Mild Conditions and Its Extension to the Construction of Various P-N or P-O Bonds.

A facile and efficient method for the synthesis of primary phosphinamides from Ar2P(O)-H reagents with stable and readily available ammonium carbonate as an ammonia source is disclosed herein for the first time. This ethyl bromoacetate-mediated primary amination proceeds smoothly under mild and simple conditions, without any metal catalyst or oxidant. Moreover, this method is also appropriate for the reaction of Ar2P(O)-H with a variety of amines, alcohols, and phenols to construct P-N or P-O bonds, with features of handy operation, good functional group tolerance, and broad substrate scope.

Palladium-Catalyzed Intramolecular Heck Dearomative Alkenylation of Indoles with N-Tosylhydrazones.

An elegant Pd-catalyzed intramolecular Heck dearomative alkenylation of aryl iodides with functionalized N-tosylhydrazones proceeded through a sequential dearomative carbopalladation, migratory insertion, and ß-hydride elimination in the presence of Pd(CF3COO)2 (10 mol %), PPh3 (30 mol %), and Cs2CO3 (2.0 equiv) in 1,4-dioxane (2.0 mL) at 120 °C for 14 h under an argon atmosphere. This cascade cycloaddition protocol provided a reliable and versatile approach to a sequence of structurally diverse indolines in moderate to good yields with good functional group compatibility. In addition, the synthetic robustness of the methodology is highlighted by a scaled-up experiment and derivatization of products via epoxidation and reduction reactions.

Palladium-Catalyzed Asymmetric Intramolecular Dearomative Heck Annulation of Aryl Halides to Furnish Indolines.

An unprecedented Pd-catalyzed asymmetric intramolecular cascade cyclization of aryl halides with readily available arylboronic acids proceeds through a Heck-type dearomative cyclization terminated with arylation in the presence of Pd2(dba)3 (10 mol %), Cu2O (5 mol %), and Cs2CO3 (2.0 equiv) in 1,2-dichloroethane (1.0 mL) at 100 °C for 15 h in air using BINOL-based phosphoramidite as the chiral ligand. This dearomative Heck protocol, which tolerates a broad variety of functional groups, is amenable to the generation of optically active indoline derivatives bearing all-carbon quaternary stereogenic centers in one step in moderate to excellent yields, with excellent diastereoselectivities (>20:1) and enantioselectivities (up to >99% ee). It is worth mentioning that no decrease in the enantiopurity of the indoline derivatives was observed during the synthetic transformations of the products.

Visible-Light-Induced C(sp2)-C(sp3) Cross-Dehydrogenative-Coupling Reaction of N-Heterocycles with N-Alkyl-N-methylanilines under Mild Conditions.

Disclosed herein is a cross-dehydrogenative-coupling reaction of N-heterocycles including 1,2,4-triazine-3,5(2H, 4H)-diones and quinoxaline-2(1H)-ones with N-methylanilines to form C(sp2)-C(sp3) under visible-light illumination and ambient air at room temperature. In this process, easily available Ru(bpy)3Cl2·6H2O serves as the catalyst, and air acts as the green oxidant. This method features high atom economy, environmental friendliness, and convenient operation and provides an efficient and practical access to aminomethyl-substituted N-heterocycles with extensive functional group compatibility in 40-86% yields.

Synthesis of 1,6-Dihydropyridine-3-carbonitrile Derivatives via Lewis Acid-Catalyzed Annulation of Propargylic Alcohols with (E)-3-Amino-3-phenylacrylonitriles.

A novel Lewis acid-catalyzed, highly efficient, practical, and atom-economical protocol for the synthesis of functionalized 1,2-dihydropyridine-3-carbonitrile derivatives in the presence of Bi(OTf)3 (10 mol %) in tetrahydrofuran (2.0 mL) at 80 °C for 8 h in air is described, starting from readily accessed propargylic alcohols and (E)-3-amino-3-phenylacrylonitriles. This cycloaddition protocol, which is scalable and proceeds under mild conditions, is amenable to the gram-scale construction of valuable 1,2-dihydropyridine-3-carbonitriles. Furthermore, the good functional group compatibility and broad scope of this strategy were demonstrated by a broad range of propargylic alcohols and (E)-3-amino-3-phenylacrylonitriles, with yields ranging from 34 to 96%.

Silver Trifluoromethanesulfonate-Catalyzed Annulation of Propargylic Alcohols with 3-Methyleneisoindolin-1-one.

A silver-catalyzed formal [3 + 3] annulation of 3-methyleneisoindolin-1-one with alkynol for the synthesis of 1,5-dihydroindolizin-3(2H)-one derivatives is disclosed. The protocol allows practical synthesis of N-heterocyclic scaffolds with a broad scope of functional groups and could be efficiently scaled up to gram scale, which incarnates a potential application of this methodology. In addition, a range of chlorine anion substitution of alkenes can be constructed by adjusting the structure of the alkynol substrates with the use of TMSCl.

Copper-Catalyzed Oxidative Cyclization of Alkynes with Sulfonylhydrazides Leading to 2-Sulfonated 9H-pyrrolo[1,2-a]indol-9-ones.

A copper-catalyzed oxidative cyclization procedure has been developed for the production of 2-sulfonated 9H-pyrrolo[1,2-a]indol-9-ones via the direct sulfonylation of N-propargyl-substituted indoles with sulfonylhydrazides and tert-butyl hydroperoxide (TBHP). This novel protocol, which tolerates a broad range of functional groups, offers a simple, efficient, and atom-economical route to a series of fluorazones in good yields under mild conditions.

Synthesis of Organophosphorus Compounds through Copper-Catalyzed Annulation Involving C-O and C-P Bond Formations.

A novel copper(II) trifluoromethanesulfonate-catalyzed, high-efficiency, and atom-economical synthesis of valuable organophosphorus compounds via cascade annulation of propargylic alcohols with diphenylphosphine oxide is described. This protocol, which has a good functional-group compatibility and insensitivity to an ambient atmosphere, provides a simple and direct pathway to the products, organophosphorus compounds, in good yields under mild conditions. The method could be efficiently scaled up to gram scale, thus highlighting a potential application of this methodology.

Lewis Acid Catalyzed Dehydrogenative Coupling of Tertiary Propargylic Alcohols with Quinoline N-Oxides.

An unprecedented Lewis acid catalyzed, high-efficiency synthesis of valuable 2-(quinolin-2-yl)prop-2-en-1-ones via dehydrogenative coupling of propargylic alkynols with quinoline N-oxides is described. This protocol, which tolerates a broad range of functional groups, provides a straightforward pathway to the products 2-(quinolin-2-yl)prop-2-en-1-one scaffolds in satisfactory yields. The conversion could be scaled up to gram scale efficiently, which underlines a latent application of this methodology.

Genetic variations in vitamin D receptor were associated with the outcomes of hepatitis C virus infection among Chinese population.

Vitamin D has been considered as an immune modulator, and exerted the effect through the vitamin D receptor (VDR). This study investigated the associations of single-nucleotide polymorphisms (SNPs) of VDR with the outcomes of Hepatitis C virus (HCV) infection. Three SNPs (rs2228570, rs757343 and rs739837) were genotyped by TaqMan assay among Chinese population, including 538 HCV spontaneous clearance subjects, 834 persistent infection subjects and 1030 uninfected subjects. Binary logistic analyses were used to control the effects of confounding factors. The results showed that subjects with the rs757343 A allele and rs739837 A allele had the significantly reduced risk of HCV susceptibility (all PBonferroni<0.05 in dominant/additive model). In the stratified analysis, the protection of rs757343 A allele and rs739837 A allele against HCV infection remained effective in some subgroups. In addition, patients carrying rs739837 CA genotype were less prone to develop persistent infection (PBonferroni=0.033) and such effect still work in several subgroups in the stratified analysis. Furthermore, haplotype analysis indicated that when compared with the most frequent GC haplotype, the haplotype carrying AA (odds ratio (OR)=0.66, 95% confidence interval (CI)=0.56-0.78) and GA (OR=0.64, 95% CI=0.47-0.85) suggested a protective effect. Our findings indicated that the polymorphisms of VDR are associated with the outcomes of HCV infection among Chinese population.

Convenient and highly efficient routes to 2 H-chromene and 4-chromanone derivatives: iodine-promoted and p-toluenesulfonic acid catalyzed cascade cyclizations of propynols.

A convenient strategy is presented for the easy preparation of a series of 2 H-chromenes under mild conditions through iodocyclization of readily accessible propynols. In addition, various 4-chromanones can be synthesized through a p-toluenesulfonic acid catalyzed cascade cyclization with high efficiency (yields up to 99 %). Our developed reaction systems are proven to have good functional-group applicability and can be scaled up to gram quantities in satisfactory yields. These systems also provide a new synthetic strategy for two types of important flavonoid skeleton without using costly and toxic metal catalysts. Additionally, the resulting halides could be further exploited in subsequent palladium-catalyzed coupling reactions, so these compounds could act as potential intermediates for the construction of some valuable drug molecules.

Lewis Acid Mediated Tandem Reaction of Propargylic Alcohols with Hydroxylamine Hydrochloride To Give α,ß-Unsaturated Amides and Alkenyl Nitriles.

We have developed a highly selective method for the synthesis of α,ß-unsaturated amides and alkenyl nitriles from readily available propargylic alcohols. The reaction proceeded smoothly under the neutral conditions with hydroxylamine hydrochloride (NH2OH·HCl) as the nitrogen source. The development of these new strategies has significantly extended the application of hydroxylamine hydrochloride to the chemistry of propargylic alcohols. Moreover, both secondary and tertiary alcohols have been highly regioselectively transformed to the desired products with good functional group compatibility.

BF3·Et2O-promoted cleavage of the Csp-Csp2 bond of 2-propynolphenols/anilines: route to C2-alkenylated benzoxazoles and benzimidazoles.

A novel BF3·Et2O-promoted tandem reaction of easily prepared 2-propynolphenols/anilines and trimethylsilyl azide is developed to give C2-alkenylated benzoxazoles and benzimidazoles in moderate to good yields. Most reactions could be accomplished in 30 min at room temperature. This tandem process involves a Csp-Csp2 bond cleavage and a C-N bond formation. Moreover, both tertiary and secondary propargylic alcohols with diverse functional groups were tolerated under the mild conditions.

Human Leukocyte Antigen Class II Alleles Are Associated with Hepatitis C Virus Natural Susceptibility in the Chinese Population.

Human leukocyte antigen (HLA) class II molecule influences host antigen presentation and anti-viral immune response. The aim of this study was to investigate whether single nucleotide polymorphisms (SNPs) within HLA class II gene were associated with different clinical outcomes of hepatitis C virus (HCV) infection. Three HLA class II SNPs (rs3077, rs2395309 and rs2856718) were genotyped by TaqMan assay among Chinese population, including 350 persistent HCV infection patients, 194 spontaneous viral clearance subjects and 973 HCV-uninfected control subjects. After logistic regression analysis, the results indicated that the rs2856718 TC genotype was significantly associated with the protective effect of the HCV natural susceptibility (adjusted OR: 0.712, 95% CI: 0.554-0.914) when compared with reference TT genotype, and this remained significant after false discovery rate (FDR) correction (p = 0.024). Moreover, the protective effect of rs2856718 was observed in dominant genetic models (adjusted OR: 0.726, 95% CI: 0.574-0.920), and this remained significant after FDR correction (p = 0.024). In stratified analysis, a significant decreased risk was found in rs2856718C allele in the male subgroup (adjusted OR: 0.778, 95% CI: 0.627-0.966) and hemodialysis subgroup (adjusted OR: 0.713, 95% CI: 0.552-0.921). Our results indicated that the genetic variations of rs2856718 within the HLA-DQ gene are associated with the natural susceptibility to HCV infection among the Chinese population.

Lewis acid mediated tandem reaction of propargylic alcohols to tetrazoles involving C-O- and C-C-bond cleavage reactions and a C-N-bond formation.

A novel and direct synthesis of 1-aryl-5-arylvinyl-tetrazoles from easily prepared propargylic alcohols and TMSN3 is developed in the presence of TMSCl under mild conditions (TMS = trimethylsilyl). The process involves an allenylazide intermediate, followed by a C-C-bond cleavage and C-N-bond formation to afford the desired products. Moreover, this method offers a good functional-group applicability and can be scaled-up to grams (yield up to 85 %).

TMSCl-mediated synthesis of α,ß-unsaturated amides via C-C bond cleavage and C-N bond formation of propargyl alcohols with trimethylsilyl azide.

A new method with high efficiency for the synthesis of α,ß-unsaturated amides from the easily prepared propargyl alcohols and TMSN3 using TMSCl as an acid promoter is developed. A wide variety of α,ß-unsaturated amides were produced in moderate to excellent yields. Mechanistic studies indicate that this transformation involves TMSCl-mediated allenylazide intermediate formation, C-C bond cleavage, and C-N bond formation. Significantly, this reaction shows good functional group compatibility and high regioselectivity, with a relatively short reaction time and inexpensive reagents.