A Practical and Regioselective Strategy for Aromatic C-H Difunctionalization via Site-Selective C-H Thianthrenation.

Herein, we present a novel Catellani-type reaction that employed aryl-thianthrenium salts as aryl substrates to trigger the subsequent palladium/norbornene cooperatively catalyzed progress. This strategy can achieve site-selective C-H difunctionalization of aryl compounds without directing groups or a known initiating reagent. A series of functionalized syntheses of bioactive molecules further demonstrated the potential of this strategy.

Ortho C-H Hydroxyalkylation or Methylation of Aryl Iodides by Ethers and TMSI via a Catellani Strategy.

In this paper, in the presence of trimethylsilyl iodide, the direct ortho-C-H hydroxyalkylation/methylation of aryl iodines was effectively realized via palladium/norbornene cooperative catalysis when low-cost tetrahydrofuran and 1,2-dimethoxyethane were used as alkyl sources. Heck, Suzuki, and Sonogashira coupling and hydrogenation were all compatible with the reaction as termination steps. In addition, neuromuscular agents and cardiovascular agents were synthesized in one step by this method, showing their potential application value.

Copper-Catalyzed Hydrogen Atom Transfer and Aryl Migration Strategy for the Arylalkylation of Activated Alkenes.

Herein, we describe the copper-catalyzed arylalkylation of activated alkenes via hydrogen-atom transfer and aryl migration strategy. The reaction was carried out through a radical-mediated continuous migration pathway using N-fluorosulfonamides as the alkyl source. The primary, secondary, and tertiary alkyl radicals formed by intramolecular hydrogen-atom transfer proceeded smoothly. This methodology is an efficient approach for the synthesis of various amide derivatives possessing a quaternary carbon center with good yields and high regioselectivity.

Site-selective coupling of remote C(sp3)-H/meta-C(sp2)-H bonds enabled by Ru/photoredox dual catalysis and mechanistic studies.

Construction of C(sp2)-C(sp3) bonds via regioselective coupling of C(sp2)-H/C(sp3)-H bonds is challenging due to the low reactivity and regioselectivity of C-H bonds. Here, a novel photoinduced Ru/photocatalyst-cocatalyzed regioselective cross-dehydrogenative coupling of dual remote C-H bonds, including inert γ-C(sp3)-H bonds in amides and meta-C(sp2)-H bonds in arenes, to construct meta-alkylated arenes has been accomplished. This metallaphotoredox-enabled site-selective coupling between remote inert C(sp3)-H bonds and meta-C(sp2)-H bonds is characterized by its unique site-selectivity, redox-neutral conditions, broad substrate scope and wide use of late-stage functionalization of bioactive molecules. Moreover, this reaction represents a novel case of regioselective cross-dehydrogenative coupling of unactivated alkanes and arenes via a new catalytic process and provides a new strategy for meta-functionalized arenes under mild reaction conditions. Density functional theory (DFT) calculations and control experiments explained the site-selectivity and the detailed mechanism of this reaction.

Three-Component Ru-Catalyzed Regioselective Alkylarylation of Vinylarenes via Meta-Selective C(sp2)-H Bond Functionalization.

We report a novel Ru-catalyzed regioselective alkylarylation of vinylarenes with alkyl halides and arenes via meta-C(sp2)-H bond functionalization to construct 1,1-diarylalkanes that generally show bioactivity. In this transformation, a wide spectrum of primary, secondary, and tertiary alkyl halides and electronically varied arenes was well-tolerated. This reaction is characterized by its exquisite regioselectivity of vinylarenes, unique meta-C(sp2)-H selectivity, and redox-neutral conditions. The mechanism presented was supported by radical probes and kinetic isotope effect studies.

Lewis-Acid-Catalyzed Tandem Cyclization by Ring Expansion of Tertiary Cycloalkanols with Propargyl Alcohols.

A new method for the efficient synthesis of hexahydro-1H-fluorene and octahydrobenzo[a]azulene derivatives through a ring-expansion strategy is reported. With an appropriate combination of thulium(III) trifluoromethanesulfonate and 13X molecular sieves, a range of unsaturated polycyclic compounds were obtained in good yields. Mechanism studies reveal that the reaction is more likely to undergo Meyer-Schuster rearrangement, ring expansion, and Friedel-Crafts-type pathways, which provide a conceptually different strategy for the ring opening of tertiary cycloalkanols.

Copper-Catalyzed Direct Allenylation of Inactive Cyclic Ethers.

We report here a direct allenylation reaction of inactive cyclic ethers. The reaction proceeds through a copper-catalyzed 1,4-difunctionalization of 1,3-enynes, with cyano group installed at the allenes simultaneously. This methodology shows a broad functional group compatibility to 1,3-enynes. Diversified allene-modified cyclic ether derivatives were synthesized with high regioselectivity under mild conditions.

Highly regioselective and stereoselective synthesis of C-Aryl glycosides via nickel-catalyzed ortho-C-H glycosylation of 8-aminoquinoline benzamides.

C-Aryl glycosides are of high value as drug candidates. Here a novel and cost-effective nickel catalyzed ortho-CAr-H glycosylation reaction with high regioselectivity and excellent α-selectivity is described. This method shows great functional group compatibility with various glycosides, showing its synthetic potential. Mechanistic studies indicate that C-H activation could be the rate-determining step.

Cu-Catalyzed Direct C-H Alkylation of Polyfluoroarenes via Remote C(sp3)-H Functionalization in Carboxamides.

A novel dehydrogenative coupling reaction of N-fluorocarboxamides with polyfluoroarenes forming C(sp2)-C(sp3) bonds enabled by copper catalysis has been accomplished. N-Fluorocarboxamides are postulated to undergo copper-mediated dehydrogenative cross-coupling reaction with electron-deficient polyfluoroarenes via a radical pathway. Benzylic C-H bonds and aliphatic C-H bonds in N-fluorocarboxamides could proceed smoothly and demonstrated excellent regioselectivity. The detailed mechanism presented is supported by control experiments and density functional theory calculations.

Formation of o-Allyl- and Allenyl-Modified Amides via Intermolecular Claisen Rearrangement.

We developed a new transition-metal-free intermolecular Claisen rearrangement process to introduce allyl and allenyl groups into the α position of tertiary amides. In this transformation, amides were activated by trifluoromethanesulfonic anhydride to produce the keteniminium ion intermediates that exhibit strong electrophilic activity. This atom-economical process delivers α position-modified amides under mild conditions in moderate to good yields and showcases a broad substrate compatibility.

Gold-Catalyzed Tandem Annulations of Pyridylhomopropargylic Alcohols with Propargyl Alcohols.

A gold-catalyzed tandem annulation of propargylic alcohols and pyridylhomopropargylic alcohols is achieved, providing an atom-economical approach to a diverse set of polycyclic dihydrobenzofurans in good yields. The reaction proceeds via the 5-endo-dig cyclization/Meyer-Schuster rearrangement/Friedel-Crafts-type pathway. In this way, three C-C bonds and one C-O bond form to give a polycyclic skeleton in a one-pot process. Moreover, the products exhibit unique optical properties, which reveal their potential application value.

Three-component ruthenium-catalyzed remote C-H functionalization of 8-aminoquinoline amides.

Multicomponent reactions can efficiently construct complex molecular structures from simple precursors. Herein, a novel ruthenium-catalyzed three-component highly selective remote C-H functionalization of 8-aminoquinoline amides has been described. The reaction tolerates a wide range of functional groups, producing arylation/difluoroalkylation products of olefins with potential biological activity and pharmaceutical value. Radical scavenging and radical clock experiments show that a free radical process is involved and a H/D exchange experiment suggests that the reaction might involve ortho-C-H activation of the aromatic ring. A possible mechanism is proposed.

Organocatalyzed Synthesis of Functionalized Quinolines.

As one of the most widely investigated compound skeleton, quinolines possess important medicinal and biological activities. As such, a great number of literatures, including reviews, have reported various methodologies to construct quinolines. Recently, organocatalyzed reactions have attracted the attention of organic chemists due to its being "green" because the reactions avoid the use of toxic metals. In this review, various distinctive contributions are surveyed with specific emphasis on organocatalyzed reactions for quinoline core constructions.

New Friedel-Crafts strategy for preparing 3-acylindoles.

A selective Friedel-Crafts acylation of indoles via an unusual cleavage of the amide C-N bond was achieved by triflic anhydride activation. This method offers rapid efficient access to high-biological-value 3-acylindoles, performs a series of scrupulous mechanistic studies and offers a strong courage that amide synthons can form new C-C bonds under transition-metal-free conditions.

Transition-metal-free multinitrogenation of amides by C-C bond cleavage: a new approach to tetrazoles.

A metal-free brand-new one-pot multinitrogenation of amides for the chemo- and regioselective synthesis of 1,5-disubstituted tetrazoles has been developed. By means of electrophilic amide activation, and further C-C bond cleavage and rearrangement, a diverse set of functionalized 1,5-DST derivatives were selectively constructed under mild conditions. As showcased in the mechanisms, the chemoselectivity is easily switched by the selection of the starting materials in the reaction.

Wnt signaling pathway involvement in genotypic and phenotypic variations in Waardenburg syndrome type 2 with MITF mutations.

Mutation in the gene encoding microphthalmia-associated transcription factor (MITF) lead to Waardenburg syndrome 2 (WS2), an autosomal dominantly inherited syndrome with auditory-pigmentary abnormalities, which is clinically and genetically heterogeneous. Haploinsufficiency may be the underlying mechanism for WS2. However, the mechanisms explaining the genotypic and phenotypic variations in WS2 caused by MITF mutations are unclear. A previous study revealed that MITF interacts with LEF-1, an important factor in the Wnt signaling pathway, to regulate its own transcription through LEF-1-binding sites on the MITF promoter. In this study, four different WS2-associated MITF mutations (p.R217I, p.R217G, p.R255X, p.R217del) that are associated with highly variable clinical features were chosen. According to the results, LEF-1 can activate the expression of MITF on its own, but MITF proteins inhibited the activation. This inhibition weakens when the dosage of MITF is reduced. Except for p.R217I, p.R255X, p.R217G, and p.R217del lose the ability to activate TYR completely and do not inhibit the LEF-1-mediated activation of the MITF-M promoter, and the haploinsufficiency created by mutant MITF can be overcome; correspondingly, the mutants' associated phenotypes are less severe than that of p.R217I. The dominant negative of p.R217del made it have a second-most severe phenotype. This study's data imply that MITF has a negative feedback loop of regulation to stabilize MITF gene dosage that involves the Wnt signaling pathway and that the interaction of MITF mutants with this pathway drives the genotypic and phenotypic differences observed in Waardenburg syndrome type 2 associated with MITF mutations.

Functional analysis of a SOX10 gene mutation associated with Waardenburg syndrome II.

Waardenburg syndrome (WS) is an autosomal dominant inherited non-syndromic type of hereditary hearing loss characterized by varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. WS is classified into four subtypes (WS1-WS4) based on additional symptoms. WS2 is characterized by the absence of additional symptoms. Recently, we identified a SOX10 missense mutation c.422T > C (p.L141P) associated with WS2. We performed functional assays and found the mutant loses DNA-binding capacity, shows aberrant cytoplasmic and nuclear localization, and fails to interact with PAX3. Therefore, the mutant cannot transactivate the MITF promoter effectively, inhibiting melanin synthesis and leading to WS2. Our study confirmed haploinsufficiency as the underlying pathogenesis for WS2.

Synthesis of Functionalized Quinolines through a Reaction of Amides and Alkynes Promoted by Triflic Anhydride/Pyridine.

A concise, novel and flexible metal-free single step to synthesize functionalized quinolines is reported. Triflic anhydride-mediated (Tf2 O) activation of amides is discussed in the presence of pyridine to offer strong electrophiles, thereby showcasing excellent productivity, high regio- and chemoselectivity, and widely tolerable substrates. This approach provides a straightforward and efficient way to construct azaheterocycle structures.

The Value of Tumor Diameter in Predicting Prognosis of Nasopharyngeal Carcinoma Treated with Intensity-Modulated Radiotherapy.

Objective The tumor, node, and metastasis staging system of nasopharyngeal carcinoma (NPC) has limitations in predicting prognosis. The aim of this study was to explore the prognostic value of tumor diameter for patients with NPC who were treated with intensity-modulated radiotherapy. Study Design Case series with chart review. Setting Affiliated Cancer Hospital of Guangxi Medical University. Subjects and Methods The cases of 137 NPC patients treated with intensity-modulated radiotherapy were retrospectively reviewed. Tumor diameter was measured on pretreatment magnetic resonance images. Receiver operating characteristic curve was used to find the optimal cutoff value of tumor diameter and to examine the predictive ability of tumor diameter combined with T classification. Results The mean tumor diameter increased with the advancing of T classification. The 5-year cumulative survival rates for patients with a tumor diameter <43 mm vs ≥43 mm were 88.4% vs 61.8% ( P < .001), respectively. In multivariate analysis, tumor diameter was an independent prognostic factor for 5-year cumulative survival. For patients with T3 + T4, the 5-year cumulative survival rate was higher in the group with a tumor diameter <43 mm vs ≥43 mm (86.2% vs 60.2%, P = .022). The area under the receiver operating characteristic curve was 70.3% for tumor diameter combined with T classification, superior to T classification (area under the curve = 66.2%). Conclusion Tumor diameter may be related to the extent of tumor invasion and can provide important information on prognosis. The incorporation of 43 mm as a cutoff value of tumor diameter may help to refine the predictive power of the current staging system for NPC.

Recommendations for Updating T and N Staging Systems for Nasopharyngeal Carcinoma in the Era of Intensity-Modulated Radiotherapy.

OBJECTIVE: The aim of this study was to compare the 2008 Chinese and the 7th edition of the American Joint Committee on Cancer (AJCC) staging systems for nasopharyngeal carcinoma and to provide proposals for updating T and N staging systems of the present staging system. METHODS: Between January 2007 and December 2012, a cohort of 752 patients with biopsy-proven, newly diagnosed, non-metastatic nasopharyngeal carcinoma who were treated with intensity-modulated radiotherapy were retrospectively analysed. Prognoses were compared by T stage, N stage, and clinical stage according to the two staging systems for overall survival (OS), local relapse-free survival (LRFS), and distant metastasis-free survival (DMFS). RESULTS: In terms of both the T and N staging systems, the two current staging systems were comparable in predicting OS. The T classification of the 2008 Chinese staging system was better in predicting LRFS, while the N classification of the 7th edition AJCC staging system was superior in predicting DMFS. In the modern era of intensity-modulated radiotherapy, the staging system should be updated by down-staging the current stage T2 to T1, and it might be rational to merge subcategories N1 and N2. CONCLUSIONS: The two current staging systems each had advantages in predicting prognosis. It seems reasonable to downstage T2 to T1 and to merge N1 and N2.