SN2 Reaction at the Amide Nitrogen Center Enables Hydrazide Synthesis.

Nucleophilic substitutions are fundamentally important transformations in synthetic organic chemistry. Despite the substantial advances in bimolecular nucleophilic substitutions (SN2) at saturated carbon centers, analogous SN2 reaction at the amide nitrogen atom remains extremely limited. Here we report an SN2 substitution method at the amide nitrogen atom with amine nucleophiles for nitrogen-nitrogen (N-N) bond formation that leads to a novel strategy toward biologically and medicinally important hydrazide derivatives. We found the use of sulfonate-leaving groups at the amide nitrogen atom played a pivotal role in the reaction. This new N-N coupling reaction allows the use of O-tosyl hydroxamates as electrophiles and readily available amines, including acyclic aliphatic amines and saturated N-heterocycles as nucleophiles. The reaction features mild conditions, broad substrate scope (>80 examples), excellent functional group tolerability, and scalability. The method is applicable to late-stage modification of various approved drug molecules, thus enabling complex hydrazide scaffold synthesis.

Photo-Triggered, Copper(II) Chloride-Catalyzed Radical Hydroalkylation and Hydrosilylation of Vinylboronic Esters To Access Alkylboronic Esters.

Alkyl boronic acids and their derivatives constitute vital building blocks in organic synthesis and are important motifs identified in medicinal chemistry. Herein, we present a phototriggered, CuCl2-catalyzed radical hydroalkylation and hydrosilylation of vinylboronic esters to alkylboronic esters. This approach exhibits mild reaction conditions, utilization of easily accessible reagents, and scalability up to a gram scale. Further synthetic transformations of the hydrosilylation products and mechanistic studies are also demonstrated.

Phosphine-Promoted Tandem Intermolecular Diels-Alder Reactions with Pentadienyl 4-Nitrobenzoate as a Diene Precursor.

A phosphine-promoted tandem Diels-Alder reaction using pentadienyl 4-nitrobenzoate (α-vinyl MBH adduct) as a diene precursor with 3-olefinic oxindoles or CF3-activated ketones as dienophiles has been developed. The reaction proceeds through the formation of a pentadienyl phosphonium intermediate via SN2'' addition, which acts as both a D-A diene and a precursor for the exomethylene moiety. This method offers a metal-free and step-efficient approach for synthesizing exomethylene-bearing spirooxindoles and dihydropyrans, which are privileged structures found in natural products.

Photoinduced C(sp3)-H borylation of alkanes mediated by copper(II) chloride.

Alkyl boronic acid and its derivatives are important motifs in organic synthesis and pharmaceuticals. Herein, we report a photoinduced, CuCl2 mediated C(sp3)-H borylation of unactivated alkanes. This protocol features mild reaction conditions, readily available reagents, and gram-scalability.

Modular and practical diamination of allenes.

Vicinal diamines are privileged scaffolds in medicine, agrochemicals, catalysis, and other fields. While significant advancements have been made in diamination of olefins, diamination of allenes is only sporadically explored. Furthermore, direct incorporation of acyclic and cyclic alkyl amines onto unsaturated π systems is highly desirable and important, but problematic for many previously reported amination reactions including the diamination of olefins. Herein, we report a modular and practical diamination of allenes, which offers efficient syntheses of ß,γ-diamino carboxylates and sulfones. This reaction features broad substrate scope, excellent functional group tolerability, and scalability. Experimental and computational studies support an ionic reaction pathway initiated with a nucleophilic addition of the in situ formed iodoamine to the electron deficient allene substrate. An iodoamine activation mode via a halogen bond with a chloride ion was revealed to substantially increase the nucleophilicity of the iodoamine and lower the activation energy barrier for the nucleophilic addition step.

Chemoselective tandem SN2'/SN2''/inter- or intramolecular Diels-Alder reaction of γ-vinyl MBH carbonates with phenols and o-hydroxychalcones.

An unprecedented consecutive SN2'/SN2'' addition of phenol to γ-vinyl MBH carbonate forms a reactive diene intermediate, followed by a dimerization/elimination process to give functionalized exocyclohexenes with excellent chemoselectivity. When using o-hydroxychalcones as pronucleophiles, an SN2'/SN2''/intramolecular Diels-Alder reaction sequence occurs, selectively producing a series of pharmaceutically intriguing tricyclic chromane derivatives with good diastereoselectivity. The good nucleophilicity and fair nucleofugicity exhibited by phenoxy anion play a pivotal role in the SN2'' addition step.

Electrochemical Trifluoromethylation of Thiophenols with Sodium Trifluoromethanesulfinate.

We developed an electrochemical trifluoromethylation of thiophenols without the use of metal catalysts and oxidants. This reaction features mild reaction conditions, readily available substrate, as well as moderate to good yields. In addition, this protocol can be easily scaled up with moderate efficiency.

Electrochemical Oxidative Esterification of Thiophenols: Efficient Access to Sulfinic Esters.

BACKGROUND: The sulfinic esters are important and useful building blocks in organic synthesis. OBJECTIVE: The aim of this study was to develop a simple and efficient method for the synthesis of sulfinic esters. MATERIALS AND METHODS: Constant current electrolysis from thiols and alcohols was selected as the method for the synthesis of sulfinic esters. RESULTS AND DISCUSSION: A novel electrochemical method for the synthesis of sulfinic esters from thiophenols and alcohols has been developed. Up to 27 examples of sulfinic esters have been synthesized using the current methods. This protocol shows good functional group tolerance as well as high efficiency. In addition, this protocol can be easily scaled up with good efficiency. Notably, heterocycle-containing substrates, including pyridine, thiophene, and benzothiazole, gave the desired products in good yields. A plausible reaction mechanism is proposed. CONCLUSION: This research not only provides a green and efficient method for the synthesis of sulfinic esters but also shows new applications of electrochemistry in organic synthesis. It is considered that this green and efficient synthetic protocol used to prepare sulfinic esters will have good applications in the future.

Photocatalytic site-selective C-H difluoroalkylation of aromatic aldehydes.

The direct photocatalyzed para-selective CAr-H difluoroalkylation of aromatic aldehyde derivatives has been accomplished using a newly explored catalytic system. In addition, when using para-substituted benzaldehydes as substrates, ortho-selective CAr-H difluoroalkylation was also accomplished. It is worth noting that all the above site-selectivity is opposite to traditional Friedel-Crafts reactions of aromatic aldehydes. The preliminary mechanistic investigations indicate that an electrophilic difluoroalkyl radical is involved in the catalytic cycle.

Endoscopic treatment for choledocholithiasis in asymptomatic patients.

BACKGROUND AND AIM: A few small retrospective studies recently found that endoscopic retrograde cholangiopancreatography (ERCP) in asymptomatic compared with symptomatic common bile duct stones (CBDSs) patients appeared to increase the risk of post-ERCP pancreatitis (PEP). This study aimed to determine the risk of ERCP in asymptomatic CBDS patients. METHODS: A total of 327 consecutive patients with native papilla were invited to participate into the study and divided into two groups: 53 in the asymptomatic group and 274 in the symptomatic group, who underwent CBDS removal by ERCP. Patient's characteristics and outcomes were analyzed. RESULTS: A total of 46 (14.1%) patients had ERCP-related complications, including PEP, cholangitis, perforation, and bleeding. The overall complication rate in the asymptomatic group was higher than in the control group (26.4% vs 11.7%, P < 0.01). PEP was the most common complication (30/327, 9.2%). Of the 30 cases of PEP, 25 (83.3%) were mild, and the severity in both groups was similar (9/1/1 vs 16/2/1, P > 0.05). The incidence rate of PEP in the asymptomatic group was higher than in the symptomatic group (20.8% vs 6.9%, P < 0.01). Multivariate regression analysis identified asymptomatic CBDSs (odds ratio = 0.241, 95% confidence interval: 0.092-0.628) as being independently associated with PEP occurrence. CONCLUSION: Asymptomatic CBDSs were associated with increased incidence of PEP compared with symptomatic CBDSs.

Endoscopic papillary large balloon dilation with minor sphincterotomy for periampullary diverticular papilla.

Background To observe the outcome of endoscopic papillary large balloon dilation (EPLBD) with minor sphincterotomy (mEST) for periampullary diverticular papilla related to stone removal. Methods Patients with confirmed periampullary diverticulum (PAD) during stone removal from May 2016 to April 2018 were reviewed retrospectively. The Chi-square test with Yates correction or Fisher's exact test was used for the analysis of categorical data and a normality test was applied for continuous data. Results A total of 154 consecutive patients (89 males and 65 females, aged 51-87 years) with confirmed PAD during stone removal were included in the study. Cases were divided into the conventional EST group (n = 79) and the mEST plus EPLBD group (n = 75). The number of patients with an initial treatment success was greater in the EPLBD+mEST group compared with the EST group (96% vs 86.1%, p=0.03) and the procedure time for EPLBD+mEST was shorter than that for EST alone (46.1±13.7 min vs 53.3±11.6 min, p=0.01). The rate of complications in the EPLBD+mEST group was lower than in the EST group (17.3% vs 32.9%, p=0.04). When PAD was >15 mm, the initial success rate was higher (92.6% vs 73.9%, p=0.04) and the rate of overall complications was lower (14.8% vs 41.7%, p=0.03) in the EPLBD+mEST group than those in the EST group. Although, this was similar when PAD was <15 mm. Conclusion EPLBD+mEST might be safer and more effective than conventional EST alone for stone removal in the presence of PAD.

Optimizing treatment of DNA methyltransferase inhibitor RG108 on porcine fibroblasts for somatic cell nuclear transfer.

Aberration in DNA methylation is believed to be one of the major causes of abnormal gene expression and inefficiency of somatic cell nuclear transfer (SCNT). RG108, a non-nucleoside DNA methyltransferase (DNMT) inhibitor, has been reported to facilitate somatic nuclear reprogramming and improved blastocyst formation. The aim of this study was to investigate interaction effect of RG108 treatment time (24-72 hr) and concentrations (0.05-50 µM) on donor cells, and further to optimize the treatment for porcine SCNT. Our results showed that RG108 treatment resulted in time-dependent decrease of genome-wide DNA methylation on foetal fibroblasts, which only happened after 72-hr treatment in our experiments, and no interaction effect between treatment time and concentration. Remarkable decrease of methylation in imprinted gene H19 and increased apoptosis was observed in 5 and 50 µM RG108-treated cells. Furthermore, the blastocyst rates of SCNT embryos were increased as the fibroblasts treated with RG108 at 5 and 50 µM, and additional treatment during cultivation of SCNT embryos would not provide any advantage for blastocyst formation. In conclusion, the RG108 treatment of 72 hr and 5 µM would be optimized time and concentration for porcine foetal fibroblasts to improve the SCNT embryonic development. In addition, combined treatment of RG108 on donor cells and SCNT embryos would not be beneficial for embryonic development.

Electrochemical synthesis of 1,2-diketones from alkynes under transition-metal-catalyst-free conditions.

We report an electrochemical protocol for the direct oxidation of internal alkynes in air to provide 1,2-diketones. A variety of functional groups and heterocycle-containing substrates can be tolerated well under mild conditions.

Irradiation-Induced Cobaloxime-Catalyzed C-H Monofluoroalkylation of Styrenes at Room Temperature.

A cobaloxime-catalyzed photochemical synthesis of allyl monofluorides from styrenes is described herein. This method is characterized by mild reaction conditions, low-cost catalyst, and broad substrate scope. Furthermore, this convenient method will provide a facile synthesis toward novel monofluoroalkylated natural product and pharmaceutical derivatives. Mechanistic investigations indicate that a monofluoroalkyl radical is involved in the catalytic cycle.

Apoptosis and developmental capacity of vitrified parthenogenetic pig blastocysts.

This study was conducted to evaluate whether the poor developmental capacity of pig embryos after vitrification was related to the occurrence of apoptosis. Parthenogenetic blastocysts were used as the research material. The blastocoel recovery rate, mitochondrial membrane potential (ΔΨm), amount of early apoptosis, activities of several caspases, and relative abundance of mRNA of apoptosis-related genes involved in mitochondria and death receptor apoptotic pathways were detected before or after vitrification. The results indicate that the blastocoel recovery rate (31.0%) and total cells (31.8) of vitrified blastocysts were less than those of fresh blastocysts (100% and 38.2, P < 0.05). The ΔΨm of vitrified blastocysts was 0.46, which was less than that of fresh blastocysts (1.02, P < 0.05). The rate of apoptotic cells in vitrified blastocysts (8.1%) after TUNEL (TdT-mediated dUTP Nick-End Labeling) assay was markedly greater than that in fresh blastocysts (3.9%, P < 0.05). The pan-caspase, caspase-3, caspase-8 and caspase-9 activities of vitrified blastocysts (20.7, 20.6, 17.6 and 19.9) were markedly greater than those of fresh blastocysts (7.4, 6.5, 5.5 and 6.3, P < 0.05). The real-time PCR results indicated that relative abundance of caspase-8 and TNF-α mRNA from death receptor apoptotic pathway and caspase-9 for the mitochondrial apoptotic pathway genes in the vitrified group were greater than those in the fresh group P < 0.05). The relative abundance of Bcl-2 and SOD-1 mRNA for the mitochondrial pathway genes in the vitrified group was less than those in the fresh group (P < 0.05). In conclusion, the poor developmental capacity of vitrified parthenogenetic pig blastocysts was closely related with apoptosis. Both mitochondria and death receptor-mediated apoptotic pathways participated the occurrence of this apoptosis.

Pd-catalyzed defluorination/arylation of α-trifluoromethyl ketones via consecutive ß-F elimination and C-F bond activation.

An unprecedented Pd-catalyzed activation of a CF3 group is reported herein. The key to the success of this reaction is the combination of consecutive ß-F elimination and C-F bond oxidative addition of a trifluoromethyl group. It also represents the first general application of α-trifluoromethyl ketones as building blocks by C-F bond activation.

Electrochemical C-O Bond Formation: Facile Access to Aromatic Lactones.

An efficient and robust methodology based on electrochemical techniques for the direct synthesis of aromatic lactones through dehydrogenative C-O cyclization is described. This new and useful electrochemical reaction can tolerate a variety of functional groups, and is scalable to 100 g under mild conditions. Remarkably, heterocycle-containing substrates can be employed, thus expanding the scope of radical C-O cyclization reactions.

Cu(II)-Mediated Decarboxylative Trifluoromethylthiolation of α,ß-Unsaturated Carboxylic Acids.

A tunable method for the direct trifluoromethylthiolation of α,ß-unsaturated carboxylic acids was developed to afford trifluoromethylthiolated ketones or alkenes. The reaction proceeds smoothly under mild conditions and shows an excellent functional group tolerance.

Visible-Light-Enabled Decarboxylative Mono- and Difluoromethylation of Cinnamic Acids under Metal-Free Conditions.

Several new mono- and difluoromethylation reactions of cinnamic acids using an Eosin Y catalytic system are reported. An efficient alkene fluoromethylation of α,ß-unsaturated carboxylic acids was accomplished under ambient temperature and metal-free conditions, with a wide range of functional group tolerance. A mechanism that involves a radical process is proposed for this reaction.

Minor endoscopic sphincterotomy followed by large balloon dilation for large choledocholith treatment.

AIM: To evaluate early and late outcomes of endoscopic papillary large balloon dilation (EPLBD) with minor endoscopic sphincterotomy (mEST) for stone removal. METHODS: A total of 149 consecutive patients with difficult common bile duct (CBD) stones (diameter ≥ 10 mm or ≥ 3 stones) underwent conventional endoscopic sphincterotomy (EST) or mEST plus EPLBD from May 2012 to April 2016. Their demographic, laboratory and procedural data were collected, and pancreaticobiliary complications were recorded. RESULTS: Sixty-nine (94.5%) of the patients in the EPLBD + mEST group and 64 (84.2%) in the conventional EST group achieved stone clearance following the first session (P = 0.0421). The procedure time for EPLBD + mEST was shorter than for EST alone (42.1 ± 13.6 min vs 47.3 ± 11.8 min, P = 0.0128). The overall rate of early complications in the EPLBD + mEST group (11%) was lower than in the EST group (21.1%); however, the difference was not significant (P = 0.0938). The cumulative recurrence rate of cholangitis and CBD stones between the two groups was also similar. The procedure time was independently associated with post-endoscopic retrograde cholangiopancreatography pancreatitis (OR = 6.374, 95%CI: 1.193-22.624, P = 0.023), CBD stone diameter ≥ 16 mm (OR = 7.463, 95%CI: 2.705-21.246, P = 0.0452) and use of mechanical lithotripsy (OR = 9.913, 95%CI: 3.446-23.154, P = 0.0133) were independent risk factors for stone recurrence. CONCLUSION: EPLBD with mEST is more effective than EST alone for difficult CBD stone removal, with shorter procedure time and fewer early complications.