Dearomative Insertion of Fluoroalkyl Carbenes into Azoles Leading to Fluoroalkyl Heterocycles with a Quaternary Center.

The skeletal ring expansion of heteroarenes through carbene insertion is gaining popularity in synthetic chemistry. Efficient strategies for heterocyclic ring expansion to access heterocycles containing a fluoroalkyl quaternary carbon center through fluoroalkyl carbene insertion are highly desirable because of their broad applications in medicinal chemistry. Herein, we report a general strategy for the dearomative one-carbon insertion of azoles using fluoroalkyl N-triftosylhydrazones as fluoroalkyl carbene precursors, resulting in ring-expanded heterocycles in excellent yields with good functional-group compatibility. The broad generality of this methodology in the late-stage diversification of pharmaceutically interesting bioactive molecules and versatile transformations of the products has been demonstrated.

Site-Selective C-H Allylation of Alkanes: Facile Access to Allylic Quaternary sp3 -Carbon Centers.

The construction of allylic quaternary sp3 -carbon centers has long been a formidable challenge in transition-metal-catalyzed alkyl-allyl coupling reactions due to the severe steric hindrance. Herein, we report an effective carbene strategy that employs well-defined vinyl-N-triftosylhydrazones as a versatile allylating reagent to enable direct assembly of these medicinally desirable structural elements from low-cost alkane feedstocks. The reaction exhibited excellent site selectivity for tertiary C-H bonds, broad scope (>60 examples and >20 : 1:0 r. r.) and good efficiency, even on a gram-scale, making it a convenient alternative to the well-known Trost-Tsuji allylation reaction for the formation of alkyl-allyl bonds. Combined experimental and computational studies were employed to unravel the mechanism and origin of site- and chemoselectivity of the reaction.

Silver-Catalyzed [2+1] Cyclopropenation of Alkynes with Unstable Diazoalkanes: N-Nosylhydrazones as Room-Temperature Decomposable Diazo Surrogates.

The [2+1] cycloaddition of alkynes with diazo compounds represents one of the most powerful and reliable methods for the construction of cyclopropenes. However, it remains a formidable challenge to accomplish the cyclopropenation of alkynes with non-stabilized diazoalkanes, owing to the fact that such compounds are unstable and prone to detonation. Herein, we report a general silver-catalyzed cyclopropenation reaction of alkynes with unstable diazoalkanes, by for the first time the discovery and application of N-nosylhydrazones as room-temperature decomposiable diazo surrogates. This method allows for the efficient assembly a wide variety of cyclopropene derivatives that are otherwise difficult to access by conventional methods.

Silver-Catalyzed Stereoselective Aminosulfonylation of Alkynes.

A silver-catalyzed intermolecular aminosulfonylation of terminal alkynes with sodium sulfinates and TMSN3 is reported. This three-component reaction proceeds through sequential hydroazidation of the terminal alkyne and addition of a sulfonyl radical to the resultant vinyl azide. The method enables the stereoselective synthesis of a wide range of ß-sulfonyl enamines without electron-withdrawing groups on the nitrogen atom. These enamines are found to be suitable for a variety of further transformations.

Decarbonylative C-C bond-forming reactions of saccharins by nickel catalysis: homocoupling and cycloaddition.

Decarbonylation of saccharins by nickel catalysis enables two kinds of CC bond-forming reactions; homocoupling of saccharins to form biaryls and cycloaddition with alkynes to form benzosultams. The former represents the first reported nickel-catalyzed decarbonylative CC homocoupling reaction, whereas the latter constitutes a powerful method to pharmaceutically relevant benzosultams. The reactions proceed with good functional-group tolerance and excellent regioselectivity.

Silver-catalyzed cascade reaction of tosylmethyl isocyanide (TosMIC) with propargylic alcohols to (E)-vinyl sulfones: dual roles of TosMIC.

An unprecedented silver-catalyzed cascade reaction of tosylmethyl isocyanide (TosMIC) with propargylic alcohols for the efficient synthesis of (E)-vinyl sulfones has been developed where TosMIC plays a dual role as both the reactant in the allenylation of propargylic alcohols and the sulfonyl source.

Silver-Catalyzed Cross-Coupling of Isocyanides and Active Methylene Compounds by a Radical Process.

Isocyanides are versatile building blocks, and have been extensively exploited in C-H functionalization reactions. However, transition-metal-catalyzed direct C-H functionalization reactions with isocyanides suffer from over-insertion of isocyanides. Reported herein is a radical coupling/isomerization strategy for the cross-coupling of isocyanides with active methylene compounds through silver-catalysis. The method solves the over-insertion issue and affords a variety of otherwise difficult to synthesize ß-aminoenones and tricarbonylmethanes under base- and ligand-free conditions. This report presents a new fundamental C-C bond-forming reaction of two basic chemicals.

Lewis and Brønsted acid cocatalyzed reductive deoxyallenylation of propargylic alcohols with 2-nitrobenzenesulfonylhydrazide.

Invited for the cover of this issue is the group of Prof. Xihe Bi at Northeast Normal University, China. The cover illustrates the reductive deoxyallenylation of challenging sterically hindered tertiary propargylic alcohols, through the reaction with 2-nitrobenzenesulfonylhydrazide (NBSH), by the combined use of FeF3 and HOTf catalysts. Read the full text of the article at 10.1002/chem.201404692.

Lewis and Brønsted acid cocatalyzed reductive deoxyallenylation of propargylic alcohols with 2-nitrobenzenesulfonylhydrazide.

Reductive deoxyallenylation of sterically hindered tertiary propargylic alcohols was realized on reaction with 2-nitrobenzenesulfonylhydrazide (NBSH) by the combined use of Lewis and Brønsted acid catalysts. This method features a broad substrate scope, mild reaction conditions, and good functional-group tolerance, and affords various mono-, di-, and trisubstituted allenes in good-to-excellent yields. The synthetic utility of this method was demonstrated by the synthesis of 2H-chromenes and 1,2-dihydroquinolines.

Silver-catalyzed cross-coupling of propargylic alcohols with isocyanides: an atom-economical synthesis of 2,3-allenamides.

Cross-coupling reactions between propargylic alcohols and isocyanides, by means of silver catalysis, have been described. This new reaction is both atom and step efficient and is applicable to a broad scope of substrates, allowing the synthesis of a range of synthetically valuable 2,3-allenamides in moderate to excellent yields.

Silver(I)-catalyzed hydroazidation of ethynyl carbinols: synthesis of 2-azidoallyl alcohols.

The hydroazidation of alkynes is the most straightforward pathway to synthetically useful vinyl azides. However, a general hydroazidation of alkynes remains elusive. Herein, a chemo- and regioselective transformation of ethynyl carbinols into vinyl azides is described. This reaction produces a wide variety of 2-azidoallyl alcohols with high efficiency and in good to excellent yields. These compounds constitute a new class of densely functionalized synthetic intermediates. Their synthetic potential has been demonstrated by further transformations into NH aziridines. The mechanistic aspects of the reaction will attract the attention of chemists working on alkyne chemistry and silver catalysis. The findings that are described in this paper represent significant advances in the regioselective hydroelementation of alkynes and open a new reaction manifold for exploitation.

Chemoselective oxidative C(CO)-C(methyl) bond cleavage of methyl ketones to aldehydes catalyzed by CuI with molecular oxygen.

Aldehyde Termination: A novel copper-catalyzed transformation from methyl ketones into aldehydes has been accomplished. This method is applicable to a wide range of aromatic and aliphatic methyl ketones and chemoselectively produces aldehydes, accompanied by the release of hydrogen (H2 ) and carbon dioxide (CO2 ) as by-products.

Silver-Catalyzed Vinylcarbene Insertion into C-C Bonds of 1,3-Diketones with Vinyl-N-triftosylhydrazones.

We describe the silver-catalyzed formal insertion of a vinylcarbene into unstrained C(CO)-C bonds of 1,3-diketones using vinyl-N-triftosylhydrazones as vinylcarbene precursors. This method allows the rapid synthesis of otherwise inaccessible 2-vinyl-substituted 1,4-diketones from relatively simple substrates. This mild catalytic protocol exhibits a good functional group tolerance and substrate scope and allows for good chemoselectivity control. The preliminary theoretical calculations suggest that the reaction proceeds through a stepwise enol cyclopropanation/retro-aldol pathway.

Transition-metal-free azide insertion of N-triftosylhydrazones using a non-metallic azide source.

Benzylic azides, an important class of active organic synthons, were synthesized in high yields from the easily accessible N-triftosylhydrazones with stable TMSN3 under mild conditions. The reaction features high efficiency and excellent functional group tolerance, as illustrated by gram-scale synthesis and the synthesis of drug-like molecules. Mechanistic studies reveal that azidation occurs at the electron-deficient diazo-carbon via the elimination of N2 by an azide ion.

Metabolic profiling studies on the toxicological effects of realgar in rats by (1)H NMR spectroscopy.

The toxicological effects of realgar after intragastrical administration (1 g/kg body weight) were investigated over a 21 day period in male Wistar rats using metabonomic analysis of (1)H NMR spectra of urine, serum and liver tissue aqueous extracts. Liver and kidney histopathology examination and serum clinical chemistry analyses were also performed. (1)H NMR spectra and pattern recognition analyses from realgar treated animals showed increased excretion of urinary Kreb's cycle intermediates, increased levels of ketone bodies in urine and serum, and decreased levels of hepatic glucose and glycogen, as well as hypoglycemia and hyperlipoidemia, suggesting the perturbation of energy metabolism. Elevated levels of choline containing metabolites and betaine in serum and liver tissue aqueous extracts and increased serum creatine indicated altered transmethylation. Decreased urinary levels of trimethylamine-N-oxide, phenylacetylglycine and hippurate suggested the effects on the gut microflora environment by realgar. Signs of impairment of amino acid metabolism were supported by increased hepatic glutamate levels, increased methionine and decreased alanine levels in serum, and hypertaurinuria. The observed increase in glutathione in liver tissue aqueous extracts could be a biomarker of realgar induced oxidative injury. Serum clinical chemistry analyses showed increased levels of lactate dehydrogenase, aspartate aminotransferase, and alkaline phosphatase as well as increased levels of blood urea nitrogen and creatinine, indicating slight liver and kidney injury. The time-dependent biochemical variations induced by realgar were achieved using pattern recognition methods. This work illustrated the high reliability of NMR-based metabonomic approach on the study of the biochemical effects induced by traditional Chinese medicine.

Synthesis and evaluation of Gd-DTPA-labeled arabinogalactans as potential MRI contrast agents.

Arabinogalactan derivatives conjugated with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) by ethylenediamine (Gd-DTPA-CMAG-A2) or hexylamine (Gd-DTPA-CMAG-A6) have been synthesized and characterized by means of Fourier transform infrared spectra (FTIR), 13C nuclear magnetic resonance (13C NMR), size exclusion chromatography (SEC), and inductively coupled plasma atomic emission spectrometry (ICP-AES). Relaxivity studies showed that arabinogalactan-bound complexes possessed higher relaxation effectiveness compared with the clinically used Gd-DTPA, and the influence of the spacer arm lengths on the T1 relaxivities was studied. Their stability was investigated by competition study with Ca2+, EDTA, and DTPA. MR imaging of Wistar rats showed remarkable enhancement in rat liver and kidney after i.v. injection of Gd-DTPA-CMAG-A2 (0.079+/-0.002 mmol/kg Gd3+): The mean percentage enhancement of the liver parenchyma and kidney was 38.7+/-6.4% and 69.4+/-4.4% at 10-30 min. Our preliminary in vivo and in vitro study indicates that the arabinogalactan-bound complexes are potential liver-specific contrast agents for MRI.

NMR-based metabonomic study on the subacute toxicity of aristolochic acid in rats.

The subacute toxicity of aristolochic acid (AA) was investigated by (1)H NMR spectroscopic and pattern recognition (PR)-based metabonomic methods. Model toxins were used to enable comparisons of the urinary profiles from rats treated with known toxicants and AA at various time intervals. Urinary (1)H NMR spectra were data-processed and analyzed by pattern recognition method. The result of visual comparison of the spectra showed that AA caused a renal proximal tubular and papillary lesion and a slight hepatic impair. Pattern recognition analysis indicated that the renal proximal tubule lesion was the main damage induced by AA, and the renal toxicity induced by AA was a progressive course with the accumulation of dosage by monitoring the toxicological processes from onset, development and part-recovery. These results were also supported by the conventional clinical biochemical parameters.

Tandem O-H Insertion/[1,3]-Alkyl Shift of Rhodium Azavinyl Carbenoids with Benzylic Alcohols: A Route To Convert C-OH Bonds into C-C Bonds.

Alcohols are among the most abundant and commonly used organic feedstock in industrial processes and academic research. The first tandem O-H insertion/[1,3]-alkyl shift reaction reported is between benzylic alcohols and rhodium azavinyl carbenoids derived from N-sulfonyl-1,2,3-triazoles, which provides a strategically novel way of cleaving C-OH bonds and forming C-C bonds. The substrate scope is broad, capable of covering 1°-, 2°-, and 3°-benzylic alcohols. Moreover, it constitutes a new and powerful synthetic method for constructing α-aminoketones. Mechanistic studies suggest that a [1,3]-alkyl shift of oxonium ylides is responsible for cleavage of the C-OH bonds.

Chemo- and regioselective reductive deoxygenation of 1-en-4-yn-ols into 1,4-enynes through FeF3 and TfOH co-catalysis.

We report chemo- and regioselective direct reductive deoxygenation of 1-en-4-yn-3-ols into 1,4-enynes through FeF3 and TfOH cooperative catalysis under NBSH-mediated conditions. Further, we show the efficient synthesis of a pharmaceutically significant 1,4-enyne. The present methodology can also be used for chemo- and regioselective direct deoxygenation of other alcohols.

Silver-Catalyzed Isocyanide-Isocyanide [3+2] Cross-Cycloaddition Involving 1,2-Group Migration: Efficient Synthesis of Trisubstituted lmidazoles.

Imidazole ring is an important five-membered aromatic heterocycle that is widely present in natural products and synthetic molecules. The isocyanide-isocyanide [3+2] cross-cycloaddition reaction constitutes a straightforward method to access imidazoles starting from the easily available chemicals. So far, only three successive reports are known and all lead to the formation of 1,4-disubstituted imidazoles. Here, we report the first isocyanide-isocyanide [3+2] cross-cycloaddition reaction allowing for the formation of 1,4,5-trisubstituted imidazoles under silver catalysis. An unexpected 1,2-migration of sulfonyl, alkoxycaybonyl, and carbamoyl groups took place during the cyclization process that is responsible for the formation of trisubstituted imidazoles. This report displayed a mechanistically novel synthetic method toward a variety of imidazole derivatives, which are otherwise difficult to access by conventional methods.