Copper-Catalyzed Oxidative Synthesis of 3-Aryl-5-fluoroalkyl-1,3,4-oxadiazol-2(3)-ones Using Perfluorocarboxylic Anhydride as a Reagent.

A copper-catalyzed oxidative annulation of sydnones with perfluorocarboxylic anhydride for the synthesis of 3-aryl-5-fluoroalkyl-1,3,4-oxadiazol-2(3)-ones is developed. A diverse array of 3-aryl-5-fluoroalkyl-1,3,4-oxadiazol-2(3)-ones are prepared with good yields (>73 examples, yields up to 95%). The synthetic utility of the developed protocol was demonstrated by gram-scale synthesis, and the synthetic transformation to 1,2,4-triazol-3-one products.

Synthesis of 2-(Trifluoromethyl)-[1,2,4]triazolo[5,1-]isoquinoline via Cycloaddition of ,-Cyclic Azomethine Imine with CFCN.

A [3 + 2] cycloaddition of ,-cyclic azomethine imine with in situ-generated CFCN for the construction of 2-(trifluoromethyl)-[1,2,4]triazolo[5,1-]isoquinoline is reported. Remarkably, this process shows a broad substrate scope with excellent functional group tolerance, which is scalable and enables a practical route to a library of 2-(trifluoromethyl)-[1,2,4]triazolo[5,1-]isoquinoline derivatives in moderate to good yields.

One-Pot Assembly of 2-Trifluoromethyl Benzothiazole and Benzoselenazole via Copper-Mediated Three-Component Cascade Reaction.

A domino one-pot synthesis of 2-(trifluoromethyl) benzothiazole via copper-mediated three-component cascade reaction starting from the easily accessible starting materials such as o-iodoanilines, methyl trifluoropyruvate, and elemental sulfur is reported. The present strategy displayed a comprehensive substrate scope and good functional group tolerance and enabled access to a variety of substituted 2-(trifluoromethyl) benzothiazoles. A 2-(trifluoromethyl) benzoselenazole has also been synthesized utilizing this reaction methodology.

Zirconium-Catalyzed Synthesis of 6-(Trifluoromethyl)-2-pyran-2-ones via C-C Bond Cleavage.

A strategy for the annulation reaction of alkynones with ethyl 4,4,4-trifluoro-3-oxobutanoate through C-C bond cleavage is described. The zirconium-catalyzed transformation provides access to a wide range of structurally diverse 6-(trifluoromethyl)-2-pyran-2-ones in moderate to good yields, utilizing NaCO as a base. Further transformations into trifluoromethylated arene derivatives have been demonstrated as well.

Copper Loading-Controlled Selective Synthesis of 2,5-Bis(trifluoromethyl) and Monotrifluoromethyl-Substituted Oxazoles.

A general domino annulation reaction of sulfonylmethyl isocyanide with trifluoroacetic anhydride in the presence of copper chloride as an additive is developed. The reaction affords 2,5-bis(trifluoromethyl)oxazoles in modest to good yields under mild conditions. A wide variety of sulfonylmethyl isocyanide and perfluorocarboxylic anhydride substrates are amenable to this transformation.

Synthesis of 2-trifluoromethyl benzimidazoles, benzoxazoles, and benzothiazoles condensation of diamines or amino(thio)phenols with CFCN.

A new and efficient method is developed for the synthesis of 2-trifluoromethyl benzimidazoles, benzoxazoles, and benzothiazoles in good to excellent yields by the condensation of diamines or amino(thio)phenols with generated CFCN. Additionally, the synthetic utility of the 2-trifluoromethyl benzimidazole and benzoxazole products is demonstrated gram scale synthesis. The mechanistic study suggests that the reaction proceeds the nucleophilic addition of trifluoroacetonitrile to the amino group of the diamine derivatives to form an imidamide intermediate, followed by intramolecular cyclization.

Synthesis of 2-trifluoromethyl thiazoles [3 + 2] cycloaddition of pyridinium 1,4-zwitterionic thiolates with CFCN.

2,2,2-Trifluoroacetaldehyde -(aryl)oxime was employed for the [3 + 2] cycloaddition of pyridinium 1,4-zwitterionic thiolates for the synthesis of 2-trifluoromethyl 4,5-disubstituted thiazoles. The reaction works well with various substituted pyridinium 1,4-zwitterionic thiolates in moderate to good yields. The synthetic potential of the obtained 2-trifluoromethyl 4,5-disubstituted thiazoles was demonstrated.

Regioselective synthesis of 3-trifluoromethyl 1,2,4-triazoles photocycloaddition of sydnone with CFCN.

A general and regioselective synthesis of 3-trifluoromethyl 1,2,4-triazoles has been achieved through photocycloaddition of sydnone with trifluoroacetonitrile. This method employed trifluoroacetaldehyde -(aryl)oxime as the CFCN precursor and tolerated various functional groups to furnish 3-trifluoromethyl 1,2,4-triazole products in moderate to good yields. Mechanistic experiments revealed an energy transfer from photocatalyst 4-CzIPN to the sydnone substrates.

Regioselective Synthesis of 5-Trifluoromethyl 1,2,4-Triazoles via [3 + 2]-Cycloaddition of Nitrile Imines with CFCN.

We herein describe a general approach to 5-trifluoromethyl 1,2,4-triazoles via the [3 + 2]-cycloaddition of nitrile imines generated in situ from hydrazonyl chloride with CFCN, utilizing 2,2,2-trifluoroacetaldehyde -(aryl)oxime as the precursor of trifluoroacetonitrile. Various functional groups, including alkyl-substituted hydrazonyl chloride, were tolerated during cycloaddition. Furthermore, the gram-scale synthesis and common downstream transformations proved the potential synthetic relevance of this developed methodology.

Modular Access to 2-(Trifluoromethyl)pyrazolo[1,5-]pyridines and Their Benzo Analogues through a Copper(I)-Catalyzed Radical Annulation.

A mechanistically distinctive copper-catalyzed radical annulation to valuable 2-(trifluoromethyl)pyrazolo[1,5-]pyridines and their benzo analogues has been described for the first time. Notably, the newly developed complementary process allows the synthesis of 4- or 6-substituted target molecular entities as a single product, which was previously challenging to access by existing methods. The utility of this process is further demonstrated by the facile construction of four different ring systems, a gram-scale synthesis, and the late-stage functionalization of bioactive molecules.

Synthesis of 4-trifluoromethyl pyridazines annulation of pyridinium ylides with trifluoroacetyl diazoester.

A base promoted annulation of pyridinium ylides with trifluoroacetyl diazoester has been reported. Highly functionalized 4-trifluoromethyl pyridazines were synthesized in good yields without the use of any heavy metal catalysts. The developed methodology was compatible with a variety of important functional groups.

2,2,2-Trifluoroacetaldehyde -(Aryl)oxime: A Precursor of Trifluoroacetonitrile.

The preparation of 2,2,2-trifluoroacetaldehyde -(aryl)oxime, a previously inaccessible precursor of trifluoroacetonitrile, via reaction of hydroxylamine and trifluoroacetaldehyde hydrate is reported. This precursor released CFCN in quantitative yield under mildly basic conditions. The precursor was successfully used in the synthesis of trifluoromethylated oxadiazoles.

An aerobic copper-mediated domino process for the synthesis of 3-(trifluoromethylseleno)indoles.

An aerobic copper-mediated domino reaction for the synthesis of 3-(trifluoromethylseleno)indoles by trifluoromethylselenolation of -Ts 2-alkynylaniline with [(bpy)CuSeCF] is reported. This reaction proceeds through sequential oxidation, alkyne coordination, and deprotonation followed by reductive elimination. This mild and robust method is highly functional group tolerant and provides straightforward access to 3-(trifluoromethylseleno)indoles in moderate to good yields.

Synthesis of 2,3-Bis(trifluoromethylseleno) Indoles through an Oxidative Copper-Mediated Domino Reaction.

An oxidative copper-mediated double trifluoromethylselenolation of terminal 2-alkynylanilines using [(bpy)CuSeCF] is reported, providing a moderately efficient and convenient approach to 2,3-bis(trifluoromethylseleno)indoles. Mechanistic studies show that a cascade sequence of oxidation, trifluoromethylselenolation, 5-- cyclization, and elimination is involved in this transformation.

Silver-Catalyzed Regioselective Synthesis of Highly Substituted 2-Trifluoromethyl Pyrroles.

An efficient and regioselective synthesis of highly substituted 2-trifluoromethyl pyrrole derivatives via silver-catalyzed cyclization of vinyl azides with ethyl 4,4,4-trifluoro-3-oxobutanoate is reported. Various α-(heteo)aryl, alkyl, β-aryl, as well as α,β-disubstituted vinyl azides, participate in this transformation. The reaction mechanism likely involves the addition of generated 2-azirine to the diketone species, followed by intramolecular addition, N-C cleavage, and elimination.

Copper-Catalyzed Synthesis of 5-Aryl-6-(Trifluoromethyl)-2,3-Dihydropyrazolo[1,2-a]Pyrazol-1(5H)-One.

An efficient protocol for the synthesis of 5-aryl-6-(trifluoromethyl)-2,3-dihydropyrazolo[1,2-a]pyrazol-1(5H)-one derivatives through a copper-catalyzed [3+2]-cycloaddition of azomethine imines with 3,3,3-trifluoropropyne (generated in situ from dehydrobromination of 2-bromo-3,3,3-trifluoropropene under base conditions) is developed. The advantages of this transformation are the broad substrate scope and the good functional group compatibility. The subsequent oxidation and nucleophilic substitution/aromatization provide a new approach to 4-trifluoromethylated pyrazol-1-yl propanoic acids.

[Content of prostate small extracorporeal protein in the urine as an index in evaluating the therapeutic effect on chronic prostatitis].

Objective: To investigate the clinical value of the prostate small extracorporeal protein (PSEP) level in the urine in evaluating the therapeutic effect on chronic prostatitis (CP).

Methods: Totally 188 CP patients were treated with minocycline and Ningmitai Capsules in our hospital and regularly returned for follow-up examination from November 2017 to November 2018. Based on the results of treatment after 4 and 8 weeks of medication, we divided the patients into a cured, an effective and an ineffective group and compared the contents of PSEP in the urine samples of the three groups of patients before and after treatment.

Collaborative Activation of Trifluoroacetyl Diazoester by a Lewis Acid and Base for the Synthesis of Polysubstituted 4-Trifluoromethylpyrazoles.

A Lewis acid- and base--mediated cyclization of trifluoroacetyl diazoester and ketones is developed. Cooperative functioning of the Lewis acid and Lewis base with trifluoroacetyl diazoester results in increased electrophilicity of terminal nitrogen atoms. The reaction affords polysubstituted 4-trifluoromethyl pyrazoles in moderate to excellent yields.

[Efficacy and safety of lycopene in the treatment of benign prostatic hyperplasia with lower urinary tract symptoms].

Objective: To investigate the efficacy and safety of lycopene in the treatment of BPH with lower urinary tract symptoms (LUTS).

Methods: Totally, 127 BPH patients with LUTS were treated with oral lycopene tablets at 500 mg bid in the Department of Andrology of Jinling Hospital from January 2018 to January 2019. At 8 and 16 weeks of medication, we compared the IPSS, quality of life (QOL) score, prostate volume, PSA level, maximum urinary flow rate (Qmax), postvoid residual urine volume (PVR) and the incidence of adverse reactions before and after treatment.

Base-Mediated Tunable Synthesis of 2-Trifluoromethylated Furans and Dihydrofuranols: Extraordinary Stable in Sulfuric Acid.

2-Trifluoromethylated furans and dihydrofuranols were tunably synthesized from the cyclization of β-ketonitriles with 3-bromo-1,1,1-trifluoroacetone mediated by bases. In addition, dehydration of dihydrofuranol compounds with concentrated sulfuric acid gave another 2-(trifluoromethyl)furans isomer. The developed methodology exhibits an excellent functional group tolerance for both aromatic and aliphatic β-ketonitriles.

Perfluorocarboxylic Anhydrides Triggered Cyclization: Access to 4-Perfluoroalkylpyridines.

A double nucleophilic addition-cyclization-elimination cascade is developed, that allows various 2,6-diaryl-4-perfluoroalkylpyridines to be synthesized in one step from easily available enamides and perfluorocarboxylic anhydrides. The procedure is also operationally simple and scalable and provides access to the facial construction of 4-fluoroalkylpyridines, which are of great interest in medicinal chemistry.

Elemental sulfur-promoted one-pot synthesis of 2-(2,2,2-trifluoroethyl)benzoxazoles and their derivatives.

A novel and direct strategy has been developed for the synthesis of 2-(2,2,2-trifluoroethyl)benzoxazoles by reaction of o-aminophenols and 2-bromo-3,3,3-trifluoropropene in the presence of elemental sulfur under metal-free conditions. The scope of this methodology was further extended to the synthesis of the trifluoroethylated benzothiazole and benzoimidazole derivatives. A plausible mechanism was proposed on the basis of isolation and characterization of a thioamide intermediate.

Synthesis of 3-(tri/difluoromethyl)-1H-1,2,4-triazol-5(4H)-ones via the cyclization of hydrazinecarboxamides with tri/difluoroacetic anhydride.

An efficient method for the synthesis of structurally diverse 4-aryl-3-(tri/difluoromethyl)-1H-1,2,4-triazol-5(4H)-ones through the cyclization of hydrazinecarboxamides with tri/difluoroacetic anhydride is presented. The method is simple and environmentally benign, providing tri/difluoromethylated 1,2,4-triazol-5(4H)-ones in moderate-to-good yields. A mechanism is proposed to proceed via a tandem reaction of tri/difluoroacetylation, nucleophilic addition and water elimination.

Copper-catalyzed chemoselective synthesis of 4-trifluoromethyl pyrazoles.

A series of 4-trifluoromethyl pyrazoles have been prepared the copper-catalyzed cycloaddition of 2-bromo-3,3,3-trifluoropropene with a variety of -arylsydnone derivatives under mild conditions. This new protocol under optimized reaction conditions [Cu(OTf)/phen, DBU, CHCN, 35 °C] afforded 4-trifluoromethyl pyrazoles in moderate to excellent yields with excellent regioselectivity.

Palladium-Catalyzed Tandem Synthesis of 2-Trifluoromethylthio(seleno)-Substituted Benzofused Heterocycles.

The tandem synthesis of 2-trifluoromethylthio(seleno)-substituted benzofurans using palladium-catalyzed conditions is reported. Trifluoromethylthio(seleno)lation of 2-(2,2-dibromovinyl)phenols with (bpy)CuSCF or [(bpy)CuSeCF] furnishes several 2-trifluoromethylthio(seleno)lated benzofurans in acceptable to good yield. Mechanistic investigations were performed to elucidate the reaction pathway, which was involved in the formation of a 2-bromobenzofuran species.