Difluoromethyl phenoxathiinium salt: A new general and versatile difluoromethylating reagent with divergent ·CF_(2)H, CF_(2)H^(+), and :CF_(2) reactivities

Development of practical and versatile electrophilic difluoromethylating reagent is still a grand challenge so far due to its inherent instability or low reactivity.Herein,we report the design and synthesis of difluoromethyl phenoxathiinium tetrafluoroborate(PT-CF_(2)H^(+)BF_(4)^(-)) as a novel difluoromethylating reagent,which proves to be a bench-stable,general,powerful and versatile reagent with divergent·CF_(2)H,CF_(2)H^(+),and:CF_(2) reactivities.Making use of this reagent,we demonstrated a vast array of difluoromethyl radical transfer reactions via diverse pathways involving photocatalyst-free visible-light induction,visible-light photoredox catalysis and visible-light mediation single electron transfer of EDA complex.Moreover,the green and highly effective CF_(2)H^(+) and:CF_(2) transfer reactions were also readily accomplished.

General radical difluoromethylation using difluoroacetic anhydride via photoredox catalysis

CF_(2)H-containing molecules play pivotal roles in diverse fields from medicinal chemistry to materials science. However, the application of existing CF_(2)H reagents as a source of CF_(2)H radical is limited by their reactivity and preparation. Herein, we develop a simple and general visible-light-catalyzed radical difluoromethylation reaction of alkenes, dienes, and heteroaromatics using commercially available, easy-to-handle, and low-cost difluoroacetic anhydride as the CF_(2)H reagent. This scalable protocol enables the convenient synthesis of a range of CF_(2)H-containing compounds under mild conditions, exhibiting a broad substrate scope and functional group tolerance. Potential applications are further demonstrated by gram-scale synthesis, sunlight experiments, derivatization experiments as well as the synthesis of bioactive molecules.

Switching from 2-pyridination to difluoromethylation:ligand-enabled nickel-catalyzed reductive difluoromethylation of aryl iodides with difluoromethyl 2-pyridyl sulfone

The divergent reductive cross-coupling with an ambident electrophile is rare.Previously,we demonstrated a nickel-catalyzed reductive 2-pyridination of aryl iodides with difluoromethyl 2-pyridyl sulfone(2-Py SO_(2)CF_(2)H)via selective C(sp^(2))-S bond cleavage of the sulfone by using a phosphine ligand.In this communication,we report a novel nickel-catalyzed reductive coupling of aryl iodides and 2-Py SO_(2)CF_(2)H reagent,which constitutes a new method for aromatic difluoromethylation.The use of a tridentate terpyridine ligand is pivotal for the selective C(sp^(3))-S bond cleavage of the sulfone.This method employs readily available nickel catalyst and 2-Py SO_(2)CF_(2)H as the difluoromethylation reagent,providing a facile access to difluoromethylarenes under mild reaction conditions without pre-generation of arylmetal reagents.

Mechanochemical Difluoromethylations of Alcohols

Difluoromethyl ethers are formed through mechanochemical reactions of alcohols with difluorocarbene in a mixer mill.The protocol could be applied to primary,secondary,and tertiary alcohols,yielding the corresponding products in excellent yields(up to 99%)after 1 h reaction time at room temperature.The transformations proceeded under solvent-free reaction conditions,followed by product purification by filtration,which drastically reduced the amount of waste generated during the process.

Selective O-difluoromethylation of 1,3-diones using S-(difluoromethyl) sulfonium salt

A facile and highly efficient approach for selective O-difluoromethylation of 1,3-diones by recently developed bench-stable S-(difluoromethyl)sulfonium salt was described.And a broad range of difluoromthyl enol ethers were readily accessed in good to excellent yields under mild reaction conditions.Mechanistic studies revealed that the O-difluoromethylation reaction proceeds mainly via a difluorocarbene pathway.

Difluoromethylation of O-, S-, N-, C-Nucleophiles Using Difluoromethyltri（n-butyl）ammonium Chloride as a New Difluorocarbene Source

Difluoromethyltri（n-butyl）ammonium chloride 1 was found to be an effective difluorocarbene reagent for O-, S-, N-, C-difluoromethylation under basic conditions. It is particularly remarkable that, when only 1.2 equivalent of reagent 1 was used, the difluoromethylated products were obtained in moderate to excellent yields.

Nickel-Catalyzed Difluoromethylation of Arylboronic Acids with Bromodifluoromethane

Although bromodifluoromethane （BrCF2H） is a simple and readily available fluorine source, direct formation of difluoromethylated arenes with BrCF2H has not been reported. Herein, we describe an efficient method to access difluoromethylated arenes through a nickel-catalyzed difluoromethylation of arylboronic acids with BrCF2H. The reaction exhibits high efficiency, good functional group tolerance and broad substrate scope, thus providing an efficient route for applications in drug discovery and development. Preliminary mechanistic studies reveal that a difluoromethyl radical is involved in the reaction.

Ligand-Controlled Copper-Catalyzed Highly Regioselective Difluoromethylation of Allylic Chlorides/Bromides and Propargyl Bromides

Highly regiodivergent copper-catalyzed allylic/propargylic difluoromethylation reactions by employing different ligands are described. When 5,6-dimethyl-1,10-phenanthroline was used as the ligand, exclusively α-difluoromethylated products were obtained, while γ-selective difluoromethylated products were generated when N-heterocyclic carbene-SIPr was used as the ligand. Likewise, high α- vs. γ-selectivities were achieved in the presence of similar copper catalysts for the reactions of propargyl bromides. Moreover, a copper-catalyzed asymmetric allylic difluoromethylation reaction with moderate to good enantioselectivity by the use of chiral ligands was developed.

Difluoromethylation of 2-Hydroxychalcones Using Sodium 2-Chloro-2,2-difluoroacetate as Difluoromethylating Agent

Difluoromethylation of 2-hydroxychalcones using sodium 2-chloro-2,2-difluoroacetate as the difluoro- methylating agent was developed. Under facile conditions, a wide range of aryl difluoromethyl ethers were obtained in yields of 36%--80%. It is noteworthy that the new addition products, 2,2-difluoro-2H-benzofuran derivatives, were also synthesized in the reactions. The yield of 2,2-difluoro-2H-benzofuran derivative could be up to 35% when 3-methyl-2-hydroxychalcone was used as the reactant. A plausible reaction mechanism was proposed.

Facile synthesis of α-difluoromethyl α-propargylamines from CF_2H-substituted N-tert-butanesulfinyl ketimines

Stereoselective approach for preparation ofα-difluoromethylα-propargylamines has been developed.1,2-Addition of lithium acetylides to diverse chiral difluoromethylated（S）-N-tert-butanesulfinyl ketimines by using Ti（O^iPr）_4 as catalyst and THF as solvent afforded N-tert-butanesulfinamides in good to excellent yields（51-93%） and good diastereoselectivities（dr.85：15 to 93：7）.The N-tert -butanesulfinyl group can be readily cleaved under mild acidic condition（4 mol/L HCl in dioxane） to provide the correspondingα-difiuoromethylα-propargylamine in excellent yields（90-95%）.

An efficient three-component domino synthesis of difluoromethyl-containing 1,4-dihydropyridines under solvent and catalyst free conditions

The difluoromethyl-containing Hantzsch 1,4-dihydropyridines were synthesized in good yields by a one-pot cyclocondensation of ethyl difluoroacetoacetate (EDFAA),a variety of aromatic aldehydes and ammonium acetate under solvent and catalyst free conditions.The comparison of reaction conditions and products was made among the different 1,3-carbonyl substrates (ethyl acetoacetate,ethyl difluoroacetoacetate and ethyl trifluoroacetoacetate) for the Hantzsch reaction.

Deconstrutive Difunctionalizations of Cyclic Ethers Enabled by Difluorocarbene to Access Difluoromethyl Ethers

An unprecedented difluorocarbene-mediated C-O bond cleavage of cyclic ethers for the construction of difluoromethyl ethers is herein disclosed.This protocol is distinguished by its mild conditions,high efficiency,and wide substrate scope,which can tolerate both sensitive functional groups such as the hydroxyl group,olefin and C-C triple bonds,as well as complex molecules.It thus demonstrates excellent chemoselectivities and great potential for late-stage modification of pharmaceutical compounds and natural products.It is worth noting that this method not only introduces fluorine atoms into the final molecules,but it can also effectively form an ester or ether linkage.

A bench-stable reagent for C-4 selective deuteriodifluoromethylation of azines

Deuteriodifluoromethyl(CF_(2)D)is a challenging and important functional group due to difficult deuterium incorporation and lack of effective precursor reagents.Herein,we report a bench-stable reagent,deuteriodifluoromethyl phosphine(DDFP)from cheap deuterium source for selectivity deuteriodifluoromethylation of azines with a high deuterium incorporation yield.The late-stage modification of complex molecules further confirmed the potential of this reagent for practical applications.We expect that our reagent to find applications in synthesis of isotope-labelled molecules of interests for drug-discovery and related ilucidation of mechanism of action.

Chlorodifluoromethane triggered formation of difluoromethylated arenes catalyzed by palladium

Subject Code:B02With the support by the National Natural Science Foundation of China,a study by the research group led by Prof.Zhang Xingang（张新刚）from the Institute of Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences demonstrates the first direct catalytic difluoromethylations from ClCF2H,

可见光催化下N-芳基甲基丙烯酰胺的二氟甲基化/环化反应研究

研究了利用二氟乙酸酐作为二氟甲基自由基源,在可见光催化下的N-芳基甲基丙烯酰胺的二氟甲基化/环化反应,合成了一系列3-甲基-3-二氟乙基吲哚酮类化合物。结果表明:该方法操作简单,产率较高,可达91%,底物适用范围广。

3-氨基-6-二氟甲基喹啉的合成

对重要中间体3-氨基-6-二氟甲基喹啉的合成工艺进行了研究,首次以6-喹啉甲酸为起始原料,经过酰化、二氟甲基化、溴化、钯催化偶联、氨基脱保护等反应合成了3-氨基-6-二氟甲基喹啉,总收率31.4%。其结构经^(1)H NMR、^(13)C NMR和LC-MS确证。

3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸合成概述

琥珀酸脱氢酶抑制剂(SDHI)类杀菌剂因其持效性和稳抗性显著,3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸作为该类杀菌剂的中间体在未来几十年具有相当广阔的市场前景。综合国内外文献研究,探讨了3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸各合成工艺方法,并对比了各种方法的优缺点,对3-(二氟甲基)-1-甲基-1H-吡唑-4-羧酸合成方法的发展进行了展望。

含二氟甲基药物及二氟甲基化试剂研究进展

本文首次介绍了2011～2018年美国FDA批准上市的所有含二氟甲基的药物,并总结了它们的主要临床用途。以化合物的电性效应为基准对国内外文献报道的二氟甲基化试剂进行分类综述,其中较为常见的是亲核二氟甲基化试剂,主要包括TMS类、Ph XCF2H类、Br CF2PO(OEt)2、苯磺酰二氟甲基类和苯磺酰二氟乙酸金属盐类,而亲电二氟甲基化试剂的研究和应用相对较少,已报道的主要有二氟甲基自由基供体和二氟有机金属盐类。

7-二氟亚甲基-5,4'-二甲氧基染料木黄酮通过下调Caspase-3的表达拮抗H_2O_2诱导的血管内皮细胞凋亡

目的研究7-二氟亚甲基-5,4'-二甲氧基染料木黄酮对H_2O_2诱导血管内皮细胞凋亡的影响,并初步探讨其作用机制。方法用1 mmol/L H_2O_2诱导人脐静脉内皮细胞建立氧化应激损伤模型。实验分为空白对照组、H_2O_2损伤组、溶媒对照组、先导化合物组(100μmol/L染料木黄酮)、不同浓度(0.1、0.3、1、3、10μmol/L)7-二氟亚甲基-5,4'-二甲氧基染料木黄酮组。DCFH-DA激活荧光流式细胞术测定活性氧的生成,吖啶橙染色荧光显微镜观察细胞凋亡形态,PI染色流式细胞术检测细胞凋亡率,Western blot测定Caspase-3的表达。结果 1 mmol/L H_2O_2孵育血管内皮细胞24 h,活性氧的生成显著增加,吖啶橙染色荧光显微镜下细胞呈现明显的凋亡形态学改变,细胞凋亡率升高,Caspase-3的表达上调。用7-二氟亚甲基-5,4'-二甲氧基染料木黄酮预处理血管内皮细胞后可见活性氧的生成减少,细胞凋亡率降低,Caspase-3的表达下调。结论 7-二氟亚甲基-5,4'-二甲氧基染料木黄酮对H_2O_2诱导血管内皮细胞凋亡有明显的抑制作用,其作用机制可能是通过降低活性氧的生成,下调Caspase-3的表达,从而拮抗H_2O_2诱导的血管内皮细胞凋亡。

茶碱二氟甲基化的研究

以茶碱与氟里昂反应合成出一种新的化合物.对二氟甲基化反应条件进行了改进,在反应体系中加入金属钾以除去易引起副反应的水,使反应产率从30%提高到86%.探讨了含氮杂环化合物的二氟甲基化的反应机理、合成条件、分子结构对反应的影响,所合成的物质用IR,UV,1HNMR,19F NMR和MS进行了分析表征.