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Hydrofluoroolefins as Trifluoromethyl Vinyl Building Blocks A Research Review
Determination of Trace Cadmium in Water by Magnetic Covalent Organic Framework-Based Solid-Phase Extraction Coupled with Graphite Furnace Atomic Absorption Spectrometry
Research Progress on the Preparation of Deep Eutectic Solvent-Mediated Nanomaterials
more..Recent Advances in Fluoroalkyl Hydroxylamine Reagents
SHOU Jia-yi;QING Feng-ling;Fluorinated motifs are ubiquitous in pharmaceuticals and agrochemicals,with approximately 20% of marketed small molecule drugs containing one or more fluorine atoms. Incorporation of fluoroalkyl groups into drug candidates can enhance chemical and metabolic stability,improve lipophilicity and bioavailability,as well as increase protein binding affinity. Hence,the development of general and practical methodologies to construct organofluorine compounds has attracted extensive research interest,and the design,synthesis,and reaction development of novel fluoroalkylation reagents represent one of the most powerful strategies for constructing organofluorine compounds.Hydroxylamine derivatives are versatile building blocks for installing nitrogenand oxygen-containing functional groups via C—N and C—O bond formation.Owing to the low bond dissociation energy of the N—O bond,these compounds can be readily activated under mild conditions,such as transition-metal catalysis,chemical reduction,photocatalytic reduction,heating or ultraviolet irradiation,to generate nitrogen-and oxygen-centered radicals or anions. In recent years,fluoroalkyl hydroxylamine reagents have shown great potential for the construction of nitrogen-and oxygen-containing organofluorine compounds.This review summarizes representative advances in the design,synthesis and application of fluoroalkyl hydroxylamine reagents over the past decade,including N-fluoroalkoxybenzoimidazoles,N-fluoroalkoxypyridiniums,Nfluoroalkoxybenzotriazoliums,O-fluoroalkyl oximes,N-fluoroalkoxyphthalimides,N-fluoroalkylhydroxylamines.
Advances in Chen's Reagent: From Nucleophilic Trifluoromethylation Reagent to Multifunctional Fluoroalkylation Reagents
SU Xue;DING Jing;ZENG Guang-yuan;PANG Wan;LIU Chao;Chen's reagent(methyl fluorosulfonyl difluoroacetate,FSO_2CF_2COOMe,also known as Qingyun Chen' s reagent) is a practical and highly efficient nucleophilic trifluoromethylation reagent originally developed by Academician Chen Qingyun,a Chinese scientist.This reagent is readily scalable for large-scale production using inexpensive industrial raw materials such as tetrafluoroethylene,sulfur trioxide,and methanol. Thanks to its unique molecular framework and multiple activation pathways,it demonstrates broad application potential in fields such as organofluorine chemistry,drug molecule modification,and functional materials.In recent years,continuous breakthroughs have been achieved in the derivatization of the skeleton of Chen's reagent,the development of new reactions,the expansion of catalytic systems,and mechanistic studies.Through structure-directed modification,a series of derivatized reagents—including copper salts,silver salts,trimethylsilyl esters,sulfonyl chlorides,and carboxylic acids—have been successfully developed.These derivative systems have overcome the limitations of single nucleophilic reactions,enabling a wide range of applications,from nucleophilic trifluoromethylation to radical bifunctionalization,deoxyfluorination,electrophilic fluoroalkylation,and photocatalytic transformations. Based on these advances,this paper systematically reviews the development history,structural characteristics,reaction types,mechanisms of action,and relevant applications of Chen' s reagent and its derivatives.The review focuses on new reaction types,catalytic systems,and functionalization applications reported between 2020 and 2026. It also summarizes application examples from the interdisciplinary fields of pharmaceuticals,pesticides,functional polymers,and electrochemical energy storage,analyzes the limitations of existing systems,and outlines future development directions.
Research Progress on Electrophilic Trifluoromethylthiolation Reagents
JIANG Jian-hao;HUANG Wei-chen;The trifluoromethylthio group(-SCF3) exhibits high lipophilicity(Hansch parameter π= 1. 44) and a strong electronwithdrawing effect,which can significantly improve the pharmacokinetics and metabolic stability of drugs,making it highly promising for applications in pharmaceuticals,agrochemicals,and materials science.Early reagents such as CF_3SCl and CF_3SSCF3 faced limitations due to high toxicity and inconvenient handling,prompting research efforts to develop safe and efficient novel electrophilic trifluoromethylthiolation reagents.Based on structural characteristics and historical evolution,this review classifies ten representative reagents into four categories: early gaseous reagents(CF_3SCl),N-SCF3 structural reagents(Reagents Ⅱ ～ Ⅵ),OSCF3 and hypervalent iodine reagents(Reagents Ⅶ ～ Ⅸ),and trifluoromethyl sulfoxide-type reagents(Reagent Ⅹ). Among these,N-SCF3 reagents are the most widely applied: Reagent Ⅱ achieved the transition from gaseous to solid state; Reagent Ⅲcompletely avoided the use of highly toxic CF_3SCl; Reagents Ⅳ and Ⅴ significantly enhanced electrophilicity through the introduction of sulfonyl groups,with Reagent Ⅴ possessing a Tt~+DA value as low as 9. 8 kcal/mol,enabling trifluoromethylthiolation of inert arenes without activators; and Reagent Ⅵ represents a chiral version. Reagent Ⅶ exhibits both electrophilic and radical activity; Reagent Ⅸ was successfully applied for the selective modification of cysteine in peptides; and Reagent Ⅹ represents a novel activation strategy through the interrupted Pummerer reaction. From the perspective of reaction types,electrophilic trifluoromethylthiolation has expanded from early electrophilic aromatic substitution to alkene difunctionalization,asymmetric catalysis,and radical pathways,greatly enriching the synthetic toolkit for constructing SCF3-containing molecules. This review systematically discussed the synthetic methods,electrophilic activity,substrate scope,advantages,and disadvantages of various reagents,and summarizes representative applications.In addition,a comprehensive table is provided to compare the electrophilic reactivity,key advantages,and disadvantages of the ten reagents,offering readers a convenient reference for reagent selection. Future directions should focus on designing new reagents balancing activity and stability,expanding chiral reagents,advancing industrial applications,and improving atom economy. Developing next-generation reagents with shorter synthetic routes,lower costs,scalability,and high atom economy to facilitate the transition from laboratory research to practical industrial production is also a key priority in this field.This review aims to provide a reference for researchers in selecting appropriate electrophilic trifluoromethylthiolation reagents.
Progress in Visible-Light-Induced Reactions of Fluoroalkyl Siloxycarbenes
WANG Mei-xin;LIU Shan-shan;SHEN Xiao;Fluoroalkyl acylsilanes represent a new class of carbene precursors.Under mild visible-light irradiation,they can either be directly excited or undergo photocatalyzed radical Brook rearrangement to generate fluoroalkyl siloxycarbenes. Under the synergistic effect of the electron-withdrawing inductive effect of the fluoroalkyl group and the electron-donating conjugative effect of the siloxy group,fluoroalkyl siloxycarbenes exhibit both electrophilic and nucleophilic properties,displaying a unique ambiphilic“donor-acceptor” character.They are capable of reacting with both electron-rich and electron-deficient substrates.This versatility greatly expands the substrate scope of carbene chemistry and offers novel strategies for the diversity-oriented synthesis of complex fluorinated molecules.Based on these key findings,the team of Xiao Shen at Wuhan University has systematically carried out a series of original research work on the visible-light-induced transformations of fluoroalkyl acylsilanes, including:(1) organocatalytic [2 + 1] cycloaddition with alkynes to synthesize α-trifluoromethyl-substituted cyclopropenyl ethers and cyclopropenols;(2) using fluoroalkyl acylsilanes as carbyne cation equivalents for the one-pot modular construction of functionalized fluoroalkyl-substituted cyclopropenes from alkynes and nucleophiles;(3) cyclopropanation with terminal alkenes to construct fluorocyclopropanols with high cis-selectivity;(4) divergent synthesis of fluoroalkyl ketones through in situ generation of organoboronate complexes with organoboronic esters,with product selectivity tuned by the workup conditions(base or peroxide);(5) C(sp2) —H alkylation of 1,3-azoles,which for the first time reveals the dual role of fluoroalkyl acylsilanes as both carbene precursors and diradical-forming species that promote aza-cyclopropane ring opening; and(6) in situ generation of ketenimine intermediates from isocyanides,followed by tandem reactions with nucleophiles(anilines or phenols),enabling the one-pot synthesis of α-trifluoromethyl amidines and imidates.This review systematically delineates the design rationale,reaction condition screening,and optimization of the above-mentioned work,comprehensively present the substrate scope and functional-group tolerance for each transformation,dissect the mechanistic investigations,and summarize the application of these methods in latestage modification of natural products and synthesis of drug molecule analogues.Finally,we envision the broad prospects of such ambiphilic carbenes,which possess both donor and acceptor characteristics,in the precise construction of fluorinated organic compounds,and discuss the current unresolved challenges and potential future breakthrough directions,aiming to inspire more design concepts based on visible-light photocatalysis and novel carbene reagents.
Recent Advances in the Synthesis of Chiral α-gem-Difluoroalkyl Compounds
XIAO Xin;LIU Shi-xun;NIE Dan;GUO Jin-yu;MIAO Jia-yi;XU Shi-bo;WU Fan-hong;WU Jing-jing;The gem-difluoromethyl(CF2) and difluoromethylene(CF_2H) units serve as versatile bioisosteres for carbonyl and oxygen functionalities,and are consequently prevalent in pharmaceuticals,agrochemicals,and functional materials. Given that stereoisomers bearing these motifs often exhibit substantially divergent pharmacological profiles,the development of efficient and straightforward methodologies for constructing difluoroalkylated stereocenters has become a topic of considerable academic and industrial interest.Current asymmetric difluoroalkylation strategies generally fall into three mechanistic categories: nucleophilic,electrophilic,and radical-type transformations.Recent advances in transition metal catalysis,organocatalysis,and photochemistry,particularly through the judicious design of chiral ligands and catalysts,have rendered the enantioselective assembly of α-gemdifluoroalkyl compounds increasingly feasible and synthetically useful.This review provides a systematic overview of progress made since 2018 in the asymmetric construction of α-gem-difluoroalkyl scaffolds. We highlight representative catalytic systems,their underlying stereocontrol mechanisms,and the scope of applicable substrates. At the same time,we critically assess persistent challenges that limit broader utility,including narrow substrate generality,harsh reaction conditions,and insufficient functional group tolerance in certain protocols.Some catalytic systems remain highly substrate-dependent,while others suffer from moderate enantioselectivities or limited scalability,hampering their practical implementation. In addition,we discuss emerging strategies aimed at overcoming these obstacles,such as the development of novel chiral ligands with enhanced versatility,the integration of cooperative or multifunctional catalytic regimes,and the exploration of more sustainable and operationally simple reaction pathways.Finally,we offer a forward-looking perspective on future directions,emphasizing the potential of combining photoredox and asymmetric catalysis,leveraging machine learning for ligand optimization,and expanding the repertoire of difluoroalkylating reagents.We anticipate that continued innovation in catalyst design and reaction engineering will further elevate the efficiency,selectivity,and accessibility of asymmetric difluoroalkylation,paving the way for broader applications in medicinal chemistry and materials science.This review aims to serve as a useful reference for researchers engaged in fluorine chemistry and asymmetric synthesis,and to stimulate further advances in this dynamically evolving field.
Journal Information
Journal Name: Chemical Reagents
First Published: April 1979 • Monthly
Governed by: China Petroleum and Chemical Industry Federation
Sponsored by:
China Association for Analysis and Testing
Sinopharm Chemical Reagents Co., Ltd.
Beijing Guohua Jingshi Consulting Co., Ltd.
Edited and Published by: Editorial Office of Chemical Reagents
Editor-in-Chief: Qing Fengling
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