Introduction of New Fluorination and Fluoroalkylation Reagents

Introduction

Fluorination and fluoroalkylation reagents play an important role in the field of organofluoride chemistry because they are powerful tools for the synthesis of biologically active fluorine-containing compounds and fluorine-containing materials, and most fluorine chemical reactions are carried out around these two classes of reagents. However, the lack of effective fluorination and fluoroalkylation reagents makes the synthesis of diverse fluorinated compounds still a great challenge. So even if the various types of fluorination and fluoroalkylation reagents based on B, N, Si, P, S, have been successfully developed, scientists are still committed to the research and development of new fluorination and fluoroalkylation reagents. Nowadays, many new fluorination and fluoroalkylation reagents are reported every year. Herein, according to the report of Qing et al ^[1], Alfa Chemistry briefly introduces some new fluorination and fluoroalkylation reagents that reported after 2010, in order to provide help or some research ideas for your scientific research.

New Fluorination Reagents

• Nucleophilic fluorination reagents: The commonly used nucleophilic fluorination reagents include metal fluoride salts, Et₃N·3HF, fluorinated hypervalent silicates, etc. In 2014 and 2017, two novel HF-based reagents, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU)·(HF)x and KHSO₄·(HF)x were developed.

Fig.1. The structures of (DMPU)·(HF)x and KHSO₄·(HF)x

• Electrophilic fluorination reagents: Over the past decade, a series of new electrophilic fluorination reagents have been developed. They are N-fluorobenzenesulfonimide (NFSI) derivatives (EF-I), chiral analogs of NFSI (EF-II), a chiral reagents based on the dicationic structural core of Selectfluor (EF-III), an air- and moisture-stable cyclic hypervalent iodine-based reagents (EF-IV) and a chiral iodine (III) reagents (EF-V), respectively.

Fig.2. The structures of EF-I, EF-II, EF-III, EF-IV and EF-V.

• Deoxyfluorination reagents: Classic deoxyfluorination reagents include SF₄ and its derivatives (e.g., diethylaminosulphur trifluoride (DAST), DeoxoFluor, and XtalFluor). In 2010, two deoxyfluorination reagents, 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead) with high thermal stability and unusual resistance to aqueous hydrolysis and 2-Pyridinesulfonyl fluoride (PyFluor) with an inexpensive and thermally stable were discovered. And then 3,3-difluoro-1,2- diarylcyclopropenes (CpFluors) as a class of novel deoxyfluorination reagents with an all-carbon scaffold was developed in 2017.

Fig.3. The structures of Fluolead and PyFluor.

New Fluoroalkylation Reagents

• Trifluoromethylation reagents: (Trifluoromethyl)dibenzothiophenium salts (Umemoto reagents), 1-trifluoromethyl-3,3-dimethyl-1,2-benziodoxole or 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one (Togni reagents I and II), TMSCF₃, PhSO₂CF₃ and PhSOCF₃ are widely used as the trifluoromethylation reagents. In recent years, trifluoromethyl-substituted sulfonium ylide (ETF-I), second-generation Umemoto's reagents (Umemoto reagents II) with thermally stable, one-pot-preparable and recyclable and the Umemoto type reagent trifluoromethyl thianthrenium triflate (TT-CF₃⁺ OTf⁻, ETF-II) were reported in 2015, 2017, 2021, respectively.

Fig.4. The structures of ETF-I, Umemoto reagents II and ETF-II.

• Difluoromethylation reagents: In 2015 and 2016, several novel difluoromethylation reagents were reported, including NHC-ligated difluoromethylated silver complex [(SIPr)Ag(CF₂H)] (it is thermally stable and well-defined and can be used in transition metal-mediated or -catalyzed diflfluoromethylating reactions), zinc diflfluoromethyl reagent (DMPU)₂ Zn(CF₂H)₂,  (difluoromethyl)triphenylphosphonium bromide ([Ph₃PCF₂H]⁺Br^–), and a difluoromethyl radical reagent produced by 2-[(difluoromethyl)sulfonyl]benzo[d]thiozole (2-BTSO₂CF₂H).
• Trifluoromethylthiolation reagents: N-(triflfluoromethythio)phthalimide (ESF-I, Munavalli reagent) as one of important electrophilic trifluoromethylthiolation reagents was developed before 2010. Later, a hypervalent iodonium ylide skeleton-based reagent (ESF-II), Lu-Shenreagent (ESF-III), N-trifluoromethylthiosaccharin (ESF-IV, Shen reagent) and N-trifluoromethylthio bis(phenylsulfonyl)imide (ESF-V, Shen reagent II) as electrophilic trifluoromethylthiolation reagents were reported. For nucleophilic trifluoormethylthio sources, AgSCF₃ and CuSCF₃ as well as Me₄NSCF₃ were widely used. In 2012, two stable nucleophilic trifluoromethylthiolation reagents (L)CuSCF₃ (L = 2,2-bipyridine (bpy) and 1,10-phenanthroline (phen)) were reported. Likewise, in 2015, two stable trifluoromethylthiolated copper(I) complexes (Ph₃P)₂CuSCF₃ and (dppf)CuSCF₃ as nucleophilic reagents were prepared.

Fig.5. The structures of ESF-I, ESF-II and ESF-III, ESF-IV and ESF-V.

Alfa Chemistry has accumulated extensive knowledge and experience in organofluorine chemistry. And we have been at the forefront of fluorination and fluoroalkylation reagents and offer a wide range of fluorination and fluoroalkylation reagents. In addition, we offer fluorination and fluoroalkylation reagents development service. Whether you need fluorination and fluoroalkylation reagents for research or want to related solutions and consulting services, we have got you covered.

Reference

1. Qing F. L., et al. A fruitful decade of organofluorine chemistry: new reagents and reactions[J]. CCS Chemistry, 2022, 4(8): 2518-2549.