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The selective introduction of perfluoro- tert -butyl group (PFtB, the bulkier analogue of CF 3 group) into arenes has long been sought after but remains a formidable task. We herein report the first general synthetic protocol to realize aromatic perfluoro- tert -butylation. The key to the success is the identification of PFtB phenyl sulfone as a new source of PFtB anion, which reacts with arynes in a highly regioselective manner to afford perfluoro- tert -butylated arenes in high yields. The application of the method is demonstrated by the preparation of sensitive 19 F-labeled NMR probes with an extraordinary resolving ability.

A new method for the generation of the "PhSO2CF2Cu" species from readily available difluoromethyl phenyl sulfone (PhSO2CF2H) has been developed. The "PhSO2CF2Cu" reagent can be applied in (phenylsulfonyl)difluoromethylation of arylboronic acids, which affords a convenient approach to introducing the PhSO2CF2 group into aromatics.

The direct conversion of diaryl ketones and enolizable aliphatic aldehydes into gem-difluoroalkenes has been a long-standing challenge in organofluorine chemistry. Herein, we report efficient strategies to tackle this problem by using difluoromethyl 2-pyridyl sulfone as a general gem-difluoroolefination reagent. The gem-difluoroolefination of diaryl ketones proceeds by acid-promoted Smiles rearrangement of the carbinol intermediate; the gem-difluoroolefination is otherwise difficult to achieve through a conventional Julia-Kocienski olefination protocol under basic conditions due to the retro-aldol type decomposition of the key intermediate. Efficient gem-difluoroolefination of aliphatic aldehydes was achieved by the use of an amide base generated in situ (from CsF and tris(trimethylsilyl)amine), which diminishes the undesired enolization of aliphatic aldehydes and provides a powerful synthetic method for chemoselective gem-difluoroolefination of multi-carbonyl compounds. Our results provide new insights into the mechanistic understanding of the classical Julia-Kocienski reaction., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The first highly efficient and stereoselective difluoromethylation of structurally diverse N-tert-butylsulfinyl ketimines has been achieved with an in situ generated PhSO(2)CF(2)(-) anion, which provides a powerful synthetic method for the preparation of a variety of structurally diverse homochiral α-difluoromethyl tertiary carbinamines, including α-difluoromethyl allylic amines and α-difluoromethyl propargylamines. The stereocontrol mode of the present diastereoselective difluoromethylation of ketimines was found to be different from that of other known fluoroalkylations of N-tert-butylsulfinyl aldimines, which suggests that a cyclic six-membered transition state may be involved in the reaction.

Alkoxide-induced nucleophilic pentafluoroethylation and trifluoromethylation of aldehydes, ketones, and imines using pentafluoroethyl phenyl sulfone (PhSO(2)CF(2)CF(3), 1) and trifluoromethyl phenyl sulfone (PhSO(2)CF(3), 2), respectively, have been successfully achieved. High diastereoselectivity was observed during the perfluoroalkylation of homochiral sulfinimines to give the corresponding perfluoroalkyl sulfinamides.

Difluoromethyl 2-pyridyl sulfone, a previously unknown compound, was found to act as a novel and efficient gem-difluoroolefination reagent for both aldehydes and ketones. It was found that the fluorinated sulfinate intermediate in the reaction is relatively stable, which can be observed by (19)F NMR and trapped with CH(3)I.

We have successfully accomplished the nucleophilic fluoroalkylation of alpha,beta-enones, arynes, and activated alkynes with fluorinated sulfones. It was found that for acylic alpha,beta-enones, although the reaction medium and the structure of the enones can all influence the regioselectivity of the nucleophilic alkylation reactions, the hard/soft nature of the carbanions played a major role. By using the 1,4- and 1,2-addition product ratio as a probe to determine the hard/soft nature of the above-mentioned four halogenated carbanions, the order of the softness of these carbanions can be given as follows: [(PhSO2)2CF(-)] (20) approximately = PhSO2CCl2(-) (32) > PhSO2CHF(-) (31) > PhSO2CF2(-) (30). In the case of fluoroalkylation of aryne (35 as the precursor) and alpha,beta-acetylenic ketones 46 with fluorobis(phenylsulfonyl)methane (21), fluorobis(phenylsulfonyl)methylated arenes 36 and beta-fluorobis(phenylsulfonyl)methylated alpha,beta-enones 47 were obtained as the corresponding products in good yields. During the reaction between 2-fluoro-2-(phenylsulfonyl)acetophenone (34) and arynes or activated alkynes 46, an intramolecular tandem reaction process leads to the formation of acyl-fluoroalkylated arenes 43 or alpha-acyl-beta-fluoroalkylated alpha,beta-enones 48. It turned out that the softness of a fluorine-bearing carbanion (such as 20 or 33 derived from 21 or 34) plays a crucial role for the success of the nucleophilic fluoroalkylation reactions with arynes and some activated alkynes (alpha,beta-acetylenic ketones).

Chlorodifluoromethyl phenyl sulfone, a previously unknown compound that can be readily prepared from non-ODS-based precursors, was found to act as a robust difluorocarbene reagent for O- and N-difluoromethylations.

Efficient fluoroalkylations have been proven to be a highly useful strategy for the synthesis of bioactive fluorine-containing compounds and other materials. The design and use of a single category of reagents for multiple synthetic goals are much more attractive to preparative organic chemists. In this Account, we show how we have succeeded in the nucleophilic trifluoromethylation, difluoromethylation, difluoromethylenation, (phenylsulfonyl)difluoromethylation, (phenylthio)difluoromethylation, and monofluoromethylation as well as radical (phenylsulfonyl)difluoromethylation and electrophilic difluoromethylation by using fluorinated sulfones, sulfoxides, sulfides, or fluorinated sulfonium salts. The chemistry not only provides practically powerful synthetic methods, but the molecular design concept that we have developed may also be adopted to tackle other related chemical problems.

The unprecedented nucleophilic fluoroalkylation of simple epoxides with fluorinated sulfones was achieved to give the beta-fluoroalkyl alcohols in one step. The negative "fluorine effect" in the nucleophilic fluoroalkylation of epoxides with fluorinated carbanions was probed by the reactivity comparison between carbanions PhSO2CF2- (3) and PhSO2CCl2- (4) and between carbanions PhSO2CHF- (7) and PhSO2CHCl- (13). The mediation of this fluorine effect by introducing another electron-withdrawing benzenesulfonyl group was found to be an effective way to significantly increase the nucleophilicity of the fluorinated carbanions, with the reactivity order [(PhSO2)2CF-] (16) > PhSO2CFH- (7) >> PhSO2CF2- (3).

Ligand coupling on hypervalent main group elements has emerged as a pivotal methodology for the synthesis of functionalized N‐heteroaromatic compounds in recent years due to the avoidance of transition metals and the mildness of the reaction conditions. In this direction, the reaction of N‐heteroaryl sulfur(IV) and N‐heteroaryl phosphorus(V) compounds has been well studied. However, the ligand coupling of sulfur(VI) is still underdeveloped and the reaction of alkyl N‐heteroarylsulfones is still elusive, which does not match the high status of sulfones as the chemical chameleons in organic synthesis. Here we present a ligand coupling‐enabled formal SO2 extrusion of fluoroalkyl 2‐azaheteroarylsulfones under the promotion of Grignard reagents, which not only enriches the chemistry of sulfones, but also provides a novel and practical synthetic tool towards N‐heteroaromatic fluoroalkylation. [ABSTRACT FROM AUTHOR]

Molecules containing a difluoromethyl group or a propargylic stereocenter are widely used in pharmaceuticals and agrochemicals, and 1,2‐functionalization of olefins is an important method for introducing the two groups into molecules simultaneously. The construction of the propargylic stereocenter with terminal alkynes usually requires bases. However, difluoromethylating agents with high reduction potentials often decompose in the presence of bases because of their acidities, and those with low reduction potentials are stable but difficult to undergo the desired single electron transfer (SET) reduction. Using the linear relationship between reduction potential differences (ΔE) and Hammett substituent constants (σ) of difluoromethyl aryl sulfones, we solved the dilemma between acidities and reduction potentials of difluoromethylating agents. Herein, we report the first enantioselective difluoromethylation‐alkynylation of olefins with difluoromethyl 4‐chlorophenyl sulfone with high enantioselectivity (>90 % ee). We also extended this asymmetric fluoroalkylation‐alkynylation reaction with other fluoroalkyl sulfones, which enabled efficient installation of trifluoromethyl, difluoroalkyl, difluorobenzyl, (benzenesulfonyl)‐difluoromethyl and monofluoromethyl groups into products. [ABSTRACT FROM AUTHOR]

A photocatalytic protocol for the reductive coupling of tetrafluoropyridyl‐substituted sulfones with α‐(trifluoromethyl)styrenes in the presence of zinc and sodium iodide is reported. Sulfones were obtained by oxidation of the corresponding sulfides catalyzed by molybdenum or ruthenium salts. A combination of sulfonyl fragment and electron depleting fluorinated pyridyl group is a key feature determined properties of these sulfones. Their propensity to undergo single electron reduction and to form electron donor‐acceptor complexes with N‐arylamines were evaluated. Plausible pathways of fragmentation of radical anion generated after single electron reduction of sulfones were analyzed, and the pathway leading to the formation of the alkyl radical and the sulfinate anion was found preferable. [ABSTRACT FROM AUTHOR]

Trifluoromethyl phenyl sulfone is traditionally a nucleophilic trifluoromethylating agent. Herein, we report the first example of the use of trifluoromethyl phenyl sulfone as a trifluoromethyl radical precursor. Arylthiolate anions can form electron donor–acceptor (EDA) complexes with trifluoromethyl phenyl sulfone, which can undergo an intramolecular single electron transfer (SET) reaction under visible light irradiation, thus realizing the S-trifluoromethylation of thiophenols under photoredox catalyst-free conditions. Similar S-perfluoroethylation and S-perfluoro-iso-propylation of thiophenols are also achieved using the corresponding perfluoroalkyl phenyl sulfones. [ABSTRACT FROM AUTHOR]

Radical fluoroalkylation of alkenes has been developed by electrochemical reduction of fluoroalkyl sulfones. A series of electron-deficient alkenes readily undergo hydrofluoroalkylation in good to excellent yields. This chemistry represents the first example of electrochemical generation of fluoroalkyl radicals from sulfones, which are used for practical radical fluoroalkylation of organic compounds. [ABSTRACT FROM AUTHOR]

The iron‐catalyzed alkyl–aryl coupling reaction between sulfones and arylboron compounds has remained a challenge. We report the first iron‐catalyzed radical difluoroalkylation of arylborates with N‐heteroaryl sulfones. The coordination between the iron catalyst and the nitrogen atom of N‐heteroaryl sulfones was identified to be important in overcoming the reduction potential limitation of sulfones in the intermolecular single‐electron‐transfer process, which enables both fluoroalkyl N‐heteroaryl sulfones (with relatively high reduction potentials) and nonfluorinated alkyl N‐heteroaryl sulfones (with low reduction potentials) to serve as powerful alkylation reagents. [ABSTRACT FROM AUTHOR]

A novel Ph2P(O)Cl‐mediated direct fluoroalkanesulfinylation of electron‐rich (het)arenes using fluoroalkyl heteroaryl sulfones as the RfSO source (Rf=C4F9, CF2Cl, CF2Br, and CF2COOEt) was developed. This is the first example where 2‐HetSO2Rf performs as the RfSO synthon in organic synthesis via both C(Het)−S and S=O bond cleavage. [ABSTRACT FROM AUTHOR]

Research has been conducted on tri- and difluoromethylsilanes. The authors describe the preparation of these compounds via the use of magnesium metal-mediated reductive tri- and difluoromethylation of chlorosilanes.

The radical fluoroalkylation of isocyanides with fluorinated sulfones is enabled by visible-light photoredox catalysis. A wide range of readily available mono-, di-, and trifluoromethyl heteroaryl sulfones can thus be used as efficient radical fluoroalkylation reagents under mild conditions. This method not only describes a new synthetic application of fluorinated sulfones, but also provides a new route to fluoroalkyl radicals. [ABSTRACT FROM AUTHOR]

A highly stereoselective synthesis of tetrasubstituted monofluoroalkenes with aldehydes and fluorobis(phenylsulfonyl)methane (FBSM) in one pot has been developed. The reaction was amenable to para- and meta-substituted aryl aldehydes, 2-naphthaldehyde, and cinnamaldehyde, giving phenylsulfonyl-substituted monofluoroalkenes in 40%-86% yields with 98/2-99/1 Z/ E ratios. The presence of the sulfonyl group enables the further transformation of the products into more useful monofluoroalkenes. [ABSTRACT FROM AUTHOR]

Abstract: A facile palladium-catalyzed fluoroalkylation of alkynes with monofluorinated sulfones in the presence of acetic acid has been achieved. By using different α-substituted fluoro(phenylsulfonyl)methane derivatives, a variety of allylated monofluoromethyl compounds were obtained with high regio- and stereoselectivity. Substrate scope and limitation were also examined, and it was found that the reaction was amenable to both 1-aryl-substituted propynes and 3-aryl-substituted propynyl ethers. [Copyright &y& Elsevier]

The introduction of one or two fluorine atoms into a carbon-carbon double bond often brings about profound changes of physical, chemical and/or biological properties of the target molecule. Fluorinated alkenes are a class of important compounds and widely used in medicinal chemistry and materials science. Julia and Julia-Kocienski reactions could be used in the synthesis of fluorinated alkenes by employing α-fluorinated sulfones. In this review, the synthesis of fluorinated alkenes through Julia and Julia-Kocienski reactions are summarized, and the contents are categorized by target molecules and sulfone reagents. The difference between the reaction conditions for monofluoromethyl sulfones and difluoromethyl sulfones reflects the unique effect of fluorine substituents. [Display omitted] • Synthesis of monofluoroalkenes and gem -difluoroalkenes via Julia or Julia-Kocienski reaction is summarized. • Monofluoromethyl or difluoromethyl sulfones are used as the olefination reagents. • gem -Difluoroolefination reaction proceeds at low temperature. • Low Z/E selectivities are obtained in monofluoroolefination reactions. [ABSTRACT FROM AUTHOR]

Abstract: Stereoselective free radical (phenylsulfonyl)difluoromethylation of terminal alkynes with iododifluoromethyl phenyl sulfone (PhSO2CF2I) has been accomplished by using Et3B/air as an initiator. The obtained PhSO2CF2-substituted vinyl iodides, which can be further subjected to Suzuki coupling and Sonogashira coupling reactions, are useful precursors for the preparation of many structurally diverse PhSO2CF2- and CF2H-substituted alkenes. [Copyright &y& Elsevier]

[Display omitted] • The synthetic applications of PhSO 2 CF 2 H reagent since 2009 are reviewed. • The reagent was used as difluoromethyl and difluoromethylene synthons. • Nucleophilic, electrophilic, and radical difluoroalkylations are presented. • The reagent was used in transition metal-mediated fluoroalkylation reactions. • Difluorocarbene-involved reactions are also discussed. Organofluorine compounds often possess unique chemical, physical and biological properties and therefore, they play important roles in pharmaceuticals, agrochemicals, and advanced materials. Notably, the introduction of CF 2 motif as an oxygen surrogate could significantly improve the metabolic stability and bioavailability of the target molecules. Therefore, selective introduction of the CF 2 group into organic molecules is an appealing task. It has been realized that the (phenylsulfonyl)difluoromethyl group is a versatile CF 2 building block, which can be readily transformed into other useful fluorinated functionalities such as difluoromethyl (CF 2 H), difluoromethylene (–CF 2 –), and difluoromethylidene (=CF 2) groups. This article overviews the recent advance of (phenylsulfonyl)difluoromethylation reactions as well as their synthetic applications in organic synthesis within the past decade. Five modes of difluoroalkylation reactions have been developed, including nucleophilic (phenylsulfonyl)difluoromethylations, electrophilic (phenylsulfonyl)difluoromethylations, radical (phenylsulfonyl)difluoromethylations, difluorocarbene reactions, and transition-metal mediated (phenylsulfonyl)difluoromethylations. [ABSTRACT FROM AUTHOR]

The previously developed stereoselective [3+2] cycloaddition between N‐tert‐butanesulfinyl ketimines and arynes has been extended to the synthesis of enantiopure [(2‐pyridyl)sulfonyl]difluoromethylated cyclic sulfoximines. The use of 2‐PySO2CF2 as the facilitating group offers new opportunities for the elaboration of the [3+2] cycloaddition products by virtue of the diverse relativity of 2‐pyridyl sulfones. [ABSTRACT FROM AUTHOR]

A highly stereoselective method for the synthesis of tetrasubstituted (Z)-monofluoroalkenes is developed. [ABSTRACT FROM AUTHOR]

Abstract: A palladium-catalyzed allylation reaction of PhSO2CH2CF3 (2) with a variety of allyl carbonates has been successfully developed for selective 2,2,2-trifluoroethylation under neutral conditions. With this method, the 1-phenylsulfonyl-2,2,2-trifluoroethyl moiety was efficiently transferred into organic compounds without the competing β-elimination of fluoride, to afford a range of mono-allylated and di-allylated compounds. [Copyright &y& Elsevier]

Abstract: We have investigated the different chlorodifluoromethyl aryl ketones 1a–1g and sulfones 2a–2h as difluorocarbene reagents for O- and N-difluoromethylations. It was found that the sulfone reagents 2 were generally more efficient in difluoromethylation than the ketone reagents 1. Furthermore, while the different substituents on ketone reagents 1 did not show a remarkable impact on the difluoromethylation reaction, the substituent effect on the sulfone reagents 2 was much more significant. Finally, we found that p-chlorophenyl chlorodifluoromethyl sulfone 2d and p-nitrophenyl chlorodifluoromethyl sulfone 2h were among the most powerful difluorocarbene reagents in this category for O-difluoromethylations. [Copyright &y& Elsevier]

Abstract: 1-tert-Butyl-1H-tetrazol-5-yl fluoromethyl sulfone (TBTSO2CH2F) has been developed as a new and efficient fluoromethylidene synthon for the synthesis of both terminal and internal monofluoroalkenes via Julia–Kocienski olefination reaction. The base-mediated reaction between TBTSO2CH2F and carbonyl compounds (aldehydes and ketones) provided terminal monofluoroalkenes in good yields with moderate E/Z selectivity. The dominance of E- or Z-fluoroalkenes could be controlled by selection of proper reaction solvent and temperature. TBTSO2CH2F reagent was also found to be readily α-alkylated, acylated, and phenylsulfonylated to give corresponding α-functionalized fluorosulfones, which could be used in the synthesis of alkyl-, acyl-, and phenylsulfonyl-substituted internal monofluoroalkenes via Julia–Kocienski olefination reactions. [Copyright &y& Elsevier]

A thermodynamically controlled and reversible nucleophilic addition of a monofluorinated sulfone, α -fluoro- α -phenylthio- α -phenylsulfonylmethane (FTSM), to aldehydes has been developed, which allows the efficient synthesis of β -fluorinated carbinols with high diastereoselectivity. Control experiments showed that the fluorine substitution not only promotes the addition process, but also improves the diastereoselectivity. Image 1 • An unusual thermodynamically controlled nucleophilic addition of a carbanion to aldehydes is developed. • The efficient synthesis of β -fluorinated carbinols with high diastereoselectivity is achieved. • The fluorine substitution not only promotes the addition process, but also improves the diastereoselectivity. [ABSTRACT FROM AUTHOR]

The article presents chemical equations for article "Nucleophilic Iododifluoromethylation of Carbonyl Compounds Using Difluoromethyl 2-Pyridyl Sulfone" by W. Miao and others published in 2016 issue of journal "Organic Letter."

The reagent 'PhSO2CF2Cu' is generated in the reaction from sulfone (I) and it further reacts with aryl- and heteroarylboronic acids to afford the desired products. [ABSTRACT FROM AUTHOR]

Aliphatic as well as aromatic aldehydes undergo nucleophilic difluoro(phenylsulfonyl)methylation by reaction with PhSO2CF2H (I). [ABSTRACT FROM AUTHOR]

The article presents chemical equations which explain the metal-free cross dehydrogenative coupling between α-fluorinated sulfones and tertiary amines mediated by diisopropyl azodicarboxylate (DIAD).

Desulfoximination of resulting compounds (III) results in the formation of enantiomerically enriched difluoromethyl alcohols shown for (IIIa). [ABSTRACT FROM AUTHOR]

Structurally diverse allylic carbonates (I) are reacted with sulfone (II) under neutral conditions. [ABSTRACT FROM AUTHOR]