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The monofluoroalkene motif is important in drug development as it serves as a peptide bond isostere and is found in a number of biologically active compounds with various pharmacological activities. Direct olefination of carbonyl compound is a straightforward way to prepare monofluoroalkenes; however, these methods often result in a mixture of Z- and E-isomers that cannot be easily separated. We discovered a unique spontaneous resolving reaction that simultaneously addresses the problems in the synthesis and separation of Z- and E-monofluoroalkenes. The reaction is accompanied by a highly efficient spontaneous kinetic resolution and phase labeling of monofluoroalkene precursors which allows the separation of Z- and E-monofluoroalkenes by liquid-liquid extraction. The application of the method is demonstrated by the synthesis and separation of potential anticancer agents, which are inseparable by HPLC.

A AgF-mediated fluorination with a concomitant cross-coupling between a gem-difluoroolefin and a non-fluorinated olefin is reported. This highly efficient method provides facile access to both α-CF3 alkenes and β-CF3 ketones, which otherwise remain challenging to be directly prepared. The application of this method is further demonstrated by the synthesis of bioactive isoxazoline derivatives. This approach represents a conceptually novel route to trifluoromethylated compounds that combines the in situ generation of the CF3 moiety and a C-H functionalization in a single reaction system., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Iodo- and bromodifluoromethylated compounds are important synthetic intermediates and halogen-bond acceptors. However, direct introduction of -CF(2)I and -CF(2)Br groups through nucleophilic addition is particularly challenging because of the high tendency of decomposition of CF(2)Br(-) and CF(2)I(-) to difluorocarbene. In this work, we have developed a formal nucleophilic iodo- and bromodifluoromethylation for carbonyl compounds. The key strategy of the method is the halogenation of in situ-generated sulfinate intermediates from the Julia-Kocienski reaction to change the reaction pathway from the traditional olefination to alkylation. Interesting halogen-π interactions between the halocarbon and aromatic donors were observed in the crystal structures of the products. The method could also be extended to the introduction of other fluorinated groups, such as -CFClBr, -CFClI, -CFBr(2), and -CFMeI, which opens up new avenues for the synthesis of a wide range of useful fluorinated products.

Comprehensive Summary: The electrophilic addition to an alkene with an electrophile has been widely studied and applied in organic synthesis. The organic chemistry textbook describes the classical reaction between an alkene and an iodine electrophile (such as elemental iodine and N‐iodosuccinimide (NIS)) as a typical ionic reaction, in which an iodonium ion is formed and then attacked by a nucleophile. However, in this article, we report a new and unusual reaction mode between an alkene and NIS; that is, a single electron transfer (SET) process occurs between these two reactants by forming an electron‐donor acceptor complex. Not only does this unusual single electron transfer reaction between an alkene and NIS add fundamentally important knowledge to organic chemistry, it also provides a valuable synthetic method as the new SET reaction mode with opposite regioselectivity as compared with the traditional ionic mode. [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]

Perfluoro‐tert‐butylation reaction has long remained a challenging task. We now report the use of 1,1‐dibromo‐2,2‐bis(trifluoromethyl)ethylene (DBBF) as a practical reagent for perfluoro‐tert‐butylation reactions for the first time. Through a consecutive triple‐fluorination process with DBBF and CsF, the (CF3)3C− species can be liberated and observed, which is able to serve as a robust nucleophilic perfluoro‐tert‐butylating agent for various electrophiles. The power of this synthetic protocol is evidenced by the efficient synthesis of structurally diverse perfluoro‐tert‐butylated molecules. Multiple applications demonstrate the practicability of this method, as well as the superiority of perfluoro‐tert‐butylated compounds as sensitive probes. The perfluoro‐tert‐butylated product was successfully applied in 1H‐ and 19F‐magnetic resonance imaging (MRI) experiment with an ultra‐low field (ULF) MRI system. [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]

TMSCFX2 (X = Cl, Br; TMS = trimethylsilyl) have been developed as halofluorocarbene (CFX, X = Cl, Br) precursors for [2+1] cyclopropanation with alkenes. Structurally diverse halofluorocyclopropanes were obtained in good to excellent yields. It was found that the reactivity order of the three halofluorocarbene reagents (TMSCF2Br, TMSCFCl2, and TMSCFBr2) in halofluorocyclopropanation with 1,1-diphenylethylene can be very different under different reaction conditions. [ABSTRACT FROM AUTHOR]

In this paper, a fluoro‐hydroxylation of gem‐difluoroalkenes is demonstrated. This protocol uses sequential electrophilic fluorination with Selectfluor and nucleophilic hydroxylation with H218O, which can be used to prepare 18O‐labeled α‐CF3 alcohols from gem‐difluorostyrenes. The reaction is typically carried out at room temperature within 4 h in good to excellent yields. Other nucleophiles (besides H218O), such as alcohols, carboxylic acid, acetonitrile and N,N‐dimethylformamide, are also suitable for this difunctionalization of gem‐difluoroalkenes. [ABSTRACT FROM AUTHOR]

Terminal monofluoroalkenes are important structural motifs in the design of bioactive compounds, such as homeostasis regulators and mechanism-based enzyme inhibitors. However, it is difficult to control the stereoselectivity of known carbonyl olefination reactions, and olefin metathesis is limited to disubstituted terminal monofluoroalkenes. Although sulfoximines have been used extensively in organic synthesis, reports on their use in carbonyl olefination reactions have not appeared to date. Herein, we report highly stereoselective carbonyl monofluoroolefination with a fluorosulfoximine reagent. The potential of this method is demonstrated by the synthesis of MDL 72161 and by the late-stage monofluoromethylenation of complex molecules, such as haloperidol and steroid derivatives. [ABSTRACT FROM AUTHOR]

A AgF-mediated fluorination with a concomitant cross-coupling between a gem-difluoroolefin and a non-fluorinated olefin is reported. This highly efficient method provides facile access to both α-CF3 alkenes and β-CF3 ketones, which otherwise remain challenging to be directly prepared. The application of this method is further demonstrated by the synthesis of bioactive isoxazoline derivatives. This approach represents a conceptually novel route to trifluoromethylated compounds that combines the in situ generation of the CF3 moiety and a CH functionalization in a single reaction system. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: The electrophilic addition to an alkene with an electrophile has been widely studied and applied in organic synthesis. The organic chemistry textbook describes the classical reaction between an alkene and an iodine electrophile (such as elemental iodine and N‐iodosuccinimide (NIS)) as a typical ionic reaction, in which an iodonium ion is formed and then attacked by a nucleophile. However, in this article, we report a new and unusual reaction mode between an alkene and NIS; that is, a single electron transfer (SET) process occurs between these two reactants by forming an electron‐donor acceptor complex. Not only does this unusual single electron transfer reaction between an alkene and NIS add fundamentally important knowledge to organic chemistry, it also provides a valuable synthetic method as the new SET reaction mode with opposite regioselectivity as compared with the traditional ionic mode. [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]

Abstract: Tetrakis(dimethylamino)ethylene (TDAE) was found to be an effective electron-transfer agent that promoted the reactions of bromodifluoromethyl phenyl sulfone with aldehydes to give structurally diverse (benzenesulfonyl)difluoromethylated alcohols in good yield, which can be further transformed into difluoromethyl alcohols and 1,1-difluoro-1-alkenes via reductive desulfonylation and Julia olefination, respectively. [Copyright &y& Elsevier]

An abstract of the article "Spontaneous Resolution of Julia-Kocienski Intermediates Facilitates Phase Separation to Produce Z- and E-Monofluoroalkenes" by Y. Zhao and colleagues is presented.

An efficient radical (2-pyridylsulfonyl)difluoromethylation of terminal alkenes with 2-PySO 2 CF 2 I has been successfully achieved by using catalytic amount of Et 3 B/air as initiating system. This methodology was also further extended to the synthesis of 2-PySO 2 CF 2 -substituted alkanes and alkenes. [ABSTRACT FROM AUTHOR]

A novelsilver(I)-fluoride-mediated homocoupling reaction of β,β-difluorostyrenederivatives is described. The transformation is initiated via nucleophilicaddition of silver(I) fluoride to β,β-difluorostyrenes,which is followed by dimerization of the corresponding benzylsilverintermediates. The reaction shows good substrate scope, functionalgroup tolerance, and represents the first report on the reactivityof (α-trifluoromethyl)benzylsilver species. [ABSTRACT FROM AUTHOR]

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]

Abstract: Nucleophilic (phenylsulfonyl)difluoromethylation of both alkyl iodides and bromides was successfully accomplished by using CsF/15-crown-5 as an initiating system in DME, and the amount of 15-crown-5 was found to be critical to the yield of the product. The prepared (phenylsulfonyl)difluoromethylated alkanes were converted into gem-difluoroalkenes by a base-mediated 1,2-elimination reaction, and the latter species could be further transformed into trifluoromethyl compounds in the presence of KF/18-crown-6 or TBAF. [Copyright &y& Elsevier]

In contrast to previously developed methods the presented protocol has a broad substrate scope, thus offering access to various 1,1-difluoroalkenes such as difluoroacrylates, diaryldifluoroolefins and arylalkyldifluoroolefins. [ABSTRACT FROM AUTHOR]