Special Topic : Organic Chemistry Booming in China China ’ s flourishing synthetic organofluorine chemistry : innovations in the new millennium

The newmillennium has witnessed the rapid development of synthetic organofluorine chemistry all over the world, and chemists in China have made significant contributions in this field.This review aims to provide a brief introduction to China’s primary innovations from 2000 to early 2017, covering fluorination, fluoroalkylation, fluoromethylthiolation, fluoroolefination and polyfluoroarylation, as well as synthesis with fluorinated building blocks. Recent advances in the chemistry of difluorocarbene and the chemistry of carbon–fluorine bond activation are also discussed. As a conclusion, the review ends with some personal perspectives on the future development of China’s synthetic organofluorine chemistry.


INTRODUCTION
In the field of organic chemistry, fluorine is a supersubstituent due to its high electronegativity (4.0 on the Pauling scale), small atomic radius (r v = 1.47 Å) and the great strength of the carbon-fluorine (C−F) bond (averages about 116 kcal/mol) [1].The incorporation of fluorine atoms or fluorinated moieties into organic molecules can often lead to profound changes in the latter's physical, chemical and biological properties, and a variety of fluorine-containing materials, pharmaceuticals and agrochemicals have been developed [2].However, although fluorine is an abundant halogen element and ranks number 13 among all elements in the Earth's crust, naturally occurring organofluorine compounds (organic compounds bearing a C−F bond) are rare [3].Therefore, the development of efficient ways to introduce fluorine into organic compounds has become one of the hottest areas of organic synthesis research in recent years.Many efficient methodologies for the synthesis of organofluorine compounds have been developed by chemists all over the world [3][4][5][6][7][8][9][10][11][12][13][14].
China is rich in fluorspar deposits and most of the fluorine-containing basic chemicals, such as sim-ple fluorocarbons, are readily available from the Chinese chemical industry.Chinese chemists have engaged in organofluorine chemistry since the 1950s and have made significant contributions.In the past decade, many young Chinese scientists have joined this intriguing research field.Several books and book chapters have already described the development of China's organofluorine chemistry efforts prior to 2000 [15][16][17].This Review focuses on providing a brief summary of China's primary innovations in the field of synthetic organofluorine chemistry from 2000 to early 2017, covering fluorination, fluoroalkylation, fluoromethylthiolation, fluoroolefination and polyfluoroarylation, as well as synthesis with fluorinated building blocks.Special topics on the chemistry of difluorocarbene and the chemistry of the C-F bond activation are also discussed.

Nucleophilic fluorination
Nucleophilic fluorination is a fundamental methodology for the synthesis of organofluorine compounds.Huang and Guo's pioneering work at the Shanghai Institute of Organic Chemistry (SIOC) in 1981 described the deoxyfluorination of sterols with phenyl sulfur trifluorides [19]; however, the low efficiency of this method limited its adoption for widespread use.Hou et al. at SIOC, in 2004 developed an efficient and highly regioselective method for the fluorination of aziridines using BF 3 •Et 2 O as the fluoride source [20], which is one of the earli-est reports of the use of boron trifluoride for nucleophilic ring-opening fluorination reactions [12].
In more recent organofluorine chemistry, more attention has been paid to controlling selectivity and exploiting new reactivity [21].Hu et al. at SIOC recently developed a novel deoxyfluorination strategy based on cyclopropenium cation activation via the use of 3,3-difluoro-1,2-diarylcyclopropenes (CpFluors) (Scheme 1, Eq 1) [21] to tackle the problem of deoxyfluorination of alcohols not usually being sensitive toward the electronic nature of the substrates.The key to the success of this approach is the fine-tuning of the electronic nature of the CpFluor reagents to improve the nucleophilic fluorination.Moreover, the challenge of taming direct nucleophilic fluorination of arynes with fluoride ions has been achieved by the same group by using a diphenyliodonium salt as the catalyst (Scheme 1, Eq 2) [22].In addition, transition metals have also been utilized to promote reactions that are otherwise difficult to achieve.Liu et al. at SIOC [23,24], Weng et al. at Fuzhou University (FZU) [25] and Jiang et al. at the South China University of Technology [26] (Scheme 1, Eqs 3-6) have published representative works on copper-catalyzed/mediated or silver-mediated nucleophilic fluorination.

Oxidative fluorination with fluoride ion
Considering that the fluoride ion is stable and abundant in nature, the direct oxidative fluorination of substrates with a fluoride ion is an ideal alternative method for the current electrophilic fluorination reactions [53].Among various oxidants, hypervalent iodine compounds are the most usually used mild and selective oxidants.
Liu et al. at SIOC reported a highly regioselective palladium-catalyzed intramolecular aminofluorination of amino-functionalized alkenes using the combination of bis(tert-butylcarbonyloxy)iodobenzene [PhI(OPiv) 2 ] and AgF (Scheme 5) [54] in 2009.The reaction is believed to proceed through aminopalladation of alkenes followed by oxidative fluorination involving a Pd(IV)−F complex [53].In recent years, more fluorination reactions have been similarly developed by oxidation of the substrate to form an electrophilic carbon center followed by nucleophilic fluorination either under metal catalysis/mediation or metal-free conditions (Scheme 5) [55][56][57][58][59]. Wang et al. at Tsinghua University have demonstrated the aromatic C−H fluorination of azacalix [1]arene [3]pyridines via Cu(III) using a fluoride salt and a Cu(II) salt, which provides direct evidence to support the mechanism of copper-mediated fluorination of aryl halides involving a Cu(I)/Cu(III) cycle [6,59].

DIFLUOROCARBENE
Difluorocarbene is a versatile and reactive intermediate in organic synthesis.The chemistry of difluorocarbene is an important aspect of organofluorine chemistry [2].difluorocarbene in a controlled, acid-free environment and is one of the most widely used precursors for difluoromethylenation of alkenes and alkynes, including electron-poor alkenes such as α,β-unsaturated esters [61,62].However, in the new millennium, the development of novel difluorocarbene precursors is still highly desirable due to the regulation of the use of ozone-depleting substances (ODS) that are usually employed for the difluoromethylation of heteroatom nucleophiles by the Montreal protocol [63].Moreover, exploring new reactions of difluorocarbene also requires new precursors that are compatible with various substrates (Scheme 6). the molecular structure of which adopts an ionic form consisting of a [Cu(phen) 2 ] + cation and a chlorodifluoroacetate anion [69].

Nucleophilic trifluoromethylation and perfluoroalkylation
The trifluoromethyl group (−CF 3 ) has a privileged role in agrochemicals and pharmaceuticals because its incorporation into drug candidates could enhance chemical and metabolic stability, improve lipophilicity and bioavailability, and increase protein binding affinity [81].In addition, trifluoromethylated organic compounds are widely applied in materials science [2].
China's research on nucleophilic trifluoromethylation dates back to the 1980s.reagent' (Scheme 7, Eq 1) [82,83].A typical application of Chen's reagent is the first synthesis of 20 π -electron non-aromatic isophlorin [84,85].Very recently, a new trifluoromethylating, reagent copper(II) difluoro(fluorosulfonyl)acetate [Cu(O 2 CCF 2 SO 2 F) 2 ], which easily decomposes to generate active CuCF 3 species in N,Ndimethylformamide at room temperature, has been conveniently prepared from inexpensive starting materials on a large scale (Scheme 7, Eq 2) [86].Despite the high efficiency of Chen's reagents for the trifluoromethylation of aryl, alkenyl and alkyl halohydrocarbons, it is not suitable for the nucleophilic trifluoromethylation of aldehydes, ketones and imines.Hu et al. at SIOC subsequently reported the nucleophilic trifluoromethylation of aldehydes using PhSO 2 CF 3 as a practical reagent in 2010, through a magnesium metal-mediated reductive desulfonylation process (Scheme 7, Eq 3) [87].In their continuous research, PhSOCF 3 was developed as a practical trifluoromethyl source for the preparation of 'ligandless' CuCF 3 species under the activation of potassium tert-butoxide, which can be used as an alternative to the prevailing TMSCF 3 reagent in both copper-mediated nucleophilic and oxidative trifluoromethylation reactions (Scheme 7, Eq 4) [88].
Umemoto et al. and others initially developed S-trifluoromethylsulfonium salts as electrophilic trifluoromethylation reagents [89].Xiao et al. at SIOC first disclosed that the less effective Strifluoromethyl-S,S-diphenylsulfonium salt can be reduced by elemental copper to form CuCF 3 via a single electron transfer (SET) process in 2011 [90].The in-situ formed CuCF 3 species is of very high reactivity and is capable of effective trifluoromethylation of iodo-substituted heteroaromatic compounds, which is otherwise difficult to achieve (Scheme 7, Eq 5).
By using the trifluoromethyl metal species generated from either the Ruppert-Prakash (TMSCF 3 ) or Umemoto reagents, several novel nucleophilic trifluoromethylation reactions of aromatic and aliphatic compounds have been disclosed.Hu et al. at SIOC reported a copper-mediated trifluoromethylation of α-diazo esters as a new method for the preparation of α-trifluoromethyl esters in 2012.This trifluoromethylation reaction proceeds via the transformation of a trifluoromethylcopper−carbene complex and represents the first example of fluoroalkylation of a non-fluorinated carbene precursor (Scheme 8, Eq 1) [91].
Arynes are one of the most useful and structurally unique intermediates in synthetic chemistry.However, the combination of perfluoroalkyl anions with arynes is difficult because of their mismatched reactivities.Hu et al. at SIOC developed an unprecedented one-step protocol for trifluoromethylation of arynes via the use of AgCF 3 in 2013.This method provides an efficient route to various ortho-trifluoromethylated iodoarenes that are otherwise difficult to synthesize by traditional trifluoromethylation methods (Scheme 8, Eq 2) [92].
The Sandmeyer reaction is a classical and fundamental named reaction for the transformation of aryl amines to substituted aromatics via displacement of their diazonium salts with a nucleophile.Wang et al. at Peking University (PKU) and Fu et al. at University of Science and Technology of China (USTC) independently reported the first Sandmeyer-type trifluoromethylation reactions in 2013 by using AgCF 3 and CuCF 3 , respectively (Scheme 8, Eq 3) [93,94].
The asymmetric nucleophilic trifluoromethylation of carbonyl compounds is challenging due to the interference of the autocatalytic background reaction [45].Feng et al. at Sichuan University developed a new combinatorial catalyst system in 2007, composed of the disodium (R)-binaphtholate and a chiral quaternary ammonium salt for enantioselective trifluoromethylation of aromatic aldehydes with TMSCF 3 (Scheme 9, Eq 1) [95,96].The reaction proceeds in moderate to good enantioselectivity, which represents one of the few examples of highly enantioselective trifluoromethylation of aldehydes.Tang et al. at SIOC reported an asymmetric 1,2-perfluoroalkyl migration reaction of hydrate of 1-perfluoroalkyl-1,2-diketones with chiral alcohols as an alternative method for asymmetric nucleophilic perfluoroalkylation.The reactions are promoted by a Zn(II)/bisoxazoline complex and form enantioenriched α-hydroxy-α-perfluoroalkyl esters (Scheme 9, Eq 2) [97].

Oxidative trifluoromethylation and perfluoroalkylation
The study of oxidative perfluoroalkylation has a strong background in China.Huang et al. at SIOC first proposed the direct generation of perfluoroalkyl radicals from perfluoroalkanesulfinate salts through single electron oxidation [98] as early as 1989.In this context, perfluoroalkanesulfinate salts have been developed to be useful perfluoroalkylation reagents for the transformation of alkenes and (hetero)aromatic compounds under the action of various oxidants [5,16].Langlois, Baran and others have used a similar methodology for trifluoromethylation with CF 3 SO 2 Na [5,[99][100][101][102][103][104][105] since 1991.Liu et al. [102] at LZU's oxidative decarboxylative trifluoromethylation of α,β-unsaturated carboxylic acids is particularly noteworthy.Wang et al. [103] at Sun Yat-sen University's development of trifluromethylative oxidation of alkenyl boronates is similarly significant.
Qing et al. at SIOC first proposed the concept of 'oxidative trifluoromethylation', namely, the reaction of nucleophilic substrates and nucleophilic trifluoromethylation reagents in the presence of oxidants (Scheme 10) [104], in 2010.Mechanistically, the reactions proceed through three different pathways: the oxidation of the substrates, the oxidation of the CF 3 anion, and a transition metal-mediated or -catalyzed oxidative coupling reaction.Based on this concept, copper-mediated or -catalyzed or metal-free oxidative C−H trifluoromethylation of terminal alkynes, tertiary amines, arenes, heteroarenes and terminal alkenes was developed.In addition to various C−H bonds, aryl boronic acids are also suitable nucleophilic partners for copper-mediated or -catalyzed cross-coupling reactions with TMSCF 3 .They also developed silvercatalyzed hydrotrifluoromethylation of unactivated olefins and silver-mediated O-trifluoromethylation of phenols and alcohols [104][105][106].These investigations have explored boronic acids, C−H bonds, P−H bonds and O−H bonds as novel nucleophiles in transition metal-mediated or -catalyzed crosscoupling reactions with TMSCF 3 , opening up new avenues for future trifluoromethylation reactions.O-trifluoromethylation constitutes one of the most straightforward methods by which trifluoromethyl ethers can be obtained [9,105,106].Qing et al. also achieved the oxidative trifluoromethylthiolation of aryl boronic acids and terminal alkynes to synthesize trifluoromethyl sulfides by employing TMSCF 3 and S 8 as the CF 3 S anion source.All these oxidative trifluoromethylation and trifluoromethylthiolation reactions tolerate a wide range of functional groups, affording structurally diverse CF 3 -and CF 3 S-containing compounds with high efficiencies, and provide elegant and complementary alternatives to classical trifluoromethylation and trifluoromethylthiolation reactions [104][105][106].Similar synthetic strategies have also found application in the trifluoromethylation of primary and secondary alkylboronic acids [107], as well as ortho C-H trifluoromethylation of arenes [108].The concept of oxidative trifluoromethylation has been extended to difluoromethylation and difluoroalkylation relations [109][110][111][112].
In metal-mediated fluoroalkylation reactions, copper usually has a good partnership with trifluoromethylation; however, palladium-promoted trifluoromethylation reactions are relatively rare [8].Liu et al. at SIOC developed a novel palladiumcatalyzed oxidative trifluoromethylation of indoles at room temperature, in which iodobenzene diacetate [PhI(OAc) 2 ] was used as an oxidant and TMSCF 3 as a trifluoromethylating reagent (Scheme 11, Eq 1) [113], in 2011.The reaction is proposed to proceed through the oxidation of the Ar-Pd(II) intermediate by PhI(OAc) 2 /TMSCF 3 to generate the Ar−Pd(IV)-CF 3 intermediate, which undergoes reductive elimination to form an Ar−CF 3 bond.This work is the first example of Pd(II)/Pd(IV)-catalysis involved oxidative trifluoromethylation with a nucleophilic trifluoromethylating reagent [8].Thereafter, a similar strategy was applied to a palladium-catalyzed intramolecular oxidative aryltrifluoromethylation reaction of activated alkenes (Scheme 11, Eq 2) [114].

Electrophilic trifluoromethylation and perfluoroalkylation
Electrophilic trifluoromethylation of nucleophilic substrates has been on its way since the development of the Umemoto reagent, which constitutes one of the most popular electrophilic trifluoromethylating agents (Scheme 12) [89].To date, the trifluoromethylation of many substrates including aryl boronic acids, alkenes, arenes and organometallic reagents, which had been unattainable by merely relying on the innate reactivity of the Umemoto or Togni reagent, has been achieved by utilizing metal or non-metal catalysis [115][116][117].
Chemists in China have made elegant contributions to expand the synthetic applications of the Scheme 12.The structures of the Umemoto and Togni reagents.
Liu et al. at USTC and Shen et al. at SIOC independently reported the first copper(I)-catalyzed cross-coupling trifluoromethylations with aryl boronic acids using electrophilic trifluoromethylating regents under mild conditions in early 2011 (Scheme 13, Eq 1) [128,129].Xiao et al. at SIOC have developed a reductive system with elemental copper that is also applicable to the trifluoromethylation of aryl boronic acids with S-trifluoromethylsulfonium salt in the absence of an additional ligand (Scheme 13, Eq 2) [130].
Buchwald et al. at the Massachusetts Institute of Technology, Wang et al. at PKU and Liu et al. at USTC independently reported, in the middle of 2011, an unprecedented type of reaction for copper(I)-catalyzed direct trifluoromethylation of terminal alkenes to prepare trifluoromethylated allylic compounds using the Togni or Umemoto reagents (Scheme 13, Eq 3) [131][132][133].The coppercatalyzed reactions mentioned here constitute early examples of the construction of a C(sp 3 )−CF 3 bond from alkenes with electrophilic trifluoromethylating agents, and opened the door for the trifluoromethylative transformation of alkenes [8].
Liu et al. at Northeast Normal University first demonstrated, in 2013, that the acyclic hypervalent iodide trifluoromethylating species [PhICF 3 ] + can be generated in situ by simple mixing of PhI(OAc) 2 , TMSCF 3 and KF under metal-free conditions [134].This species is capable of sp 2 C−H trifluoromethylation of indoles with higher reactivity than Togni's cyclic hypervalent iodine reagent (Scheme 14) [115,134,135].
Furthermore, Chinese chemists have also developed a cooperative catalytic system for trifluoromethylative asymmetric reactions [136,137] reaction for the construction of C−CF 3 and C−O bonds by virtue of a copper(I)/Brønsted acid cooperative catalytic system in 2014 (Scheme 15, Eq 1) [136].This reaction may proceed through radical trifluoromethylation of an unactivated alkene to initiate a subsequent 1,5-hydrogen shift and enantioselective functionalization of α-C-H bonds of the amides.Very recently, the same group developed another novel asymmetric radical amido-trifluoromethylation of alkenes [137], providing straightforward access to CF 3 -containing aza-heterocycles with excellent enantioselectivity (Scheme 15, Eq 2).
Perfluoroalkyl halides R f −X (X = I, Br) can form donor-acceptor complexes with heteroatoms such as N, O and S through halogen bonding.Zhu [143].Very recently, this kind of interaction has been applied to initiate radical perfluoroalkylation reactions of R f −X [144].

DIFLUOROMETHYLATION AND DIFLUOROALKYLATION
Difluoroalkylation, including difluoromethylation, is a streamlined synthetic methodology for introducing the CF 2 and CF 2 H group into molecules.The CF 2 group can function as a bioisostere for an oxygen atom or a carbonyl group, and the CF 2 H group can be used as a bioisostere of a carbinol moiety and as a more lipophilic hydrogen bond donor [145].The selective incorporation of difluoroalkyl groups has gained much attention in recent years [146].Due to the easy availability of many difluorinated building blocks from the industry, China has unique advantages for the development of difluoromethylation and other difluoroalkylation chemistry.Indeed, Chinese chemists have been leading the development of this field and have made many major contributions [5,[145][146][147][148][149].

Nucleophilic difluoromethylation
Di-and monofluoromethylation are featured topics in fluoroalkylation chemistry.Although nucleophilic trifluoromethylation has been known for a long time, less attention has been paid to nucleophilic di-and monofluoromethylation [145,[147][148][149] characterized for the first time.This species is a very mild nucleophilic difluoromethylating agent and is recognized to be a key intermediate in the difluoromethylation of enolizable ketones [153].
Hu et al. at SIOC developed the first highly stereoselective difluoromethylation of carbonyl compounds in 2012, by employing a 'choreographed' chiral S-difluoromethyl sulfoximine reagent [154].The chemistry of fluorinated sulfoximines, which originate from the research on fluorinated sulfones, not only provides useful methods for synthesizing organofluorine compounds, but also expands our knowledge of sulfoximine chemistry and represents a featured topic in organofluorine chemistry [155].
Hu et al. used the (2-Py)SO 2 CF 2 H reagent initially designed for gem-difluoroolefination to develop a formal nucleophilic iodo-and bromodifluoromethylation method for carbonyl compounds by 'hijacking' of the sulfinate intermediates in the Julia−Kocienski reaction [156].This work is the first example concerning the application of the Julia−Kocienski olefination intermediate for a nonolefination reaction and has inspired the further investigation of nucleophilic halodifluoromethylation [157,158].
Since the first publication of direct nucleophilic difluoromethylation, TMSCF 2 H has been used by many groups for various transformations [153,[159][160][161]. Qing et al. at SIOC reported coppermediated direct difluoromethylation of electrondeficient aryl iodides (Scheme 17, Eq 1) [159].Shen et al. at SIOC have developed a cooperative dual palladium/silver catalyst system for direct difluoromethylation of aryl bromides and iodides (Scheme 17, Eq 2) [160,161].This difluoromethylation method is compatible with a wide range of functional groups, including both electron-rich and electron-poor groups.

Electrophilic difluoromethylation
Chen et al. at SIOC reported a smooth reaction of HCF 2 I with alkenes and alkynes in the presence of Na 2 S 2 O 4 , providing difluoromethylated adducts in moderate to good yields [162], as early as 1994.However, HCF 2 I is not an ideal difluoromethylation REVIEW Scheme 18. Electrophilic difluoromethylating reagents and their representative applications.

Scheme 19. Representative nucleophilic difluoroalkylation reactions.
reagent due to its gaseous property, limited availability and relatively low reactivity.
Hu et al. at SIOC, by taking advantage of the excellent softening ability of sulfur on the 'hard' fluorine and the 'chemical chameleon' character of the phenylsulfonyl and related groups, flipped the reactivity of fluorinated sulfones from nucleophilicity to electrophilicity by slightly changing the substituents and thus invented a series of electrophilic difluoromethylating reagents, ranging from sulfones, sulfoximines and sulfinates (Scheme 18) [5,139,163].Together with the developed difluorocarbene reagents [64], these reagents have been successfully used to exploit novel or practical elec-trophilic difluoromethylation reactions.Hu et al. reported the first examples of decarboxylative fluoroalkylation of α,βand β,γ -unsaturated carboxylic acids by employing the I(III)-CF 2 SO 2 Ph reagent [164,165].Very recently, heteroaryl difluoromethyl sulfones have been exploited for practical radical difluoromethylation under photocatalysis.Note that this radical fluoroalkylation strategy is capable of incorporating both difluoromethyl and many other fluoroalkyl groups such as trifluoromethyl, difluoromethyl and monofluoromethyl groups [139].Qing et al. at SIOC have also reported the use of bromodifluoromethyl-and difluoromethyltriphenylphosphonium bromide as an alternative photocatalyzed radical difluoromethylation reagent [166,167].
Previously, the electrophilic difluoromethylation of heteroatoms mainly relied on difluorocarbene reagents.Mechanistically, the CF 2 H group is not introduced as a whole, but is constructed via a stepwise reaction involving the protonation of a difluorinated carbanion intermediate.In this context, Shen et al. at SIOC developed a S-difluoromethylsulfonium ylide for direct electrophilic difluoromethylation of alcohols [168].

Nucleophilic difluoroalkylation
Nucleophilic difluoroalkylation involving the introduction of a functionalized difluoromethyl anion or its equivalent is a traditional research topic [146].In recent years, the development of asymmetric synthesis and metal catalysis has extended the research scope of this topic.
Zhou et al. at East China Normal University reported a highly efficient 'on-water', catalyst-free nucleophilic addition reaction of silyl difluoroenol ethersin 2014, which exhibits dramatic fluorine effects.The C-F/H-O interactions between difluorinated enol ethers and the hydrogen bond network of water at the phase boundary of the reactants may promote the formation of a unique microstructure, thus facilitating the 'on-water' catalyst-free addition reaction (Scheme 19, Eq 1) [169].Zhou et al. subsequently developed a chiral secondary amine phosphoramide catalyst for the highly enantioselective Michael addition of both diand monofluorinated enol silyl ethers to tetrasubstituted olefins [170], which belongs to one of the few examples of efficient syntheses of quaternary chiral carbon atoms with a mono-or difluoroalkyl group (Scheme 19, Eq 2).Hao et al. at Shanghai University first studied the copper(0)-promoted direct reductive gem-difluoromethylenation of aryl or alkenyl halides with bromodifluoromethylated heteroaromatics, expanding the scope of metal-mediated nucleophilic difluoroalkylation reactions (Scheme 19, Eq 3) [171].
Zhang et al. at SIOC have, since 2014, systematically studied the palladium-or nickel-catalyzed difluoroalkylation of boronic acids with a broad range of functionalized halodifluoroalkylating reagents such as bromodifluoroacetates, boromodifluorophosphonates, boromodifluoromethyl alkenes, boromodifluoromethyl alkynes and bromodifluoromethyl arenes, and even unactivated 1-bromo-1,1-difluoroalkanes (Scheme 20) [173][174][175][176][177]. When the catalyst is used with nickel, which is abundant in nature, the organic boronic acid is capable of reacting with a less reactive chlorodifluoroalkylating agent.Moreover, the first example of a transition metal-catalyzed carbonylative fluoroalkylation reaction has been achieved by using a palladium catalyst in the presence of CO [178].Zhang et al. at SIOC and Wang et al. at USTC have, complementarily, reported palladium-and nickel-catalyzed difluoroalkylation of alkenes, respectively [179,180].These investigations not only broaden the scope of electrophilic difluoroalkylation, but also reveal the principle that metal catalysts such as palladium and nickel exhibit higher activities in difluoroalkylation than perfluoroalkylation.
Recent advances in photocatalysis with visible light have provided new opportunities for electrophilic difluoroalkylation with bromodifluoroalkylated compounds [181][182][183][184], and representative work in China has been summarized in a recent review [185].

Electrophilic monofluoromethylation
N-Tosyl-S-monofuoromethyl-S-phenylsulfoximine has been used as a new efficient monofuoromethylating reagent for O-, S-, Nand P-nucleophiles.The preliminary mechanistic study suggests that the reaction proceeds through a radical mechanism involving a SET process.This is the first example of a fluoroalkylation using a sulfoximine as a fluoroalkyl radical precursor [190].
In the case of metal-catalyzed reactions, examples of electrophilic monofluoromethylation of arylboronic esters [191], arylboronic acids [192,193] and isocyanides [139,194] employing the monofluorinated alkyl halides have been reported.Of note is the use of CH 2 FI and CH 2 FBr as the direct monofluoromethylating reagents [191,193].

Nucleophilic monofluoroalkylations
Asymmetric alkylation of an activated fluorinated methylene carbon is an important method for the construction of a fluorinated chiral carbon center [195,196].Han et al. at Nanjing University reported the first asymmetric deacetylative aldol reaction of substituted 2-fluoro-1,3-diketones in 2015, providing a new approach for the preparation of biologically relevant products containing C-F quaternary stereogenic centers 22) [196].
Xu et al. at Xiamen University recently reported an efficient and highly chemoselective electrochemical intramolecular oxidative cross-coupling reaction of activated monofluoroalkanes with electron-rich arenes employing Cp 2 Fe as the redox catalyst, which was proved to be a straightforward, modular and efficient approach for the synthesis of functionalized 3-fluorooxindoles [197].

TRIFLUOROALKYLATION
β,β,β-Trifluoroalkylation is an alternative approach for incorporating a trifluoromethyl group, which is an important topic of organofluorine chemistry due to the unique β-fluorine effect.Previously, much attention has been paid to the chemistry of activated α-trifluoromethyl carbanions (2,2,2trifluoroalkanide anion) and organometallic species, whose spontaneous release of fluoride ions to produce difluoroalkenes was inhibited by the activation groups.However, the use of non-activated (2,2,2-trifluoroalkyl)metal species in trifluoroalkylation had been largely unexplored.

TRI-AND DIFLUOROMETHYLTHIOLATION
The trifluoromethylthio group (−SCF 3 ) is an important structural motif in many pharmaceuticals and agrochemicals because of its high lipophilicity and strong electron-withdrawing properties [14,208,209].Chen et al. at SIOC reported, as early as 1993, a direct trifluoromethylthiolation reaction of aryl halides employing elemental sulfur and the trifluoromethylating reagent FSO 2 CF 2 CO 2 Me under the promotion of a stoichiometric amount of copper iodide [210].However, the concept of trifluoromethylthiolation has only become prevalent in recent years.Qing et al. at SIOC developed coppercatalyzed oxidative trifluoromethylthiolation of aryl boronic acids, TMSCF 3 and elemental sulfur in 2012 [211].Tang et al. at Nankai University and Chen et al. simultaneously demonstrated the first example of oxidative trifluoromethylthiolation of unactivated C(sp 3 )-H bond in 2014 by using silver trifluoromethylthiolate (AgSCF 3 ) as the reagent [212,213].Lu, Shen and coworkers at SIOC have developed three different types of air-and moisture-stable electrophilic trifluoromethylthiolating reagents since 2012: trifluoromethanesulfenates, N-trifluoromethylthiosaccharin and N-trifluoromethylthiodibenzenesulfonimide (Scheme 24) [209,214].Comprehensive studies have shown that both types of reagents are highly reactive toward a wide range of nucleophiles, yet with complementary substrate scopes.Trifluoromethanesulfenate reagents are more suitable for transition metal-catalyzed reactions such as copper-catalyzed trifluoromethylthiolation of aryl/vinyl/alkyl boronic acids and silver-catalyzed decarboxylative trifluoromethylthiolation of aliphatic carboxylic acids, as well as for organocatalytic asymmetric trifluoromethylthiolation of β-keto esters and oxindoles.In contrast, N-trifluoromethylthiosaccharin is more applicable for direct trifluoromethylthiolation of nucleophilic substrates such as alcohols, amines, thiols and electron-rich arenes.The merits of these reagents, including the ease of their preparation, broad scope and mild reaction conditions, render them extremely useful for the ready introduction of the CF 3 S group into various organic molecules [209].
Weng et al. at FZU developed nucleophilic trifluoromethylthiolation with a well-defined copper complex in 2013 [219].In addition, the reduction of CF 3 SO 2 Na with a phosphine reagent was first explored for practical, electrophilic or nucleophilic trifluoromethylthiolation by chemists in China [220,221].

Transformation of gem-difluoroolefins
The C−F bond is commonly regarded as the strongest single bond formed with carbon, and the selective activation of the C−F bond has emerged as an interesting methodology to obtain fluorinated compounds [227].Chinese chemists began to investigate the selective cleavage of C−F bonds in the 1980s.Huang et al. at SIOC found that the 'Cr-H' species could enable defluorinative hydrogenation of the trimer of perfluorinated propylene [15].Over the last five years, numerous efforts have been made to develop useful reactions via the selective cleavage of C-F bonds in gem-difluoroolefins (Scheme 26) [228][229][230][231]. Cao et al. at East China University of Science and Technology recently summarized advances in this research area [223].
On the other hand, fluoride addition-induced β,β,β-trifluoroalkylation with difluoroolefins has been developed as a new method for the transformation of gem-difluoroolefins [232,233], which is highly efficient for the generation of β,β,βtrifluorinated carbanions compared to the traditional deprotonative approach (Scheme 26).Hu et al. at SIOC reported an AgF-mediated fluorinative homocoupling of gem-difluoroolefins in 2014 [234].On the basis of this finding, a AgF-mediated fluorinative cross-coupling of gem-difluoroolefins and non-fluorinated olefins was developed for the first time (Scheme 26) [202].Loh et al. at Nanjing Tech University more recently demonstrated a palladiumcatalyzed allylic β,β,β-trifluoroalkylation by using similar method (Scheme 26) [203].

Monofluoroolefination
For monofluoroolefination, controlling Z/Estereoselectivity still remains a challenging task.In the past decade, scholars of China have developed a series of stereoselective monofluoroolefination methods.Hu et al. at SIOC disclosed a novel olefination method for the first highly stereoselective one-step synthesis of Z-monofluoroalkenes by reacting nitrones with the fluorosulfoximine reagents in 2009 (Scheme 27) [235].Very recently, by slightly changing the S-substituent of sulfoximine from phenyl to 2-pyridyl with a modification of the electronic property of the N-substituent, the highly stereoselective carbonyl olefination for both diand trisubstituted terminal monofluoroalkenes has become reality (Scheme 27) [236].Interestingly, although the sulfonyl group is not a good stereocontrol element, it can facilitate isomer separation.Thus, monofluoroolefination with 2-pridyl sulfone reagents has led to the easy preparation of both isomers of monofluoroalkenes in one pot, which is due to the spontaneous kinetic resolution of the syn-/anti-sulfinate intermediates during their decomposition to Z/E-monofluoroalkenes [237].In addition to the direct construction of C=C bonds, the functionalization of gem-difluoroolefins [223,228] and gem-difluorocyclopropanes [238] via selective activation of the C−F bonds has also been exploited for the stereoselective synthesis of monofluoroalkenes.

POLYFLUOROARYLATION AND FURTHER TRANSFORMATION Polyfluoroarylation
Perfluorinated aromatic rings are prominent structural motifs that have numerous applications in materials and life science.Chen et al. at SIOC studied the photoinduced reactions of pentafluorophenyl perfluoro-and polyfluoroalkanesulfonates (R f SO 3 C 6 F 5 ) for the synthesis of pentafluorophenylated molecules as early as the 1990s [239].Zhang et al. at SIOC first reported palladium-catalyzed dehydrogenative crosscoupling of polyfluoroarenes with activated alkenes and heteroaromatics under the action of a silver salt in 2010 (Scheme 28) [240][241][242].A series of perfluoroarene-containing compounds were synthesized with potential applications in functional materials for electronic devices.Su et al. at the Fujian Institute of Research on the Structure of Matter [243] and Shi et al. at PKU [244] shortly after reported similar reactions for the C-H/C-H cross-coupling of polyfluoroarenes and simple arenes.Of note, these recent reports constitute the few early examples of oxidative coupling reactions with electron-deficient arenes.This concept has been extended to oxidative polyfluoroarylation of aromatic carboxylic acids [245], aromatic sulfinate salts [246] and aryl ethyl ketones [247].

SYNTHESIS WITH FLUORINATED SUBSTRATES
Synthesis with fluorinated building blocks/substrates is a very important method for the introduction of fluorine atoms or fluoroalkyl groups into target molecules.In the building blocks/substrates, where the fluorine or fluoroalkyl substitution is directly connected at a reactive site, the fluorine effect has significant influence on the outcome of their reactions.Indeed, most of this review has concentrated on synthesis with fluorinated building blocks, either C-1 or C-2.Ma et al. at TJU have published a comprehensive review on asymmetric synthesis with prochiral trifluoromethylated substrates [261].Here, we only list some tri-or difluorinated substrates recently designed or extensively studied by Chinese chemists (Scheme 30) [262][263][264][265][266][267][268][269][270] to demonstrate that the transformation of fluorinated substrates has attracted extensive attention in China.

CONCLUSIONS
The past 16 years has witnessed rapid development of Chinese synthetic organofluorine chemistry.On the one hand, a number of novel fluoroalkylation reagents have been developed to facilitate the introduction of privileged fluorine-containing groups, which can impart desirable chemical and biological properties on organic molecules such as materials, pharmaceuticals and agrochemicals.On the other hand, many new methods for the construction of C−F bonds and fluorinated C−C bonds with known fluorination and fluoroalkylation reagents have been developed, which permits the preparation of fluorinated molecules with structural diversity.
However, most of the new strategies still lack practicality and cost efficiency with regard to industrial production.Future research will need to focus on the development of green synthetic methods for the more general and practical introduction of fluorine atoms and fluoroalkyl groups, which is in line with the concept of sustainable development advocated by Chinese government.Because the formation of C−F bonds is the basic foundation of organofluorine chemistry, the development of efficient fluorination methods with inorganic fluorides is also highly desirable.
In the future, attention should also be paid to challenging tasks such as synthesis of trifluoromethyl ethers (ROCF 3 ) [9,105,106,[271][272][273][274][275], synthesis of pentafluorosulfanyl compounds (RSF 5 ) [10], [ 18 F] radioisotope-labeled synthesis of organic molecules for positron emission tomography [11], as well as region-and stereoselective fluorination and fluoroalkylation [45].Moreover, exploiting new methods for the conversion of difluorocarbene and fluorinated alkenes, both of which have a close relationship with fluorinated polymers, is also a fascinating field that deserves much attention.
Since nature lacks efficient mechanisms to construct C−F bonds, almost all organofluorine compounds that we use today have to be man-made.Therefore, synthetic organofluorine chemistry in China still has a long way to go, not only to meet the increasing demand for various organic fluorochemicals, but also to gain deeper insights into the unique features of fluorine in organic reactions and related sciences.Last but not least, we would like to emphasize that fluorspar, as the most basic material for developing organofluorine chemistry and industry, is a limited and non-renewable natural resource in China, so we must make rational utilization of fluorspar deposits and develop new methods and technologies for the recovery and reuse of fluorochemicals.
Li et al. at Shandong University reported the selective C−F bond activation of fluorine-containing arenes in the presence of stoichiometric amounts of cobalt or iron complexes in 2006 [251,252].Although many methods have been developed for the selective cleavage of C−F bonds, either catalytically or stoichiometrically, most of them are based on the electronic effects of the substituents [253,254].Zhang et al. at SIOC and others have investigated the chelating group-oriented ortho-selective C-F activation of polyfluoroarenes since 2012 (Scheme 29) [255-260].

Scheme 7. Representative reagents/methods for nucleophilic trifluoromethylation. Scheme 8. Metal-mediated nucleophilic trifluoromethylation.
et al. at SIOC reported two different kinds of endless chains of alternating α,ω-diiodoperfluoroalkane and oxygenin 2001, which represent the earliest examples of stable O...I−R f complexes . Hu et al. at SIOC have studied nucleophilic di-and monofluoromethylation since 2005 [150].Hu et al. conducted a study of nucleophilic ringopening fluoroalkylation of epoxides in 2006 that summarized the influence of α-fluorine substitution on the chemical reactivities of various carbanions.In this paper, they first proposed a 'negative fluorine effect' (NFE) in nucleophilic fluoroalkylation et al., Wang et al. and Xiao et al. have independently developed gem-difluoroolefination via transformation of diazo compounds, in addition to carbonyl olefination [70-72,205,226].Representative transformations of gem-difluoroolefins.