Versatile Fluorine-Containing Building Blocks: β-CF3-1,3-enynes

The development of diversity-oriented synthesis based on fluorine-containing building blocks has been one of the hot research fields in fluorine chemistry. β-CF3-1,3-enynes, as one type of fluorine-containing building blocks, have attracted more attention in the last few years due to their distinct reactivity. Numerous value-added trifluoromethylated or non-fluorinated compounds which have biologically relevant structural motifs, such as O-, N-, and S-heterocycles, carboncycles, fused polycycles, and multifunctionalized allenes were synthesized from these fluorine-containing building blocks. This review summarizes the most significant developments in the area of synthesis of organofluorine compounds based on β-CF3-1,3-enynes, providing a detailed overview of the current state of the art.

In an elegant piece of work, The Trost group reported palladium-catalyzed trimethylenemethane cycloadditions with α-trifluoromethyl-styrenes, trifluoromethyl-enynes, and dienes under mild reaction conditions. The trifluoromethyl group serves as a unique σ-electron-withdrawing group for the activation of the olefin toward the cycloaddition. This method allows for the formation of exomethylene cyclopentanes bearing a quaternary center substituted by the trifluoromethyl group (Scheme 4) [41]. Diaminophosphite ligand was employed in this reaction to afford desired cycloaddition product in moderated to excellent yields (45-93%). The obtention of the cycloadduct unaccompanied by fluoride elimination may be suggestive of a concerted mechanism. In an elegant piece of work, The Trost group reported palladium-catalyzed trimethylenemethane cycloadditions with α-trifluoromethyl-styrenes, trifluoromethyl-enynes, and dienes under mild reaction conditions. The trifluoromethyl group serves as a unique σ-electron-withdrawing group for the activation of the olefin toward the cycloaddition. This method allows for the formation of exomethylene cyclopentanes bearing a quaternary center substituted by the trifluoromethyl group (Scheme 4) [41]. Diaminophosphite ligand was employed in this reaction to afford desired cycloaddition product in moderated to excellent yields (45-93%). The obtention of the cycloadduct unaccompanied by fluoride elimination may be suggestive of a concerted mechanism. Scheme 3. Synthesis of trifluoromethylated 1-methylene indenes derivatives.
In 2017, we developed a concise approach to access ring-trifluoromethylated cyclopentene frameworks, utilizing silver-catalyzed double hydrocarbonation reaction of β-CF 3 -1,3enynes with bisnucleophiles 1,3-dicarbonyl compounds [42] (Scheme 5). β-CF 3 -1,3-enynes possessing electron-withdrawing aryl groups on the alkyne moiety smoothly underwent the cyclization reaction with 1,3-dicarbonyl compounds to give ring-trifluoromethylated cyclopentene in moderate to excellent yields. A series of β-diketones, malonate derivatives as well as β-ketoesters could be employed as reaction partner to afford the corresponding ring-trifluoromethylated cyclopentenes in good to excellent yields. Unsymmetrical 1,3-diketone or β-keto esters afford the desired cyclopentenes as a mixture of two diastereomers in excellent yields with moderate to good diastereoselectivity. The use of organic base effectively suppressed the defluorination process.
Interestingly, Chang and Zhang recently revealed that inorganic base K 3 PO 4 can effectively promote synthesis of CF 3 -substituted cyclopentenes when using malononitrile as carbon nucleophile to react with β-CF 3 -1,3-enynes. Their developed protocol disclosed that the fluorine retention of β-CF 3 -1,3-enynes did not rely on organic base and the additional patterns did not depend on electron-deficient β-CF 3 -1,3-enynes. The reasons may mainly be due to the stability of in situ formed carbon anion intermediates containing the cyano group and CF 3 -substituted cyclopentenes with double bond migration formed [43] (Scheme 6). In 2017, we developed a concise approach to access ring-trifluoromethylated cyclopentene frameworks, utilizing silver-catalyzed double hydrocarbonation reaction of β-CF3-1,3-enynes with bisnucleophiles 1,3-dicarbonyl compounds [42] (Scheme 5). β-CF3-1,3-enynes possessing electron-withdrawing aryl groups on the alkyne moiety smoothly underwent the cyclization reaction with 1,3-dicarbonyl compounds to give ring-trifluoromethylated cyclopentene in moderate to excellent yields. A series of β-diketones, malonate derivatives as well as β-ketoesters could be employed as reaction partner to afford the corresponding ring-trifluoromethylated cyclopentenes in good to excellent yields. Unsymmetrical 1,3-diketone or β-keto esters afford the desired cyclopentenes as a mixture of two diastereomers in excellent yields with moderate to good diastereoselectivity. The use of organic base effectively suppressed the defluorination process. Interestingly, Chang and Zhang recently revealed that inorganic base K3PO4 can effectively promote synthesis of CF3-substituted cyclopentenes when using malononitrile as carbon nucleophile to react with β-CF3-1,3-enynes. Their developed protocol disclosed that the fluorine retention of β-CF3-1,3-enynes did not rely on organic base and the additional patterns did not depend on electron-deficient β-CF3-1,3-enynes. The reasons may  In 2020, Liu's group reported the phosphine-catalyzed [3 + 2] cycloadditions of trifluoromethyl enynes/enediynes with allenoates to form cyclopentenes containing a CF3-substituted quaternary carbon center with great regioselectivity [44] (Scheme 7). This reaction occurs with excellent regioselectivity under mild conditions, affording alkyne-and diyne-tethered cyclopentene derivatives containing a CF3-substituted quaternary carbon center in moderate to good yields. In 2020, Liu's group reported the phosphine-catalyzed [3 + 2] cycloadditions of trifluoromethyl enynes/enediynes with allenoates to form cyclopentenes containing a CF 3substituted quaternary carbon center with great regioselectivity [44] (Scheme 7). This reaction occurs with excellent regioselectivity under mild conditions, affording alkyne-and diyne-tethered cyclopentene derivatives containing a CF 3 -substituted quaternary carbon center in moderate to good yields.
In 2014, the Zhang group disclosed an iron-promoted electrophilic annulation of trifluoromethyl-containing aryl enynes with disulfides or diselenides affording polysubstituted naphthalenes in moderate to excellent yields. The reaction proceeded with high selectivity to provide the 6-endo-dig cyclization product and showed good functional group tolerance. The authors observed that the aryl groups bearing electron-withdrawing substituents in these substrates results in lower yields. The utilization of inexpensive ferric chloride and commercially available disulfides and diselenides as electrophiles are significant advantages for the usefulness of this reaction [46] (Scheme 9).
Based on their experimental results, a plausible mechanism was outlined, as shown in Scheme 9b. The reaction of disulfide with iodine may take place to produce the active RSI in situ. The presence of BPO promotes the generation of free radical RS • which subsequently reacted with I 2 to form RSI. The electrophilic addition of RSI to the triple bond of enyne affords intermediate A (Path 1). The Lewis acid (FeCl 3 )-catalyzed intramolecular electrophilic attack on the neighboring aryl group provides intermediate B, and subsequent deprotonation yields the desired products. However, a free radical pathway cannot be ruled out (Path 2), in view of the fact that the product can be isolated in the absence of I 2 . The addition of RS • to enyne produces a vinyl radical C, which then undergoes an intramolecular cyclization to form radical D. The following oxidation by I 2 or FeCl 3 produces the corresponding carbocation, which loses a H + to yield desired products.

Construction of Six-Membered Trifluoromethylated Carboncycles
In 2013, the Gevorgyan group demonstrated the synthesis of trifluoromethylated benzene derivatives via chemo-and regioselective Pd-catalyzed [4 + 2] cross-benzannulation of β-CF3-1,3-enynes with diynes [45] (Scheme 8). Both β-F-1,3-enynes and β-perfluoroalkylated 1,3-enynes also are good reaction partners in these Pd-catalyzed [4 + 2] cross-benzannulation reaction affording corresponding trifluoromethylated and perfluoroalkylated benzene derivatives. This cycloaddition strategy proved to be effective for the rapid construction of aromatic fluorides from easily available acyclic starting materials. In 2014, the Zhang group disclosed an iron-promoted electrophilic annulation of trifluoromethyl-containing aryl enynes with disulfides or diselenides affording polysubstituted naphthalenes in moderate to excellent yields. The reaction proceeded with high selectivity to provide the 6-endo-dig cyclization product and showed good functional group tolerance. The authors observed that the aryl groups bearing elec-
benzyl sulfide with various terminal acetylenes afforded the corresponding (E)-2-CF3-1-buten-3-ynyl benzyl sulfides in good to high yields. Subsequent iodocyclization afforded the corresponding 4-CF3-3-iodo-2-substituted thiophenes in good to high yields. It is noteworthy that the substrate bearing a triisopropylsilyl group was intact under optimal reaction conditions due to the bulky silyl group hindering the approach of electrophilic iodine [47] (Scheme 10). Other methods to construct thiophene derivatives from β-CF3-1,3-enynes were also reported. In 2020, Song group developed a divergent strategy for the construction of 3-SCF2H-4-CF3-thiophenes from readily available 1,3-enynes and S8 via a tandem thiophene construction/selective C3 thiolation/difluoromethylthiolation under a ClCF2H atmosphere with excellent substrate compatibility. Experiments had shown that the construction of the thiophene ring may be a radical annulation process with S3 •− generated in situ, and freon is used as a cheap difluoromethylation reagent. A series of 3-SeCF2H-4-CF3-selenophenes can also be constructed by similar strategies [48] (Scheme 11). Other methods to construct thiophene derivatives from β-CF 3 -1,3-enynes were also reported. In 2020, Song group developed a divergent strategy for the construction of 3-SCF 2 H-4-CF 3 -thiophenes from readily available 1,3-enynes and S 8 via a tandem thiophene construction/selective C3 thiolation/difluoromethylthiolation under a ClCF 2 H atmosphere with excellent substrate compatibility. Experiments had shown that the construction of the thiophene ring may be a radical annulation process with S 3 •− generated in situ, and freon is used as a cheap difluoromethylation reagent. A series of 3-SeCF 2 H-4-CF 3 -selenophenes can also be constructed by similar strategies [48] (Scheme 11).
In their subsequent work, they developed a divergent method for precise constructions of cyclic unsymmetrical diaryl disulfides or diselenides and polythiophenes from β-CF 3 -1,3-enynes and S 8 when the ortho group is F, Cl, Br, and NO 2 on aromatic rings. However, when the ortho group is H, disulfides (diselenides) were constructed These transformations undergo a cascade thiophene construction/selective C3-position thiolation process. A novel plausible radical annulation process was proposed and validated by DFT calculations [49] (Scheme 12).
In their subsequent work, they developed a divergent method for precise constructions of cyclic unsymmetrical diaryl disulfides or diselenides and polythiophenes from β-CF3-1,3-enynes and S8 when the ortho group is F, Cl, Br, and NO2 on aromatic rings. However, when the ortho group is H, disulfides (diselenides) were constructed These transformations undergo a cascade thiophene construction/selective C3-position thiolation process. A novel plausible radical annulation process was proposed and validated by DFT calculations [49] (Scheme 12). Scheme 11. Synthesis of 3-SCF 2 H-4-CF 3 -thiophenes derivatives.
Following the above work, we subsequently developed a novel NIS-mediated oxidative cyclization of N-(2-trifluoromethyl-3-alkynyl) hydroxylamine under mild conditions, which provides a facile route to various 4-trifluoromethyl-5-acylisoxazoles. It was found that the NIS acts as both an oxidant and an electrophile for this sequential transformation. The key intermediate oxime formed by oxidation of hydroxylamine by NIS could be isolable, which underwent I + -induced O-selected 5-exo-dig cyclization and subsequent cascade reaction to afford 4-trifluoromethyl-5-acylisoxazoles. It is also noteworthy that no desired product was obtained when alkyne bearing TMS group or terminal alkyne was used as substrate [51] (Scheme 14a). Control experiments indicated that the oxygen atom of the ketone originated from water rather than from molecular dioxygen (Scheme 14b). The exclusive O-selected 5-exo-dig cyclization of oxime in the above transformation conditions have aroused our interest because oximes can be employed as N-selective nucleophiles or as O-selective nucleophiles in many chemical transformations. We deduced that the Brønsted acid (HI) in situ formed in the above transformation conditions decreases the nucleophilicity of oxime nitrogen and destroys the inter-or intramolecular hydrogen bond between oxime oxygen and trifluoromethyl group, thus facilitating O-selective 5-exo-dig cyclization. We envisioned that with a proper choice of transition metal catalysts, the isolated oximes might undergo N-selective 5-endo-dig electrophilic cyclization owing to their inter-or intramolecular hydrogen bond between oxime oxygen and the trifluoromethyl group, which decreased the nucleophilicity of the oxime oxygen [52]. Thus, another type of interesting nitrogen containing heterocycle i.e., fluorinated N-hydroxypyrroles, could be obtained (Scheme 15, path a). Furthermore, if excess NIS and molecular iodine (I 2 ) formed in situ in the reaction were reduced with a proper reductant, the in situ formed Brønsted acid would catalyze the O-selective 5-exo-dig or 6-endo-dig electrophilic cyclization of oximes; thus, an easy two-step, one-pot-synthesis of 4-trifluoromethyl-5-alkylisoxazoles (Scheme 15, path b) would be developed. Based on the above considerations, we developed the divergent regioselective cyclizations of N-(2-trifluoromethyl-3-alkynyl) oximes by subtle choice of gold(I) or Brønsted acid catalyst system, leading to 4-trifluoromethyl N-hydroxypyrroles or 5-akylisoxazoles. In order to avoid the tedious separation of unstable N-(2-trifluoromethyl-3-alkynyl) oximes, an easy two-step, one-pot synthesis of 4-trifluoromethyl-5-alkylisoxazoles from N-(2-trifluoromethyl-3-alkynyl) hydroxyl-amines is realized. This two-step, one-pot procedure is a complementary method for the synthesis of 4-trifluoromethyl-5-alkyl isoxazoles from those unstable N-(2-trifluoromethyl-3-alkynyl) oximes [53] (Scheme 15). Following the above work, we subsequently developed a novel NIS-mediated oxidative cyclization of N-(2-trifluoromethyl-3-alkynyl) hydroxylamine under mild conditions, which provides a facile route to various 4-trifluoromethyl-5-acylisoxazoles. It was found that the NIS acts as both an oxidant and an electrophile for this sequential trans- The exclusive O-selected 5-exo-dig cyclization of oxime in the above transformation conditions have aroused our interest because oximes can be employed as N-selective nucleophiles or as O-selective nucleophiles in many chemical transformations. We deduced that the Brønsted acid (HI) in situ formed in the above transformation conditions decreases the nucleophilicity of oxime nitrogen and destroys the inter-or intramolecular hydrogen bond between oxime oxygen and trifluoromethyl group, thus facilitating O-selective 5-exo-dig cyclization. We envisioned that with a proper choice of transition metal catalysts, the isolated oximes might undergo N-selective 5-endo-dig electrophilic After we studied the chemistry of β-CF 3 -1,3-enynes with the bisnucleophile hydroxylamine and subsequent transformations, we then studied the reaction of β-CF 3 -1,3-enynes with the bisnucleophile 2-aminomalonates. A dramatic substituent effect was observed in the reaction of β-CF 3 -1,3-enynes with the bisnucleophile 2-aminomalonates. When N-tosylated 2-aminomalonate was used as bisnucleophile, the reactions proceeded smoothly to afford 2-fluoro-2-pyrrolines via double direct C-F substitutions [54]. In contrast, either 4-trifluoromethyl pyrrolidines or gem-difluoro-1,3conjugated enynes were delivered when N-acetylated 2-aminomalonate was used as reaction partner. β-CF 3 -1,3-enynes show an interesting substituent effect on the product diversity. β-CF 3 -1,3-enynes bearing electrondonating or weak electron-withdrawing groups, such as Me, MeO, Cl and Br, on the aryl substituent of the alkyne moiety afford functionalized gem-difluoro-1,3-conjugated enynes in moderate to good yields, whereas 4-trifluoromethyl pyrrolidines are isolated as the predominant product in moderate to good yields from those β-CF 3 -1,3-enynes with strong electron-deficient aromatic substituent. Various functionalized 4-(difluoromethylene)-1,2,3,4-tetrahydropyridines could be obtained in good yields via the gold(I)-catalyzed intramolecular 6-endo-dig cyclization of the corresponding gem-difluoro-1,3-conjugated enynes under mild conditions [55] (Scheme 16).
In 2017, we developed the first example of tandem intermolecular hydroamination and cyclization reaction of β-CF 3 -1,3-enynes with bisnucleophile primary amines affording 4-trifluoromethyl-3-pyrrolines by employing a cheap silver catalyst under mild reaction conditions. This new method is compatible with alkyl, aryl, and allyl primary amines, representing an atom-economic protocol for the construction of 4-trifluoromethyl-3-pyrrolines for the first time. It should be noted that the reaction also works well for aromatic primary amines, albeit requiring a higher reaction temperature [56] (Scheme 17).
Following the above work, we subsequently developed a facile two-step, one-pot method for the synthesis of a range of halogenated trifluoromethylated pyrroles from β-CF 3 -1,3-enynes, readily aliphatic primary amines and halogenating agents, such as NBS and NIS. By variation of the halogenating agents, ring trifluoromethylated monoiodo pyrrole or dibromo pyrrole skeletons can be readily accessed in moderate to good yields. The different outcome of the reactions with NIS and NBS may be due to their different electrophilic properties towards pyrrole. This two-step, one-pot method employs a key halogenating-agents mediating step to trigger a cascade process featuring an initial electrophilic cyclization of the first intermolecular hydroamination product [57] (Scheme 18). functionalized gem-difluoro-1,3-conjugated enynes in moderate to good yields, whereas 4-trifluoromethyl pyrrolidines are isolated as the predominant product in moderate to good yields from those β-CF3-1,3-enynes with strong electron-deficient aromatic substituent. Various functionalized 4-(difluoromethylene)-1,2,3,4-tetrahydropyridines could be obtained in good yields via the gold(I)-catalyzed intramolecular 6-endo-dig cyclization of the corresponding gem-difluoro-1,3-conjugated enynes under mild conditions [55] (Scheme 16). Scheme 16. Divergent synthesis of trifluoromethylated pyrrolidines or difluoromethylidene tetrahydropyridines.
In 2017, we developed the first example of tandem intermolecular hydroamination and cyclization reaction of β-CF3-1,3-enynes with bisnucleophile primary amines affording 4-trifluoromethyl-3-pyrrolines by employing a cheap silver catalyst under mild reaction conditions. This new method is compatible with alkyl, aryl, and allyl primary amines, representing an atom-economic protocol for the construction of 4-trifluoromethyl-3-pyrrolines for the first time. It should be noted that the reaction also works well for aromatic primary amines, albeit requiring a higher reaction temperature [56] (Scheme 17). Following the above work, we subsequently developed a facile two-step, one-pot method for the synthesis of a range of halogenated trifluoromethylated pyrroles from β-CF3-1,3-enynes, readily aliphatic primary amines and halogenating agents, such as NBS and NIS. By variation of the halogenating agents, ring trifluoromethylated monoiodo pyrrole or dibromo pyrrole skeletons can be readily accessed in moderate to good yields. The different outcome of the reactions with NIS and NBS may be due to their different electrophilic properties towards pyrrole. This two-step, one-pot method employs a key halogenating-agents mediating step to trigger a cascade process featuring an initial electrophilic cyclization of the first intermolecular hydroamination product [57] (Scheme 18). More recently, in 2021, we developed the first example of a tandem double hydroamination reaction of β-CF3-1,3-enynes with bisnucleophiles hydrazine derivatives under mild reaction conditions. By variation of the substituents on the hydrazine nitrogen atom, three types of trifluoromethylated pyrazolidines, pyrazolines and pyrazoles Scheme 18. Synthesis of halogenated trifluoromethylated pyrroles.

Scheme 20. Synthesis of 4-trifluoromethyl-2H-pyrans derivatives.
A straightforward and efficient approach to alkyne-functionalized ring-monofluorinated 4H-pyrans via a simple base-mediated cascade reaction of β-CF 3 -1,3-enynes with 1,3-dicarbonyl compounds or monocyano-substituted carbon nucleophiles, such as 3-oxo-3-phenylpropanenitrile, 3-oxo-butyronitrile was developed by our group [60] and Chang [10]. Substituted alkynyl group was used as an activating group. The key events of this reaction involve two consecutive C-F substitutions under very mild conditions (Scheme 21). Very recently, we developed the first example of a tandem intermolecular hydrocarbonation/intramolecular heterocyclization reaction of β-CF3-1,3-enynes with bisnucleophiles β -ketothioamides under mild reaction conditions. By variation of the substituents linked to the carbonyl or on the β-ketothioamides nitrogen atom, ring trifluoromethylated pyrans, or thiopyrans, can be readily accessed in moderate to good yields. Enynes possessing electron-withdrawing aryl groups on the alkyne moiety are generally good candidates for present transformation and β-ketothioamides bearing a piperidine substituent on the amide moiety, and (hetero)aryl groups on the keto moiety would mainly afford pyran, whereas β-ketothioamides bearing pyrrolidine substituent on the amide moiety and (hetero)aryl or alkyl groups on keto moiety lead to the formation of thiopyrans. Other substituted forms of N,N-disubstituted β-ketothioamides would give mixtures of pyrans and thiopyrans. We think that the formation of the oxygen enol or sulfur enol intermediate Int-B could be affected by electronic and spatial effects of substituents on either the keto moiety or the nitrogen atom of the β-ketothioamide from the reaction of Int-A under basic conditions, which results in pyrans or thiopyrans. β-ketothioamides bearing a piperidine substituent on the amide moiety and (hetero)aryl groups on the keto moiety would mainly form oxyenols, leading to the formation of pyran, whereas sulfur enol would predominantly form β-ketothioamides bearing a pyrrolidine substituent on the amide moiety and (hetero)aryl or alkyl groups on the keto moiety, leading to the formation of thiopyrans. Other substituted forms of N,N-disubstituted β-ketothioamides would give mixtures of oxygen enol and sulfur enol which result in mixtures of pyrans and thiopyrans. The salient features of this tandem include atom-economical, mild reaction condition, ease of operation and product diversity [61] (Scheme 22).
Very recently, we developed the first example of a tandem intermolecular hydrocarbonation/intramolecular heterocyclization reaction of β-CF 3 -1,3-enynes with bisnucleophiles β -ketothioamides under mild reaction conditions. By variation of the substituents linked to the carbonyl or on the β-ketothioamides nitrogen atom, ring trifluoromethylated pyrans, or thiopyrans, can be readily accessed in moderate to good yields. Enynes possessing electron-withdrawing aryl groups on the alkyne moiety are generally good candidates for present transformation and β-ketothioamides bearing a piperidine substituent on the amide moiety, and (hetero)aryl groups on the keto moiety would mainly afford pyran, whereas β-ketothioamides bearing pyrrolidine substituent on the amide moiety and (hetero)aryl or alkyl groups on keto moiety lead to the formation of thiopyrans. Other substituted forms of N,N-disubstituted β-ketothioamides would give mixtures of pyrans and thiopyrans. We think that the formation of the oxygen enol or sulfur enol intermediate Int-B could be affected by electronic and spatial effects of substituents on either the keto moiety or the nitrogen atom of the β-ketothioamide from the reaction of Int-A under basic conditions, which results in pyrans or thiopyrans. β-ketothioamides bearing a piperidine substituent on the amide moiety and (hetero)aryl groups on the keto moiety would mainly form oxyenols, leading to the formation of pyran, whereas sulfur enol would predominantly form β-ketothioamides bearing a pyrrolidine substituent on the amide moiety and (hetero)aryl or alkyl groups on the keto moiety, leading to the formation of thiopyrans. Other substituted forms of N,N-disubstituted β-ketothioamides would give mixtures of oxygen enol and sulfur enol which result in mixtures of pyrans and thiopyrans. The salient features of this tandem include atom-economical, mild reaction condition, ease of operation and product diversity [61]

Construction of Other Value-Added Trifluoromethylated or Non-Fluorinated Organic Compounds
The divergent synthesis of thioether-functionalized trifluoromethyl-alkynes, 1,3-dienes and allenes from the regioselective nucleophilic addition reactions of β-CF3-1,3-enynes with sulfur nucleophiles was discovered by our group in 2018. The addition patterns depend on the type of enynes, sulfur nucleophiles and reaction conditions used. 1,4-addition leading to thioether-functionalized trifluoromethyl-allenes was realized when enynes possessing electron-withdrawing aryl groups on the alkyne moiety were used as reaction partners and alkanethiols were used as nucleophiles, whereas solvent-controlled construction of thioether-functionalized 1,3-dienes and alkynes were realized, respectively, via 3,4-addition pattern or 1,2-addition pattern if thiophenols were applied as nucleophiles. The three types of compounds containing both sulfur and fluo-Scheme 22. Synthesis of ring trifluoromethylated pyrans, or thiopyrans.

Construction of Other Value-Added Trifluoromethylated or Non-Fluorinated Organic Compounds
The divergent synthesis of thioether-functionalized trifluoromethyl-alkynes, 1,3-dienes and allenes from the regioselective nucleophilic addition reactions of β-CF 3 -1,3-enynes with sulfur nucleophiles was discovered by our group in 2018. The addition patterns depend on the type of enynes, sulfur nucleophiles and reaction conditions used. 1,4-addition leading to thioether-functionalized trifluoromethyl-allenes was realized when enynes possessing electron-withdrawing aryl groups on the alkyne moiety were used as reaction partners and alkanethiols were used as nucleophiles, whereas solvent-controlled construction of thioether-functionalized 1,3-dienes and alkynes were realized, respectively, via 3,4-addition pattern or 1,2-addition pattern if thiophenols were applied as nucleophiles. The three types of compounds containing both sulfur and fluorine elements are valuable building blocks for synthesis of multifunctional trifluoromethylated vinyl sulfides and thiophenes derivatives [62] (Scheme 23). In 2020, Song and coworkers reported three unprecedented Cu-catalyzed regio-and stereo-divergent chemoselective sp 2 /sp 3 1,3-and 1,4-diborylation of β-CF3-1,3-enynes, affording a broad array of diborylated compounds containing CF3 group in simple and efficient ways. Homopropargylic boronates and homoallenyl boronates as the key intermediates for the above three transformations were obtained after carefully modifying the reaction conditions. DFT calculations explain the reactivity, regioselectivity, as well as the stereoselectivity in these transformations in detail [63] (Scheme 24). Scheme 23. Synthesis of thioether-functionalized CF 3 -alkynes, 1,3-dienes and allenes.
In 2020, Song and coworkers reported three unprecedented Cu-catalyzed regio-and stereo-divergent chemoselective sp 2 /sp 3 1,3-and 1,4-diborylation of β-CF 3 -1,3-enynes, affording a broad array of diborylated compounds containing CF 3 group in simple and efficient ways. Homopropargylic boronates and homoallenyl boronates as the key intermediates for the above three transformations were obtained after carefully modifying the reaction conditions. DFT calculations explain the reactivity, regioselectivity, as well as the stereoselectivity in these transformations in detail [63] (Scheme 24).

Conclusions
In this review, we have summarized recent efforts to develop new diversity-oriented synthesis based on β-CF3-1,3-enynes in one type of fluorine-containing building blocks. The distinct reactivity of β-CF3-1,3-enynes and their variants allow these reactions to deliver numerous value-added fluorine-containing compounds which have Scheme 29. Synthesis of pyridines bearing a CF 3 -substituted quaternary center.

Conclusions
In this review, we have summarized recent efforts to develop new diversity-oriented synthesis based on β-CF 3 -1,3-enynes in one type of fluorine-containing building blocks. The distinct reactivity of β-CF 3 -1,3-enynes and their variants allow these reactions to deliver numerous value-added fluorine-containing compounds which have biologically relevant structural motifs, such as O-, N-, and S-heterocycles, carboncycles, fused polycycles, and multifunctionalized allenes. While the advances made to date are remarkable, further inventing novel and efficient transformations of β-CF 3 -1,3-enynes to synthesize diverse trifluoromethylated cyclic molecules, such as furan and acyclic molecules, is still interesting and urgent.