New Electrophilic Bromodifluoromethylation and Pentafluoroethylation Reagents

Abstract

S-(fluoroalkyl)diphenylsulfonium salts have been successfully synthesized from the reaction between fluoroalkylsul­finates and triflic anhydride in dichloromethane through a one-pot procedure. These S-(fluoroalkyl)diphenylsulfonium salts have been demonstrated to be effective reagents to fluoroalkylate C-nucleophilic substrates. Ionic substitution and radical or halogenophilic mechanism might be all involved in the reactions.

Compounds containing the fluoroalkyl group have been confirmed to be very important in organic chemistry. The introduction of the fluoroalkyl group into organic molecules often changes their physical, chemical, and physiological properties. [¹] Due to the recent progress in these fields, methodologies for the direct introduction of the perfluoroalkyl group are now available through nucleophilic, free radical, and electrophilic approaches. [²] Electrophilic perfluoroalkylation, one of the three fundamental fluoroalkylation methods, has become increasingly important in organic synthesis. However, it is not a trivial task. The formation of the fluoroalkyl cation in these electrophilic fluoroalkylation reagents is quite difficult due to the highest electronegativity of the fluorine atoms. [³] Even so, many reagents have been developed to introduce the fluoroalkyl group into organic molecules. In 1970’s, Yagupolskii reported a method for perfluoroalkylation using (perfluoroalkyl)-p-tolyl-iodonium salts as the first electrophilic perfluoroalkylation reagent in polar solvent under mild conditions. [4] In 1984, two trifluoromethyl sulfonium salts were prepared as another class of electrophilic perfluoroalkylation reagent, which could react with sodium p-nitrothiophenolate in DMF to give p-nitrophenyltrifluoromethyl sulfide in high yield. [5] Umemoto ­further extended these methods to the synthesis of (per­fluoroalkyl)phenyliodonium trifluoromethanesulfonates, (perfluoroalkyl)-phenyliodonium hydrogensulfates, and some powerful electrophilic perfluoroalkyl sulfonium agents that could transfer the perfluoroalkyl group to different kinds of organic molecules. [6] In 1998, Shreeve and co-workers developed an alternative route to prepare the analogous trifluoromethyl sulfonium salts from inexpensive reagents and improved their electrophilic power by introducing electron-withdrawing substituents on the ­benzene rings. [³b] Recently, Prakash reported two new ­electrophilic fluoromethylating reagents, S-(difluoromethyl)diaryl-sulfonium tetrafluoroborate and S-(monofluoromethyl)diarylsulfonium tetrafluoroborate, which were shown to be effective for the introduction of difluoromethyl or monofluoromethyl group into C, S, O, N, and P nucleophiles. [7] Although these reagents are very useful, they are always prepared by multistep and laborious synthetic procedures. In 2006, E. Magnier et al. developed a very short and efficient method to synthesize aryl trifluoromethyl sulfonium salts in one pot. [8] Then they extended this method and successfully synthesized some new trifluoromethyl dibenzothiophenium salts such as Umemoto-type reagents. [9] So far, most studies are limited to simple fluoroalkyl sulfonium salts. In order to acquire more information about the electrophilicity of bromodi­fluoroalkyl and long fluoroalkyl sulfonium salts, we investigated the synthesis and reaction of these fluoroalkyl sulfonium salts.

Based on the previous reports, [³b] [8] [9] S-(fluoroalkyl)diphenylsulfonium salts were synthesized from the simple and inexpensive material in a one-pot procedure (Table  [¹] ). Reactivity was tuned successfully via trifluoromethanesulfonylation of fluoroalkylsulfinates with triflic anhydride in dichloromethane. For example, (bromo-difluoromethyl)diphenylsulfonium trifluoromethanesulfonate (1a) was formed in 44% yield when sodium bromodifluoromethanesulfinate reacted with benzene and triflic anhydride in dichloromethane at 0 ˚C for 2 hours and then at room temperature for 22 hours (Table  [¹] , entry 1). Its structure was confirmed by single-crystal X-ray diffraction analysis (Figure  [¹] ). [¹0] The reaction became complicated, and the expected sulfonium salts were obtained in a minor amount with longer fluoroalkyl chains. As shown in Table  [¹] , only 20% of (pentafluoroethyl)diphenylsulfonium triflate (1b) was formed even after 4 days (entry 2). ^¹9F NMR analysis of the reaction mixture showed that many side reactions occurred. Oxidation of fluoroalkyl sulfinate happened during the reaction. Similar results were obtained in the case of sodium 2-chloro-1,1,2,2-tetrafluoroethanesulfinate (entry 3).

Table 1 One-Pot Synthesis of S-(Fluoroalkyl)diphenylsulfonium Salts [¹¹]

Entry	R F	R F SO2Na/ Tf2O	Time (d)a	L	Yield (%)b
1	BrCF2	1:2.4	1	CF3SO3	1a 44
2	CF3CF2	1:2.4	4	CF3SO3	1b 20
3	Cl(CF2)2	1:2.4	4	Cl(CF2)2SO3, CF3SO3	1c 8
4	Cl(CF2)4	1:2.4	5	Cl(CF2)4SO3	1d 4.5
a Reacted first at 0 ˚C for 2 h and then at r.t. b Isolated yield.

Trifluoromethanesulfonate and 2-chloro-1,1,2,2-tetra­fluoroethanesulfonate anions were both involved in the sulfonium salts 1c. Efforts to isolate the two salts failed. In addition, when sodium 4-chloro-1,1,2,2,3,3,4,4-octa­fluorobutanesulfinate reacted with benzene and triflic anhydride in dichloromethane, (4-chloro-1,1,2,2,3,3,4,4-octafluorobutyl)diphenylsulfonium salt (1d) with only one anion was obtained, but the yield was extremely poor (entry 4). Oxidation of 4-chloro-1,1,2,2,3,3,4,4-octafluorobutanesulfinate to the corresponding sulfonate also happened. Triflic anhydride has been known for its oxidative properties, [¹²] yet there is no explanation proposed. Tri­fluoromethanesulfonate anions existing in sulfonium salts became easier to be replaced by the oxidized sulfonate with increasing length of the fluoroalkyl chain. The purity of the sodium fluoroalkylsulfinate is an essential factor for the success of this reaction, just as the literature reported. [9] Lower purity of the sodium 2-chloro-1,1,2,2-tetrafluoroethanesulfinate always resulted in the failure of preparation of the desired sulfonium salts. The temperature also has an influence on the yield of the reaction. At the beginning of the reaction, lower reaction temperature had to be employed to assure the mild transformation of fluoroalkylsulfinates. Otherwise, only trace amount of the product was obtained.

With these new S-(fluoroalkyl)diphenylsulfonium salts in hand, we investigated their potential to act as electrophiles in alkylation reactions. Sulfonium salts 1a and 1b were taken as examples. Bromodifluoromethylation of (2-phenylethynyl)lithium with 1a proceeded smoothly (Table  [²] , entry 1). (2-Phenylethynyl)lithium was prepared in situ before 1a was added in this reaction. Arylethynyl lithium with electron-donating or electron-withdrawing substituent at para position of the phenyl ring was bromodifluoromethylated equally well under this reaction condition (entries 2 and 3). Both 2b and 2c were formed in moderate yield. Similar result was obtained while treating 1a with hept-1-ynyllithium (entry 4). Other C-nucleophiles were also successfully bromodifluoromethylated with 1a. Compound 2e was satisfactorily produced when 1a reacted with ethyl 2-methyl-3-oxobutanoate in DMF at -50 ˚C to room temperature (entry 5).

Table 2 Electrophilic Fluoroalkylation of Sulfonium Salts [¹³,¹4]

Entry	Substrates	Conditions (base, temp, solvent)a	Products	Yield (%)b
1		BuLi, -78 ˚C, 1a, then r.t., THF		2a 47
2		BuLi, -78 ˚C, 1a, then r.t., THF		2b 52
3		BuLi, -78 ˚C, 1a, then r.t., THF		2c 57
4		BuLi, -78 ˚C, 1a, then r.t., THF		2d 45
5		NaH, -50 ˚C, 1a, then r.t., DMF		2e 55
6		NaH, -50 ˚C, 1a, then r.t., DMF		2f 50
7		BuLi, -78 ˚C, 1b, then r.t., THF		2g 25
8		NaH, -50 ˚C, 1b, then r.t., DMF		2h 33
a Anions was first generated in the reaction with BuLi or NaH at -78 or -50 ˚C. Then the fluoroalkylating agents were added. The cooling bath was removed, and the reaction system was warmed to r.t. b Isolated yield.

A comparison of these results with the previous reports led us to think that an electrophilic mechanism might be involved in this bromodifluoromethylation reaction. [³b] [6c] However, when ethyl 2-methyl-3-oxo-butanoate was replaced by 2-methylcyclopentane-1,3-dione in this reaction, 3-(difluoromethoxy)-2-methyl-cyclopent-2-enone (2f) was obtained in 50% yield (entry 6). Trace of bromodifluorinated product could be detected by ^¹9F NMR but not isolated due to its low yield. This indicated that the radical or halogenophilic mechanism could not be excluded in this reaction system. [6c] These mechanisms might coexist and compete with each other. The predominant pathway might depend on the nucleophiles and the reaction conditions.

Pentafluoroethylated product was similarly formed in the reaction of sulfonium salt 1b with phenylacetylene or ethyl 2-methyl-3-oxobutanoate (entries 7 and 8). ^¹9F NMR measurement of the reaction course (entries 7 and 8) showed the simultaneous formation of undesired 1H-pentafluoroethanes (CF₃CF₂H). This might be another evidence for the coexistence of the radical and ionic substitution mechanism in these reactions.

In summary, we have successfully synthesized S-(bromodifluoromethyl)- and S-(pentafluoroethyl)diphenylsulfonium salts by using a slightly modified Magnier’s approach. Because of the strong electronegativity of the fluorine atoms, sulfonium salts with long fluoroalkyl chain are very difficult to synthesize. The purity of the sodium fluoroalkylsulfinate as well as the temperature used at the beginning of the reaction has great influence on the reaction. These S-(fluoroalkyl)-diphenyl-sulfonium salts have been demonstrated to be effective electrophilic fluoroalkylating agents of C-nucleophilic substrates. Ionic substitution and radical or halogenophilic mechanism might be all involved in these fluoroalkylation reactions.

Supporting Information for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.

Acknowledgment

We thank the Chinese Academy of Sciences (Hundreds of Talents Program) and the National Natural Science Foundation (20772147, 20972179) for financial support.

References and Notes

• 1a Chambers RD. In Fluorine in Organic Chemistry   John Wiley and Sons; New York: 1973. 
• 1b In Organofluorine Chemistry, Principles and Commercial Applications   Banks RE. Smart BE. Tatlow JC. Plenum Press; New York: 1994. 
• 1c In Fluorine-Containing Amino Acids, Synthesis and Properties   Kukhar VP. Soloshonok VA. John Wiley and Sons; Chichester: 1995. 
• 1d Matsnev A. Noritake S. Nomura Y. Tokunaga E. Nakamura S. Shibata N. Angew. Chem. Int. Ed.  2010,  49:  572 
  Search in Google Scholar
• 2 Umemoto T. Chem. Rev.  1996,  96:  1757 
  CrossrefPubMedSearch in Google Scholar
• 3a Huheey JE. J. Phys. Chem.  1965,  69:  3284 
  Search in Google Scholar
• 3b Yang J.-J. Kirchmeier RL. Shreeve JM. J. Org. Chem.  1998,  63:  2656 
  Search in Google Scholar
• 4a Yagupolskii LM. Maletina II. Kondratenko NV. Orda VV. Synthesis  1978,  835 
• 4b Yagupol’skii LM. Mironova AA. Maletina II. Orda VV. Zh. Org. Khim.  1980,  16:  232 
  Search in Google Scholar
• 4c Yagupolskii LM. J. Fluorine Chem.  1987,  36:  1 
  Search in Google Scholar
• 5 Yagupolskii LM. Kondratenko NV. Timofeeva GN. J. Org. Chem. USSR  1984,  20:  103 
  Search in Google Scholar
• 6a Umemoto T. Kuriu Y. Shuyama H. Miyano O. Nakayama S.-I. J. Fluorine Chem.  1982,  20:  695 
  Search in Google Scholar
• 6b Umemoto T. Kuriu Y. Shuyama H. Miyano O. Nakayama S.-I. J. Fluorine Chem.  1986,  31:  37 
  Search in Google Scholar
• 6c Umemoto T. Ishihara S. J. Am. Chem. Soc.  1993,  115:  2156 
  Search in Google Scholar
• 7a Prakash GKS. Weber C. Chacko S. Olah GA. Org. Lett.  2007,  9:  1863 
  Search in Google Scholar
• 7b Prakash GKS. Ledneczki I. Chacko S. Olah GA. Org. Lett.  2007,  10:  557 
  Search in Google Scholar
• 8 Magnier E. Blazejewski J.-C. Tordeux M. Wakselman C. Angew. Chem. Int. Ed.  2006,  45:  1279 
  CrossrefPubMedSearch in Google Scholar
• 9 Macé Y. Raymondeau B. Pradet C. Blazejewski J.-C. Magnier E. Eur. J. Org. Chem.  2009,  1390 
  Crossref
• 12a Maas G. Stang P. J. Org. Chem.  1981,  46:  1606 
  Search in Google Scholar
• 12b Baraznenok IL. Nenajdenko VG. Balenkova ES. Tetrahedron  2000,  56:  3077 
  Search in Google Scholar
• For the preparation of sodium fluoroalkylsulfinates, see:
• 15a Huang W.-Y. Zhang H.-Z. Chin. J. Chem.  1992,  10:  274 
  Search in Google Scholar
• 15b Hu L.-Q. DesMarteau DD. Inorg. Chem.  1993,  32:  5007 
  Search in Google Scholar
• 15c Huang W.-Y. Huang B.-N. Wang W. Huaxue Xuebao  1985,  663 

CCDC 759656 contains the supplementary crystallographic data for the compound 1a. This data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.

Typical Procedure for the Preparation of 1a-d
Under nitrogen atmosphere, benzene (7.5 mL, 84.0 mmol) and trifluoromethanesulfonic anhydride (6.0 mL, 35.5 mmol) were added into a suspension of sodium pentafluoro-ethanesulfinate^¹5 (3.18 g, 15.4 mmol) in CH₂Cl₂ (5 mL), which was well cooled by ice bath. After vigorously stirring at 0 ˚C for 2 h, the reaction mixture was warmed to r.t. and continued to react for 4 d. Then the reaction mixture was diluted with CH₂Cl₂ (60 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using CH₂Cl₂-MeCN (4:1) as the eluent. After recrystallization from pentane-EtOAc, 1.40 g of 1b (20%) was obtained as a white solid. ^¹H NMR (300 MHz, CDCl₃): δ = 7.84 (t, J = 7.7 Hz, 2 H), 7.95 (t, J = 8.2 Hz, 1 H), 8.34 (d, J = 8.2 Hz, 2 H). ^¹9F NMR (282 MHz, CDCl₃): δ = -94.5 (s, 2 F), -75.7 (s, 3 F), -76.8 (s, 3 F). ^¹³C NMR (100 MHz, CDCl₃): δ = 137.4, 133.9, 132.3, 120.7 (q, J = 318.5 Hz, CF₃), 117.0. ESI-MS: m/z = 305.0 [M⁺]. IR (KBr): 3067, 1477, 1455, 1331, 1288, 1254, 1234, 1160, 1128, 1031, 938, 757, 639, 517, 504 cm^-¹. Anal. Calcd for C₁₅H₁₀F₈O₃S₂: C, 39.65, H, 2.22. Found: C, 39.64, H, 2.51.

Typical Procedure for the Fluoroalkylation of 2a-d,g To a 25 mL round-bottomed flask, 1-ethynylbenzene (50 mg, 0.49 mmol) and anhyd THF (4 mL) were added and maintained under a N₂ atmosphere at -78 ˚C. n-BuLi (0.22 mL of a 2.5 mol L^-¹ solution in hexane, 0.55 mmol) was added, and the reaction mixture was stirred at -78 ˚C for 30 min. Then 1b (226 mg in 2 mL of anhyd THF, 0.50 mmol) was added. After 1 h, the cooling bath was removed, and the reaction was warmed naturally to r.t. Then the reaction mixture was poured into H₂O (30 mL), extracted with Et₂O (30 mL), washed with brine (3 × 20 mL), and dried over anhyd Na₂SO₄. Et₂O was evaporated under reduced pressure, and the residue was purified by column chroma­-tography on silica gel using pentane as the eluent; 28 mg of 2g (25%) was obtained as a colorless liquid. ^¹H NMR: δ = 7.57 (d, J = 7.7 Hz, 2 H), 7.49 (t, J = 7.3 Hz, 1 H), 7.40 (t, J = 7.7 Hz, 2 H). ^¹9F NMR: δ = -101.2 (q, J = 4.2 Hz, 2 F), -85.3 (t, J = 4.2 Hz, 3 F).

Typical Procedure for the Fluoroalkylation of 2e-f,h
To a 25 mL round-bottomed flask, ethyl 2-methyl-3-oxobutanoate (70 mg, 0.49 mmol) was dissolved in anhyd DMF (4 mL). NaH (24 mg, 56%, 0.56 mmol) was added under a N₂ atmosphere. The reaction mixture was stirred at r.t. for 30 min then cooled to -50 ˚C. Compound 1b (226 mg in 2 mL of anhyd DMF, 0.50 mmol) was added, and the cooling bath was removed. After warming naturally to r.t., the reaction mixture was poured into H₂O (30 mL), extracted with Et₂O (30 mL), washed with brine (3 × 20 mL), and dried over anhyd Na₂SO₄. The ether layer was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using PE-EtOAc (10:1) as the eluent; 42 mg of 2h (33%) was obtained as a colorless liquid. ^¹H NMR (300 MHz, CDCl₃): δ = 4.29 (q, J = 7.3 Hz, 2 H), 2.34 (s, 3 H), 1.61 (s, 3 H), 1.30 (t, J = 7.3 Hz, 3 H). ^¹9F NMR (282 MHz, CDCl₃): δ = -113.5 (dd, AB, ^² J _FF  = 282.5 Hz, 2 F), -78.8 (s, 3 F). ^¹³C NMR (100 MHz, CDCl₃): δ = 197.1, 166.1, 63.3 (t, J = 19.5 Hz), 62.8, 27.9, 15.6, 13.7. MS (EI): m/z = 43 (100), 44 (5.3), 73 (3.0), 77 (2.9), 105 (7.3), 123 (6.1), 192 (3.4), 220 (7.3). IR (KBr): 2988, 2942, 1734, 1466, 1389, 1365, 1338, 1260, 1209, 1107, 1004, 745 cm^-¹. HRMS: m/z calcd for C₉H₁₁O₃F₅: 262.0628; found: 262.0625.

References and Notes

• 1a Chambers RD. In Fluorine in Organic Chemistry   John Wiley and Sons; New York: 1973. 
• 1b In Organofluorine Chemistry, Principles and Commercial Applications   Banks RE. Smart BE. Tatlow JC. Plenum Press; New York: 1994. 
• 1c In Fluorine-Containing Amino Acids, Synthesis and Properties   Kukhar VP. Soloshonok VA. John Wiley and Sons; Chichester: 1995. 
• 1d Matsnev A. Noritake S. Nomura Y. Tokunaga E. Nakamura S. Shibata N. Angew. Chem. Int. Ed.  2010,  49:  572 
  Search in Google Scholar
• 2 Umemoto T. Chem. Rev.  1996,  96:  1757 
  CrossrefPubMedSearch in Google Scholar
• 3a Huheey JE. J. Phys. Chem.  1965,  69:  3284 
  Search in Google Scholar
• 3b Yang J.-J. Kirchmeier RL. Shreeve JM. J. Org. Chem.  1998,  63:  2656 
  Search in Google Scholar
• 4a Yagupolskii LM. Maletina II. Kondratenko NV. Orda VV. Synthesis  1978,  835 
• 4b Yagupol’skii LM. Mironova AA. Maletina II. Orda VV. Zh. Org. Khim.  1980,  16:  232 
  Search in Google Scholar
• 4c Yagupolskii LM. J. Fluorine Chem.  1987,  36:  1 
  Search in Google Scholar
• 5 Yagupolskii LM. Kondratenko NV. Timofeeva GN. J. Org. Chem. USSR  1984,  20:  103 
  Search in Google Scholar
• 6a Umemoto T. Kuriu Y. Shuyama H. Miyano O. Nakayama S.-I. J. Fluorine Chem.  1982,  20:  695 
  Search in Google Scholar
• 6b Umemoto T. Kuriu Y. Shuyama H. Miyano O. Nakayama S.-I. J. Fluorine Chem.  1986,  31:  37 
  Search in Google Scholar
• 6c Umemoto T. Ishihara S. J. Am. Chem. Soc.  1993,  115:  2156 
  Search in Google Scholar
• 7a Prakash GKS. Weber C. Chacko S. Olah GA. Org. Lett.  2007,  9:  1863 
  Search in Google Scholar
• 7b Prakash GKS. Ledneczki I. Chacko S. Olah GA. Org. Lett.  2007,  10:  557 
  Search in Google Scholar
• 8 Magnier E. Blazejewski J.-C. Tordeux M. Wakselman C. Angew. Chem. Int. Ed.  2006,  45:  1279 
  CrossrefPubMedSearch in Google Scholar
• 9 Macé Y. Raymondeau B. Pradet C. Blazejewski J.-C. Magnier E. Eur. J. Org. Chem.  2009,  1390 
  Crossref
• 12a Maas G. Stang P. J. Org. Chem.  1981,  46:  1606 
  Search in Google Scholar
• 12b Baraznenok IL. Nenajdenko VG. Balenkova ES. Tetrahedron  2000,  56:  3077 
  Search in Google Scholar
• For the preparation of sodium fluoroalkylsulfinates, see:
• 15a Huang W.-Y. Zhang H.-Z. Chin. J. Chem.  1992,  10:  274 
  Search in Google Scholar
• 15b Hu L.-Q. DesMarteau DD. Inorg. Chem.  1993,  32:  5007 
  Search in Google Scholar
• 15c Huang W.-Y. Huang B.-N. Wang W. Huaxue Xuebao  1985,  663 

CCDC 759656 contains the supplementary crystallographic data for the compound 1a. This data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.

Typical Procedure for the Preparation of 1a-d
Under nitrogen atmosphere, benzene (7.5 mL, 84.0 mmol) and trifluoromethanesulfonic anhydride (6.0 mL, 35.5 mmol) were added into a suspension of sodium pentafluoro-ethanesulfinate^¹5 (3.18 g, 15.4 mmol) in CH₂Cl₂ (5 mL), which was well cooled by ice bath. After vigorously stirring at 0 ˚C for 2 h, the reaction mixture was warmed to r.t. and continued to react for 4 d. Then the reaction mixture was diluted with CH₂Cl₂ (60 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using CH₂Cl₂-MeCN (4:1) as the eluent. After recrystallization from pentane-EtOAc, 1.40 g of 1b (20%) was obtained as a white solid. ^¹H NMR (300 MHz, CDCl₃): δ = 7.84 (t, J = 7.7 Hz, 2 H), 7.95 (t, J = 8.2 Hz, 1 H), 8.34 (d, J = 8.2 Hz, 2 H). ^¹9F NMR (282 MHz, CDCl₃): δ = -94.5 (s, 2 F), -75.7 (s, 3 F), -76.8 (s, 3 F). ^¹³C NMR (100 MHz, CDCl₃): δ = 137.4, 133.9, 132.3, 120.7 (q, J = 318.5 Hz, CF₃), 117.0. ESI-MS: m/z = 305.0 [M⁺]. IR (KBr): 3067, 1477, 1455, 1331, 1288, 1254, 1234, 1160, 1128, 1031, 938, 757, 639, 517, 504 cm^-¹. Anal. Calcd for C₁₅H₁₀F₈O₃S₂: C, 39.65, H, 2.22. Found: C, 39.64, H, 2.51.

Typical Procedure for the Fluoroalkylation of 2a-d,g To a 25 mL round-bottomed flask, 1-ethynylbenzene (50 mg, 0.49 mmol) and anhyd THF (4 mL) were added and maintained under a N₂ atmosphere at -78 ˚C. n-BuLi (0.22 mL of a 2.5 mol L^-¹ solution in hexane, 0.55 mmol) was added, and the reaction mixture was stirred at -78 ˚C for 30 min. Then 1b (226 mg in 2 mL of anhyd THF, 0.50 mmol) was added. After 1 h, the cooling bath was removed, and the reaction was warmed naturally to r.t. Then the reaction mixture was poured into H₂O (30 mL), extracted with Et₂O (30 mL), washed with brine (3 × 20 mL), and dried over anhyd Na₂SO₄. Et₂O was evaporated under reduced pressure, and the residue was purified by column chroma­-tography on silica gel using pentane as the eluent; 28 mg of 2g (25%) was obtained as a colorless liquid. ^¹H NMR: δ = 7.57 (d, J = 7.7 Hz, 2 H), 7.49 (t, J = 7.3 Hz, 1 H), 7.40 (t, J = 7.7 Hz, 2 H). ^¹9F NMR: δ = -101.2 (q, J = 4.2 Hz, 2 F), -85.3 (t, J = 4.2 Hz, 3 F).

Typical Procedure for the Fluoroalkylation of 2e-f,h
To a 25 mL round-bottomed flask, ethyl 2-methyl-3-oxobutanoate (70 mg, 0.49 mmol) was dissolved in anhyd DMF (4 mL). NaH (24 mg, 56%, 0.56 mmol) was added under a N₂ atmosphere. The reaction mixture was stirred at r.t. for 30 min then cooled to -50 ˚C. Compound 1b (226 mg in 2 mL of anhyd DMF, 0.50 mmol) was added, and the cooling bath was removed. After warming naturally to r.t., the reaction mixture was poured into H₂O (30 mL), extracted with Et₂O (30 mL), washed with brine (3 × 20 mL), and dried over anhyd Na₂SO₄. The ether layer was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using PE-EtOAc (10:1) as the eluent; 42 mg of 2h (33%) was obtained as a colorless liquid. ^¹H NMR (300 MHz, CDCl₃): δ = 4.29 (q, J = 7.3 Hz, 2 H), 2.34 (s, 3 H), 1.61 (s, 3 H), 1.30 (t, J = 7.3 Hz, 3 H). ^¹9F NMR (282 MHz, CDCl₃): δ = -113.5 (dd, AB, ^² J _FF  = 282.5 Hz, 2 F), -78.8 (s, 3 F). ^¹³C NMR (100 MHz, CDCl₃): δ = 197.1, 166.1, 63.3 (t, J = 19.5 Hz), 62.8, 27.9, 15.6, 13.7. MS (EI): m/z = 43 (100), 44 (5.3), 73 (3.0), 77 (2.9), 105 (7.3), 123 (6.1), 192 (3.4), 220 (7.3). IR (KBr): 2988, 2942, 1734, 1466, 1389, 1365, 1338, 1260, 1209, 1107, 1004, 745 cm^-¹. HRMS: m/z calcd for C₉H₁₁O₃F₅: 262.0628; found: 262.0625.

• Supplementary Material