1,6-Nucleophilic Di- and Trifluoromethylation of para-Quinone Methides with Me3SiCF2H/Me3SiCF3 Facilitated by CsF/18-Crown-6

The direct 1,6-nucleophilic difluoromethylation, trifluoromethylation, and difluoroalkylation of para-quinone methides (p-QMs) with Me3SiRf (Rf = CF2H, CF3, CF2CF3, CF2COOEt, and CF2SPh) under mild conditions are described. Although Me3SiCF2H shows lower reactivity than Me3SiCF3, it can react with p-QMs promoted by CsF/18-Crown-6 to give structurally diverse difluoromethyl products in good yields. The products can then be further converted into fluoroalkylated para-quinone methides and α-fluoroalkylated diarylmethanes.

In 2011, our group first demonstrated the effectiveness of utilizing Me 3 SiCF 2 H in nucleophilic difluoromethylation activated by CsF or tBuOK under mild conditions [25].This discovery made people realize that Me 3 SiCF 2 H could be used as an efficient difluoromethylation reagent.Subsequently, in 2016, our group conducted in-depth research on the 1,2-addition of Me 3 SiCF 2 H to enolizable ketones.We found that CsF/18-crown-6 acts as an initiation system to produce a pentavalent silicon reactive intermediate [(18-crown-6)Cs] + [(CH 3 ) 3 Si(CF 2 H) 2 ] − , which serves as a temporary reservoir for the difluoromethyl anion, playing a pivotal role in the success of the difluoromethylation in enolizable ketones [37].In recent years, other strong basic initiators, such as tBu-P 4 and t-AmOK, among others, have been developed for various difluoromethylations with TMSCF 2 H [26,30,31].However, identifying appropriate initiators to facilitate the difluoromethylation of basesensitive substrates with Me 3 SiCF 2 H remains a formidable challenge.

Results
We initiated the study by optimizing the reaction conditions, including the choice of initiators, temperature, and solvents, using 4-benzylidene-2,6-di-tert-butylcyclohexa-2,5dien-1-one (1a) as the model substrate and Me3SiCF2H as the difluoromethylation reagent (Table 1).We first performed the reaction under the previously reported conditions for the direct nucleophilic difluoromethylation of enolizable ketones, which involved using Scheme 1.The reactions between p-QMs and different fluorine reagents.
Furthermore, we extended our investigation to the nucleophilic trifluoromethylation of various p-QMs using Me3SiCF3 under similar reaction conditions (Table 3).A comparison of Table 2 with Table 3 indicates that there are some differences between the di-and trifluoromethylation of p-QMs; for instance, a series of p-QMs bearing Me groups (R = o-, m-, and p-Me) produced the corresponding trifluoromethylation products (Table 3, 3b-3d) in higher yields than the difluoromethyl products (Table 2, 2b-2d).As shown in Table 3, p-QMs bearing electron-donating groups (R = 4-tBu and 4-OMe) (3h-3i) generated the corresponding trifluoromethyl products in lower yields than the p-QMs bearing other groups (H, Me, and Br) (3a-3d and 3f).The other trifluoromethyl products 3j and 3k (R = naphthalene and pyridine moiety, respectively) were also obtained with yields of 78% and 30%, respectively.a Me3SiCF2H (0.8 mmol, 2 equiv) and 1 (0.4 mmol, 1.0 equiv) were used.b Isolated yields were given.
Furthermore, we extended our investigation to the nucleophilic trifluoromethylation of various p-QMs using Me3SiCF3 under similar reaction conditions (Table 3).A comparison of Table 2 with Table 3 indicates that there are some differences between the di-and trifluoromethylation of p-QMs; for instance, a series of p-QMs bearing Me groups (R = o-, m-, and p-Me) produced the corresponding trifluoromethylation products (Table 3, 3b-3d) in higher yields than the difluoromethyl products (Table 2, 2b-2d).As shown in Table 3, p-QMs bearing electron-donating groups (R = 4-tBu and 4-OMe) (3h-3i) generated the corresponding trifluoromethyl products in lower yields than the p-QMs bearing other groups (H, Me, and Br) (3a-3d and 3f).The other trifluoromethyl products 3j and 3k (R = naphthalene and pyridine moiety, respectively) were also obtained with yields of 78% and 30%, respectively.a Me3SiCF2H (0.8 mmol, 2 equiv) and 1 (0.4 mmol, 1.0 equiv) were used.b Isolated yields were given.
Furthermore, we extended our investigation to the nucleophilic trifluoromethylation of various p-QMs using Me3SiCF3 under similar reaction conditions (Table 3).A comparison of Table 2 with Table 3 indicates that there are some differences between the di-and trifluoromethylation of p-QMs; for instance, a series of p-QMs bearing Me groups (R = o-, m-, and p-Me) produced the corresponding trifluoromethylation products (Table 3, 3b-3d) in higher yields than the difluoromethyl products (Table 2, 2b-2d).As shown in Table 3, p-QMs bearing electron-donating groups (R = 4-tBu and 4-OMe) (3h-3i) generated the corresponding trifluoromethyl products in lower yields than the p-QMs bearing other groups (H, Me, and Br) (3a-3d and 3f).The other trifluoromethyl products 3j and 3k (R = naphthalene and pyridine moiety, respectively) were also obtained with yields of 78% and 30%, respectively.Furthermore, we extended our investigation to the nucleophilic trifluoromethylation of various p-QMs using Me3SiCF3 under similar reaction conditions (Table 3).A comparison of Table 2 with Table 3 indicates that there are some differences between the di-and trifluoromethylation of p-QMs; for instance, a series of p-QMs bearing Me groups (R = o-, m-, and p-Me) produced the corresponding trifluoromethylation products (Table 3, 3b-3d) in higher yields than the difluoromethyl products (Table 2, 2b-2d).As shown in Table 3, p-QMs bearing electron-donating groups (R = 4-tBu and 4-OMe) (3h-3i) generated the corresponding trifluoromethyl products in lower yields than the p-QMs bearing other groups (H, Me, and Br) (3a-3d and 3f).The other trifluoromethyl products 3j and 3k (R = naphthalene and pyridine moiety, respectively) were also obtained with yields of 78% and 30%, respectively.Furthermore, we extended our investigation to the nucleophilic trifluoromethylation of various p-QMs using Me3SiCF3 under similar reaction conditions (Table 3).A comparison of Table 2 with Table 3 indicates that there are some differences between the di-and trifluoromethylation of p-QMs; for instance, a series of p-QMs bearing Me groups (R = o-, m-, and p-Me) produced the corresponding trifluoromethylation products (Table 3, 3b-3d) in higher yields than the difluoromethyl products (Table 2, 2b-2d).As shown in Table 3, p-QMs bearing electron-donating groups (R = 4-tBu and 4-OMe) (3h-3i) generated the corresponding trifluoromethyl products in lower yields than the p-QMs bearing other groups (H, Me, and Br) (3a-3d and 3f).The other trifluoromethyl products 3j and 3k (R = naphthalene and pyridine moiety, respectively) were also obtained with yields of 78% and 30%, respectively.Furthermore, we extended our investigation to the nucleophilic trifluoromethylation of various p-QMs using Me3SiCF3 under similar reaction conditions (Table 3).A comparison of Table 2 with Table 3 indicates that there are some differences between the di-and trifluoromethylation of p-QMs; for instance, a series of p-QMs bearing Me groups (R = o-, m-, and p-Me) produced the corresponding trifluoromethylation products (Table 3, 3b-3d) in higher yields than the difluoromethyl products (Table 2, 2b-2d).As shown in Table 3, p-QMs bearing electron-donating groups (R = 4-tBu and 4-OMe) (3h-3i) generated the corresponding trifluoromethyl products in lower yields than the p-QMs bearing other groups (H, Me, and Br) (3a-3d and 3f).The other trifluoromethyl products 3j and 3k (R = naphthalene and pyridine moiety, respectively) were also obtained with yields of 78% and 30%, respectively.Furthermore, we extended our investigation to the nucleophilic trifluoromethylation of various p-QMs using Me3SiCF3 under similar reaction conditions (Table 3).A comparison of Table 2 with Table 3 indicates that there are some differences between the di-and trifluoromethylation of p-QMs; for instance, a series of p-QMs bearing Me groups (R = o-, m-, and p-Me) produced the corresponding trifluoromethylation products (Table 3, 3b-3d) in higher yields than the difluoromethyl products (Table 2, 2b-2d).As shown in Table 3, p-QMs bearing electron-donating groups (R = 4-tBu and 4-OMe) (3h-3i) generated the corresponding trifluoromethyl products in lower yields than the p-QMs bearing other groups (H, Me, and Br) (3a-3d and 3f).The other trifluoromethyl products 3j and 3k (R = naphthalene and pyridine moiety, respectively) were also obtained with yields of 78% and 30%, respectively.Furthermore, we extended our investigation to the nucleophilic trifluoromethylation of various p-QMs using Me3SiCF3 under similar reaction conditions (Table 3).A comparison of Table 2 with Table 3 indicates that there are some differences between the di-and trifluoromethylation of p-QMs; for instance, a series of p-QMs bearing Me groups (R = o-, m-, and p-Me) produced the corresponding trifluoromethylation products (Table 3, 3b-3d) in higher yields than the difluoromethyl products (Table 2, 2b-2d).As shown in Table 3, p-QMs bearing electron-donating groups (R = 4-tBu and 4-OMe) (3h-3i) generated the corresponding trifluoromethyl products in lower yields than the p-QMs bearing other groups (H, Me, and Br) (3a-3d and 3f).The other trifluoromethyl products 3j and 3k (R = naphthalene and pyridine moiety, respectively) were also obtained with yields of 78% and 30%, respectively.a Me3SiCF2H (0.8 mmol, 2 equiv) and 1 (0.4 mmol, 1.0 equiv) were used.b Isolated yields were given.
Furthermore, we extended our investigation to the nucleophilic trifluoromethylation of various p-QMs using Me3SiCF3 under similar reaction conditions (Table 3).A comparison of Table 2 with Table 3 indicates that there are some differences between the di-and trifluoromethylation of p-QMs; for instance, a series of p-QMs bearing Me groups (R = o-, m-, and p-Me) produced the corresponding trifluoromethylation products (Table 3, 3b-3d) in higher yields than the difluoromethyl products (Table 2, 2b-2d).As shown in Table 3, p-QMs bearing electron-donating groups (R = 4-tBu and 4-OMe) (3h-3i) generated the corresponding trifluoromethyl products in lower yields than the p-QMs bearing other groups (H, Me, and Br) (3a-3d and 3f).The other trifluoromethyl products 3j and 3k (R = naphthalene and pyridine moiety, respectively) were also obtained with yields of 78% and 30%, respectively.a Me3SiCF2H (0.8 mmol, 2 equiv) and 1 (0.4 mmol, 1.0 equiv) were used.b Isolated yields were given.
Furthermore, we extended our investigation to the nucleophilic trifluoromethylation of various p-QMs using Me3SiCF3 under similar reaction conditions (Table 3).A comparison of Table 2 with Table 3 indicates that there are some differences between the di-and trifluoromethylation of p-QMs; for instance, a series of p-QMs bearing Me groups (R = o-, m-, and p-Me) produced the corresponding trifluoromethylation products (Table 3, 3b-3d) in higher yields than the difluoromethyl products (Table 2, 2b-2d).As shown in Table 3, p-QMs bearing electron-donating groups (R = 4-tBu and 4-OMe) (3h-3i) generated the corresponding trifluoromethyl products in lower yields than the p-QMs bearing other groups (H, Me, and Br) (3a-3d and 3f).The other trifluoromethyl products 3j and 3k (R = naphthalene and pyridine moiety, respectively) were also obtained with yields of 78% and 30%, respectively.a Me3SiCF2H (0.8 mmol, 2 equiv) and 1 (0.4 mmol, 1.0 equiv) were used.b Isolated yields were given.
Furthermore, we extended our investigation to the nucleophilic trifluoromethylation of various p-QMs using Me3SiCF3 under similar reaction conditions (Table 3).A comparison of Table 2 with Table 3 indicates that there are some differences between the di-and trifluoromethylation of p-QMs; for instance, a series of p-QMs bearing Me groups (R = o-, m-, and p-Me) produced the corresponding trifluoromethylation products (Table 3, 3b-3d) in higher yields than the difluoromethyl products (Table 2, 2b-2d).As shown in Table 3, p-QMs bearing electron-donating groups (R = 4-tBu and 4-OMe) (3h-3i) generated the corresponding trifluoromethyl products in lower yields than the p-QMs bearing other groups (H, Me, and Br) (3a-3d and 3f).The other trifluoromethyl products 3j and 3k (R = naphthalene and pyridine moiety, respectively) were also obtained with yields of 78% and 30%, respectively.a Me3SiCF2H (0.8 mmol, 2 equiv) and 1 (0.4 mmol, 1.0 equiv) were used.b Isolated yields were given.
Furthermore, we extended our investigation to the nucleophilic trifluoromethylation of various p-QMs using Me3SiCF3 under similar reaction conditions (Table 3).A comparison of Table 2 with Table 3 indicates that there are some differences between the di-and trifluoromethylation of p-QMs; for instance, a series of p-QMs bearing Me groups (R = o-, m-, and p-Me) produced the corresponding trifluoromethylation products (Table 3, 3b-3d) in higher yields than the difluoromethyl products (Table 2, 2b-2d).As shown in Table 3, p-QMs bearing electron-donating groups (R = 4-tBu and 4-OMe) (3h-3i) generated the corresponding trifluoromethyl products in lower yields than the p-QMs bearing other groups (H, Me, and Br) (3a-3d and 3f).The other trifluoromethyl products 3j and 3k (R = naphthalene and pyridine moiety, respectively) were also obtained with yields of 78% and 30%, respectively.a Me3SiCF2H (0.8 mmol, 2 equiv) and 1 (0.4 mmol, 1.0 equiv) were used.b Isolated yields were given.
Furthermore, we extended our investigation to the nucleophilic trifluoromethylation of various p-QMs using Me3SiCF3 under similar reaction conditions (Table 3).A comparison of Table 2 with Table 3 indicates that there are some differences between the di-and trifluoromethylation of p-QMs; for instance, a series of p-QMs bearing Me groups (R = o-, m-, and p-Me) produced the corresponding trifluoromethylation products (Table 3, 3b-3d) in higher yields than the difluoromethyl products (Table 2, 2b-2d).As shown in Table 3, p-QMs bearing electron-donating groups (R = 4-tBu and 4-OMe) (3h-3i) generated the corresponding trifluoromethyl products in lower yields than the p-QMs bearing other groups (H, Me, and Br) (3a-3d and 3f).The other trifluoromethyl products 3j and 3k (R = naphthalene and pyridine moiety, respectively) were also obtained with yields of 78% and 30%, respectively.a Me3SiCF2H (0.8 mmol, 2 equiv) and 1 (0.4 mmol, 1.0 equiv) were used.b Isolated yields were given.

General Information
All reactions were carried out in oven-dried glassware under nitrogen atmosphere.Commercially available reagents were used without further purification.para-Quinone Molecules 2024, 29, x FOR PEER REVIEW 7 of 17 In addition, as illustrated in Table 4, other fluoroalkyl silane reagents Me3SiRf (Rf = CF2CF3, CF2COOEt, and CF2SPh) could also react with p-QMs to generate the corresponding 5 products in 60-88% yields.It is noteworthy that the heterocycle-containing substrates are also compatible with the reaction conditions (5d and 5e).Finally, to showcase the practical utility of the fluoroalkylation products, we explored their further transformations (Scheme 3).Oxidation of 2f with 4 equiv. of K3[Fe(CN)3] and KOH in a 1:1 mixture of hexane and H2O (v/v) at room temperature afforded difluoromethylated p-QM 6a in 78% yield.De-tert-butylation of 2f using a catalytic amount of H2SO4 at 120 °C provided 6b in 81% yield.Notably, α-difluoromethylated diarylmethanes possess potent cytotoxic activity against HCT116 cells [53,54].Moreover, we applied our protocol in the synthesis of a fluorinated analogue of the insecticide 1,1,1trichloro-2,2-bis(p-chloro phenyl)ethane (DDT) [55].Here, treatment of the trifluoromethylation product 3i with H2SO4 followed by ethylation produced the DDT analogue 7b in 67% overall yield.Scheme 3. Synthetic applications of di-and trifluoromethylated p-quinone methides.

General Information
All reactions were carried out in oven-dried glassware under nitrogen atmosphere.Commercially available reagents were used without further purification.para-Quinone Molecules 2024, 29, x FOR PEER REVIEW 7 of 17 In addition, as illustrated in Table 4, other fluoroalkyl silane reagents Me3SiRf (Rf = CF2CF3, CF2COOEt, and CF2SPh) could also react with p-QMs to generate the corresponding 5 products in 60-88% yields.It is noteworthy that the heterocycle-containing substrates are also compatible with the reaction conditions (5d and 5e).Finally, to showcase the practical utility of the fluoroalkylation products, we explored their further transformations (Scheme 3).Oxidation of 2f with 4 equiv. of K3[Fe(CN)3] and KOH in a 1:1 mixture of hexane and H2O (v/v) at room temperature afforded difluoromethylated p-QM 6a in 78% yield.De-tert-butylation of 2f using a catalytic amount of H2SO4 at 120 °C provided 6b in 81% yield.Notably, α-difluoromethylated diarylmethanes possess potent cytotoxic activity against HCT116 cells [53,54].Moreover, we applied our protocol in the synthesis of a fluorinated analogue of the insecticide 1,1,1trichloro-2,2-bis(p-chloro phenyl)ethane (DDT) [55].Here, treatment of the trifluoromethylation product 3i with H2SO4 followed by ethylation produced the DDT analogue 7b in 67% overall yield.Scheme 3. Synthetic applications of di-and trifluoromethylated p-quinone methides.

General Information
All reactions were carried out in oven-dried glassware under nitrogen atmosphere.Commercially available reagents were used without further purification.para-Quinone Molecules 2024, 29, x FOR PEER REVIEW 7 of 17 In addition, as illustrated in Table 4, other fluoroalkyl silane reagents Me3SiRf (Rf = CF2CF3, CF2COOEt, and CF2SPh) could also react with p-QMs to generate the corresponding 5 products in 60-88% yields.It is noteworthy that the heterocycle-containing substrates are also compatible with the reaction conditions (5d and 5e).Finally, to showcase the practical utility of the fluoroalkylation products, we explored their further transformations (Scheme 3).Oxidation of 2f with 4 equiv. of K3[Fe(CN)3] and KOH in a 1:1 mixture of hexane and H2O (v/v) at room temperature afforded difluoromethylated p-QM 6a in 78% yield.De-tert-butylation of 2f using a catalytic amount of H2SO4 at 120 °C provided 6b in 81% yield.Notably, α-difluoromethylated diarylmethanes possess potent cytotoxic activity against HCT116 cells [53,54].Moreover, we applied our protocol in the synthesis of a fluorinated analogue of the insecticide 1,1,1trichloro-2,2-bis(p-chloro phenyl)ethane (DDT) [55].Here, treatment of the trifluoromethylation product 3i with H2SO4 followed by ethylation produced the DDT analogue 7b in 67% overall yield.Scheme 3. Synthetic applications of di-and trifluoromethylated p-quinone methides.

General Information
All reactions were carried out in oven-dried glassware under nitrogen atmosphere.Commercially available reagents were used without further purification.para-Quinone Molecules 2024, 29, x FOR PEER REVIEW 7 of 17 In addition, as illustrated in Table 4, other fluoroalkyl silane reagents Me3SiRf (Rf = CF2CF3, CF2COOEt, and CF2SPh) could also react with p-QMs to generate the corresponding 5 products in 60-88% yields.It is noteworthy that the heterocycle-containing substrates are also compatible with the reaction conditions (5d and 5e).Finally, to showcase the practical utility of the fluoroalkylation products, we explored their further transformations (Scheme 3).Oxidation of 2f with 4 equiv. of K3[Fe(CN)3] and KOH in a 1:1 mixture of hexane and H2O (v/v) at room temperature afforded difluoromethylated p-QM 6a in 78% yield.De-tert-butylation of 2f using a catalytic amount of H2SO4 at 120 °C provided 6b in 81% yield.Notably, α-difluoromethylated diarylmethanes possess potent cytotoxic activity against HCT116 cells [53,54].Moreover, we applied our protocol in the synthesis of a fluorinated analogue of the insecticide 1,1,1trichloro-2,2-bis(p-chloro phenyl)ethane (DDT) [55].Here, treatment of the trifluoromethylation product 3i with H2SO4 followed by ethylation produced the DDT analogue 7b in 67% overall yield.Scheme 3. Synthetic applications of di-and trifluoromethylated p-quinone methides.

General Information
All reactions were carried out in oven-dried glassware under nitrogen atmosphere.Commercially available reagents were used without further purification.para-Quinone Molecules 2024, 29, x FOR PEER REVIEW 7 of 17 In addition, as illustrated in Table 4, other fluoroalkyl silane reagents Me3SiRf (Rf = CF2CF3, CF2COOEt, and CF2SPh) could also react with p-QMs to generate the corresponding 5 products in 60-88% yields.It is noteworthy that the heterocycle-containing substrates are also compatible with the reaction conditions (5d and 5e).Finally, to showcase the practical utility of the fluoroalkylation products, we explored their further transformations (Scheme 3).Oxidation of 2f with 4 equiv. of K3[Fe(CN)3] and KOH in a 1:1 mixture of hexane and H2O (v/v) at room temperature afforded difluoromethylated p-QM 6a in 78% yield.De-tert-butylation of 2f using a catalytic amount of H2SO4 at 120 °C provided 6b in 81% yield.Notably, α-difluoromethylated diarylmethanes possess potent cytotoxic activity against HCT116 cells [53,54].Moreover, we applied our protocol in the synthesis of a fluorinated analogue of the insecticide 1,1,1trichloro-2,2-bis(p-chloro phenyl)ethane (DDT) [55].Here, treatment of the trifluoromethylation product 3i with H2SO4 followed by ethylation produced the DDT analogue 7b in 67% overall yield.Scheme 3. Synthetic applications of di-and trifluoromethylated p-quinone methides.

General Information
All reactions were carried out in oven-dried glassware under nitrogen atmosphere Commercially available reagents were used without further purification.para-Quinon Scheme 3. Synthetic applications of di-and trifluoromethylated p-quinone methides.

General Information
All reactions were carried out in oven-dried glassware under nitrogen atmosphere.Commercially available reagents were used without further purification.para-Quinone methides were prepared according to the reported literature [56].The solvent DMF was dried over CaH 2 and distilled under reduced pressure.Column chromatography was performed with 300-400 mesh silica gel.All melting points are uncorrected. 1H, 13 C, and 19 F NMR spectra were recorded on a 400 MHz NMR spectrometer (Brucker, Karlsruhe, Germany).TLC was carried out with 0.2-millimeter-thick silica gel plates (GF254).Visualization was accomplished by UV light.Mass spectra were obtained on a mass spectrometer.High-resolution mass data were recorded on a high-resolution mass spectrometer in ESI positive ion mode (Q Exactive HF Orbitrap, Thermo Fisher Scientific, Waltham, MA, USA).Under nitrogen atmosphere, para-quinone methide 1 (0.4 mmol), CsF (91.14 mg, 0.6 mmol), and 18-crown-6 (158.6 mg, 0.6 mmol) were added into a Schlenk tube.The Schlenk tube was placed in a cold bath and stirred at −15 • C, and then DMF (2 mL) and TMSCF 2 H (100 mg, 107 µL, 0.80 mmol), TMSCF 3 (114 mg, 118 µL, 0.80 mmol), or TMSCF 2 R (0.80 mmol) were added.The reaction mixture was gradually warmed to room temperature and stirred overnight.Subsequently, HCl aq.(1.0 M, 1.0 mL) was added at room temperature and the above mixture was stirred for another 15 min.Finally, the mixture was extracted with methyl tert-butyl ether (3 × 20 mL).The organic phase was washed with brine and then dried over anhydrous Na 2 SO 4 .After filtration and evaporation under vacuum, the residue was subjected to silica gel column chromatography using hexane/dichloromethane (4:1-1:1, v/v) as an eluent to give products 2-5.[49]: 97 mg, 70% yield.Yellow oil.Purification by column chromatography (hexane/dichloromethane = 4:1, v/v).K 3 [Fe(CN) 6 ] (395 mg, 1.2 mmol) and KOH (71 mg, 1.26 mmol) in water (3 mL) were added in one portion to a solution of 2f (114 mg, 0.3 mmol) in hexane (3 mL) under N 2 in a 25-milliliter round-bottom flask equipped with a magnetic stir bar.The reaction mixture was stirred at room temperature for 5 h.The organic layer was separated and the aqueous layer was extracted with hexane.The combined organic layer was washed with brine and dried over Na 2 SO 4 .After filtration, the solution was concentrated by rotary evaporation.The residue was purified by silica gel flash column chromatography using petroleum ether to afford 6a (88.5 mg, 78%).A 10-milliliter sealed tube equipped with a magnetic stir bar was charged with 2f (114 mg, 0.3 mmol) and dry toluene (3 mL).The solution was added with concentrated H 2 SO 4 (1 drop) and heated at 120 • C (oil bath temperature) for 18 h with vigorous stirring.After cooling to room temperature, water (20 mL) was poured into the reaction mixture, and then the mixture was extracted with dichloromethane (3 × 20 mL).The combined organic layer was dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure.The residue was purified by flash column chromatography on silica gel using petroleum ether-ethyl acetate (5:1-1:1, v/v) as an eluent to afford the product 6b (65.0 mg, 81%).A 30-milliliter sealed tube equipped with a magnetic stir bar was charged with 3i (236 mg, 0.6 mmol) and dry toluene (5 mL).The solution was added with concentrated H 2 SO 4 (2 drops) and heated at 120 • C (oil bath temperature) for 18 h with vigorous stirring.After cooling to room temperature, water (20 mL) was poured into the reaction mixture, and then the mixture was extracted with dichloromethane (3 × 20 mL).The combined organic layer was dried over Na 2 SO 4 , filtered, and evaporated under reduced pressure.The residue was purified by flash column chromatography on silica gel using petroleum ether-ethyl acetate (5:1-1:1, v/v) as an eluent to afford the intermediate 7a (127.0 mg, 75%).
A 25-milliliter round-bottom flask was charged with a magnetic stir bar, the intermediate 7a (84.5 mg, 0.3 mmol), Cs 2 CO 3 (71 mg, 0.6 mmol), CH 3 CN (10 mL), and iodoethane (93.5 mg, 0.6 mmol).The reaction mixture was stirred for about 24 h at 90 • C (oil bath temperature) and then cooled to room temperature and filtered.The solvent was evaporated under vacuum.The residue was subjected to silica gel column chromatography using petroleum ether-ethyl acetate (10:1, v/v) as an eluent to give the product 7b (82.8 mg, 89% yield).

Me 3 2 Scheme 1 .
Scheme 1.The reactions between p-QMs and different fluorine reagents.
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Table 1 .
Optimization of reaction conditions between p-QMs 1a and Me 3 SiCF 2 H a .

Table 1 .
Optimization of reaction conditions between p-QMs 1a and Me3SiCF2H a ..EntryInitiator (

Table 2 .
Direct nucleophilic difluoromethylation of p-QMs with Me 3 SiCF 2 H a,b .

Table 2 .
Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b .

Table 2 .
Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b .

Table 2 .
Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b .

Table 2 .
Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b .

Table 2 .
Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b .

Table 2 .
Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b .

Table 2 .
Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b .

Table 2 .
Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b .

Table 2 .
Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b .

Table 2 .
Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b .

Table 2 .
Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b .

Table 2 .
Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b .

Table 2 .
Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b .

Table 2 .
Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b .

Table 2 .
Direct nucleophilic difluoromethylation of p-QMs with Me3SiCF2H a,b .

Table 3 .
Direct nucleophilic trifluoromethylation of p-QMs with Me3SiCF3 a,b .

Table 3 .
Direct nucleophilic trifluoromethylation of p-QMs with Me3SiCF3 a,b .

Table 3 .
Direct nucleophilic trifluoromethylation of p-QMs with Me3SiCF3 a,b .

Table 3 .
Direct nucleophilic trifluoromethylation of p-QMs with Me3SiCF3 a,b .

Table 3 .
Direct nucleophilic trifluoromethylation of p-QMs with Me3SiCF3 a,b .

Table 3 .
Direct nucleophilic trifluoromethylation of p-QMs with Me3SiCF3 a,b .

Table 3 .
Direct nucleophilic trifluoromethylation of p-QMs with Me3SiCF3 a,b .

Table 3 .
Direct nucleophilic trifluoromethylation of p-QMs with Me3SiCF3 a,b .

Table 3 .
Direct nucleophilic trifluoromethylation of p-QMs with Me3SiCF3 a,b .

Table 3 .
Direct nucleophilic trifluoromethylation of p-QMs with Me3SiCF3 a,b .

Table 3 .
Direct nucleophilic trifluoromethylation of p-QMs with Me3SiCF3 a,b .

Table 3 .
Direct nucleophilic trifluoromethylation of p-QMs with Me3SiCF3 a,b .

Table 3 .
Direct nucleophilic trifluoromethylation of p-QMs with Me3SiCF3 a,b .

Table 4 .
Direct nucleophilic fluoroalkylation of p-QMs with other fluoroalkyltrimethylsilane reagents a,b .

Table 4 .
Direct nucleophilic fluoroalkylation of p-QMs with other fluoroalkyltrimethylsilane reagents a,b .

Table 4 .
Direct nucleophilic fluoroalkylation of p-QMs with other fluoroalkyltrimethylsilane reagents a,b .

Table 4 .
Direct nucleophilic fluoroalkylation of p-QMs with other fluoroalkyltrimethylsilane reagents a,b .

Table 4 .
Direct nucleophilic fluoroalkylation of p-QMs with other fluoroalkyltrimethylsilane reagents a,b .

Table 4 .
Direct nucleophilic fluoroalkylation of p-QMs with other fluoroalkyltrimethylsilane reagents a,b .

Table 4 .
Direct nucleophilic fluoroalkylation of p-QMs with other fluoroalkyltrimethylsilane reagents a,b .

Table 4 .
Direct nucleophilic fluoroalkylation of p-QMs with other fluoroalkyltrimethylsilane rea gents a,b .