Introduction

The introduction of the trifluoromethyl (CF₃) and the difluoromethyl (CF₂H) groups into organic molecules has gained increasing attention due to the potential use of trifluoromethylated and difluoromethylated compounds in materials science and medicinal and agricultural chemistry.¹ Although there are few approaches to achieve this goal, fluoride-induced trifluoromethylation or difluoromethylation with organosilicon reagents (R_fSiR₃, R_f = CF₃, CF₂H) has been considered a straightforward and reliable method.² (Trifluoromethyl)trimethylsilane (TMS-CF₃), first developed by us^2b in 1989 as a nulceophilic trifluoromethylating reagent of choice under mild conditions, is widely used and also works with enolizable carbonyl compounds. Recently developed nucleophilic trifluoromethylation methods are inefficient in the case of enolizable systems.³

TMS-CF₃ was first prepared by Ruppert et al. in 1984,⁴ and since then, several other procedures have been developed by us and others via both chemical and electrochemical methods during the last two decades.⁵ However, all of these methods have some drawbacks. First of all, they all use bromotrifluoromethane (CF₃Br) or iodotrifluoromethane (CF₃I)^3a as a source for the trifluoromethyl group. Trifluoromethyl halides, particularly CF₃Br, in general are ozone depleting, and recently their manufacture and use have been regulated. Second, these procedures need special apparatus and well-controlled reaction conditions, and the product yields vary widely. Finally, none of the reported methods are amenable for the preparation of structurally diverse trifluoromethylsilanes. Compared with trifluoromethylation, little is known about nucleophilic difluoromethylation.^2f This is mainly due to the lack of general and efficient methods for the preparation of difluoromethylsilanes.⁶

We now wish to report a new general and efficient method for the preparation of both trifluoromethylsilanes and difluoromethylsilanes using unusual magnesium metal-mediated reductive tri- and difluoromethylation of various chlorosilanes. Magnesium metal-promoted reactions through an electron-transfer process have attracted increasing interest recently, including C-F bond cleavage of trifluoromethyl ketones (Scheme 1, eq I),⁷ trifluoroacetates,⁸ trifluoromethylimines,⁹ p-bis(trifluoromethyl) benzene¹⁰ and difluoromethyl ketones,¹¹ O-silylation of tertiary alcohols,¹² cross-coupling of carbonyl compounds with TMSCl,¹³ and C-acylation of aromatic ,-unsaturated carbonyl compounds.¹⁴ However, the magnesium metal-mediated reduction of trifluoromethyl and difluoromethyl sulfones or sulfoxides still has not been explored, and we felt that it may exhibit some different, interesting aspects as related to the well-known reductive C-F bond cleavage of tri- and difluoromethyl ketones.^7,11 In the trifluoromethyl and difluoromethyl sulfones or sulfoxides, due to the strong electron-withdrawing effect of CF₃ and CF₂H groups, the bond between the pseudohalide and the sulfur atom is sufficiently polarized by the pseudohalide group bearing substantial negative charge. Thus, when the electrons are transferred from magnesium metal to the sulfones and sulfoxides, reductive cleavage of the C-S bond to generate anionic CF₃^- or CF₂H^- species was anticipated over the C-F bond fission (Scheme 1, eqs II and III). Moreover, the phenyl trifluoromethyl sulfone 1a or the sulfoxide 1b can also be conveniently prepared from non-ozone depleting precursors such as trifluoromethane (CF₃H) or trifluoroacetate (Scheme 2, I),¹⁵ and the difluoromethyl phenyl sulfone 1i can be obtained using known methods (Scheme 2, II).¹⁶ Furthermore, with these sulfones and sufoxides, the bond between sulfur and aromatic carbon is also hard to cleave, resulting in the expected regioselective bond fission. With these considerations in mind, we have embarked on the study of magnesium-mediated reductive trifluoromethylation and difluromethylation of various chlorosilanes and have found a long sought after simple, efficient method for the preparation of diverse trifluoromethylsilanes and difluoromethylsilanes.

	Scheme 1 a a X = F, H; L = electrophiles such as trimethylsilyl group or magnesium cation, etc.
	Scheme 2

Results and Discussion

Reaction of sulfone 1a with 3 equiv of maganesium metal¹⁷ and the chlorotriethylsilane in DMF solution at 0 C gave exclusively (trifluoromethyl)triethylsilane, the only product detected by ¹⁹F NMR. After workup and purification, (trifluoromethyl)triethylsilane 3d was isolated in 95% yield. Diphenyl disulfide (PhSSPh) was also collected as a byproduct. TMS-CF₃ was also prepared similarly in quantitative conversions as identified by ¹⁹F NMR.

The reaction works equally well for diverse types of chlorosilanes with tri- and difluoromethyl sulfones or sulfoxides (see Table 1). In the case of phenyl trifluoromethyl sulfide 1c (entry c), the reaction was sluggish, indicating that the fluoroalkyl carbon-sulfur bond is not efficient in accepting the electron from the Mg metal. This was also confirmed by the fact that for the sulfide 1k, the Barbier product 3k (entry k) was produced in high yield without the C-S bond cleavage. In the case of bromodifluoromethyl phenyl sulfone 1l (entry l), 1,2-bis(trimethylsilyl)-1,1,2,2-tetrafluoroethane 3l was generated as the major product. This indicates that a Barbier-type coupling intermediate [PhS(O)₂CF₂CF₂S(O)₂Ph] 4 is presumably formed, which is subsequently transformed into 3l via a similar reductive fluoroalkylation process (see Scheme 3, path A).

Scheme 3

It is also possible that an alternative Barbier-type coupled intermediate 1m is formed, which can generate the trimethylsilyldifluoromethyl radical species 7 that homocouples to produce 3l (Scheme 3, path B). The likelihood of path B was supported by the experimental result that, under similar reaction conditions using Mg and TMSCl in DMF, both sulfone 1m (PhSO₂CF₂SiMe₃) and disulfone 1n (PhSO₂CF₂O₂SPh) readily produce compound 3l in good yields (Scheme 4).

Scheme 4

It should also be mentioned that the use of several reducing metals such as zinc, aluminum, indium, sodium, and lithium was explored to replace magnesium as the reducing agent, among which only zinc worked but only with a low yield of products (~30%). Other reducing or electron-donating reagents such as samarium iodide (SmI₂) and tetrakis(dimethylamono)ethylene were also investigated to no avail. Attempts to improve the reactivity of phenyl trifluoromethyl sulfide 1c via electrochemistry using magnesium or zinc rod as the sacrificial anode and platinum as the cathode in DMF were also unsuccessful. DMF is not the only solvent required for this reaction. Other solvents such as THF can also be used, although it needs prolonged reaction times. This indicates there is no need to invoke CF₃^-/DMF adduct^15a as the intermediate for these reactions. On the other hand, methyl phenyl sulfone in the presence of magnesium and TMSCl under similar conditions did not produce any tetramethylsilane.

Concerning the mechanism, we propose that a single electron transfer from magnesium metal to sulfones or sulfoxides facilitates a reductive cleavage of the C-S bond to form anionic tri- and difluoromethyl species and a sulfur-containg radical species (see Scheme 5). This mechanism provides a working model for this novel type of trifluoromethylation and difluoromethylation. The isolation of PhSSPh as a byproduct further confirms the possibility of the sulfur radical species. This mechanism is also supported by the fact that, when we used 2,2,2-trifluoroethyl phenyl sulfone [PhS(O)₂CH₂CF₃] 1o as the reactant with Mg and TMSCl under similar reaction conditions, 1,1-difluoroethene was produced readily. Obviously, 1,1-difluoroethene was obtained through the -elimination of the fluoride (F^-) from the in situ-generated anionic species (CF₃CH₂^-) from 1o via a smilar mechanism as described above (Scheme 6). Scheme 6 also shows that in the case of 2,2,2-trifluoroethyl phenyl sulfone, sulfoxide, and sulfide, the order of reactivity is sulfone > sufoxide > sulfide.

	Scheme 5
	Scheme 6

It should also be mentioned that methyl trifluoromethyl sulfone (CH₃SO₂CF₃) also reacts with magnesium metal and TMSCl in DMF to produce TMS-CF₃ in moderate yields (~40% over a period of 20 h at room temperature). However, the reaction appears to be sluggish. This indicates that the aromatic ring conjugation in 1a is important to facilitate the initial electron transfer process.

The reductive fluoroalkylation chemistry was also attempted with other electrophiles such as aldehydes, ketones, allyl bromide, benzyl chloride, or tributyltin chloride with no success. Even tributyltin hydride and allyltrimethylsilane showed no reactivity. The reason for such a behavior is not clear.

It is well-known that the phenyl trifluoromethyl sulfone 1a and sulfoxide 1b can be readily prepared from trifluoromethane (manufactured from methane¹⁸) and diphenyl disulfide.¹⁹ Since in our fluoroalkylation process, diphenyl disulfide is produced as a reductive byproduct, the presently developed method provides a novel and useful catalytic pathway (in diphenyl disulfide) for the production of (trifluoromethyl)silanes from trifluoromethane and chlorosilanes (see Scheme 7).

Scheme 7

Conclusion

In conclusion, we have developed a versatile and new non-Freon-based method for the preparation of a number of (trifluoromethyl)silanes and (difluoromethyl)silanes via a magnesium metal-mediated reductive S-C bond cleavage process of trifluoromethyl and difluoromethyl sulfones, sulfoxides, and sulfides. The method can be considered to be catalytic with respect to the diphenyl disulfide since the starting phenyl trifluoromethyl sulfones, sulfoxides, and sulfides are themselves readily prepared using non-ozone-depleting trifluoromethane²⁸ and diphenyl disulfide.

Experimental Section

(Trifluoromethyl)trimethylsilane (3a). Into a 250 mL dry Schlenk flask under an argon atmosphere were added 1.14 g of Mg turnings (47.5 mmol) and 11.8 g TMSCl (109 mmol) in 50 mL of DMF at 0 C. After the mixture was stirred for 2 min, 4.62 g (23.8 mmol) of 1b in 5 mL of DMF was added slowly via a syringe. The reaction mixture was stirred at room temperature at 0 C for 30 min and then at room temperature for another 1.5 h until all the starting material was transformed into product 3a (monitored by ¹⁹F NMR). All the low-boiling fractions were collected under vacuum into a trap (cooled in liquid nitrogen), warmed to room temperature, and then washed with ice-water (50 mL x 3). After quick drying over activated molecular sieves, the organic mixture was fractionally distilled using a 30 cm long column to give 2.73 g (81% yield) product 3a, bp 53-55 C (lit.^2d 55-55.5 C). ¹H NMR (360 MHz, CDCl₃): 0.25 (s, 9H, CH₃). ¹³C NMR (90 MHz, CDCl₃): -5.3 (s, CH₃); 131.7 (q, ¹J_C-F = 321.8 Hz, CF₃). ¹⁹F NMR (338 MHz, CDCl₃): -67.2.

Similarly, compound 1a was used to prepare 3a in 82% isolated yield. Compound 1c also could be used to prepare 3a, but the reaction was found to be sluggish.

(Trifluoromethyl)triethylsilane (3d). Into a flame-dried Schlenk flask containing 1.03 g (43 mmol) of magnesium turnings and 30 mL of DMF under argon was added 3.0 g (14 mmol) of trifluoromethyl phenyl sulfone 1a at 0 C. After the mixture was stirred for 5 min, 6.45 g (43 mmol) of triethylsilyl chloride was added dropwise via syringe. The color of the reaction mixture slowly turned yellow. The progress of the reaction was monitored by ¹⁹F periodically. After 1 h, the mixture was slowly warmed to room temperature over a 20 min period and the reaction mixture was washed with 50 mL of ice-water. After the excess Mg was removed, the solution was extracted with pentane (30 mL x 3). The pentane phase was washed carefully with cold 98% sulfuric acid (30 mL x 4) to remove most of the siloxane and silanol. Subsequently, the organic phase was washed with cold water (30 mL x 2), saturated aqueous NaHCO₃ solution (30 mL x 2), and water (20 mL x 2) and dried over anhydrous magnesium sulfate. The solvent was removed under vacuum (~100 Torr), and the resulting crude product also contained PhSSPh as a byproduct (characterized by both GC-MS and NMR). The crude product was carefully purified by small-scale fractional distillation to give 2.48 g (95% yield) of (trifluoromethyl)triethylsilane 3d, bp = 56~58 C/60 Torr (lit.²⁶ 52~54 C/10 Torr). GC-MS showed that its purity was higher than 96%. ¹H NMR (500 MHz, CDCl₃): 0.79 (q, ³J_H-H = 7.9 Hz, 6H); 1.04 (t, ³J_H-H = 7.9 Hz, 9H). ¹³C NMR (125 MHz, CDCl₃): 0.79 (s, CH₂); 6.37 (s, CH₃); 132.19 (q, ¹J_C-F = 323.5 Hz, CF₃). ¹⁹F NMR (470 MHz, CDCl₃): -61.30. ²⁹Si NMR (99 MHz, CDCl₃): 7.74 (q, ²J_Si-F = 32.0 Hz). GC-MS (m/z): 184 (M⁺), 155 (M - Et), 115(Et₃Si⁺).

(Trifluoromethyl)t-butyldimethylsilane (3f). Into a dry 250 mL Schlenk flask under an argon atmosphere were added 5.14 g of Mg turnings (214 mmol) and 32.3 g (214 mmol) of tert-butyldimethylsilyl chloride in 150 mL of DMF at -30 C. Subsequently, 15.0 g (71.4 mmol) of 1a in 10 mL of DMF was added slowly via a syringe. The reaction mixture was stirred at room temperature at -30 C for 1 h and then at room temperature for another 2 h until all the starting material was consumed (¹⁹F NMR showed that the conversion of 3f was 75%). The reaction mixture was washed with ice-water, followed by extraction with pentane (30 mL x 4). The combined pentane phase was further washed carefully with cold 98% sulfuric acid (20 mL x 4) to remove most of the siloxane and silanol. Then, the pentane phase was washed with cold aqueous NaHCO₃ solution three times until pH paper indicated neutral pH. The pentane phase was dried over MgSO₄ and the solvent evaporated to give a crude product that was fractionally distilled to give 7.46 g of colorless liquid (95 C/410 Torr), which turned to a transparent crystalline solid at room temperature (mp 52~54 C, sublimes), yield 57%. ¹H NMR (500 MHz, CDCl₃): 0.20 (s, 6H); 0.99 (s, 9H). ¹³C NMR (125 MHz, CDCl₃): -8.8; 16.0; 26.0; 132.0 (q, ¹J_C-F = 323.8 Hz, CF₃). ¹⁹F NMR (470 MHz, CDCl₃): -61.8. ²⁹Si NMR (99 MHz, CDCl₃): 8.4 (q, ²J_Si-F = 32.8 Hz). GC-MS (m/z): 184 (M⁺), 127 (M⁺ - ^tBu), 115 (M⁺ - CF₃), 99 (M⁺ - CF₃ - CH₃), 57 (tBu⁺). High-resolution GC-MS (EI): m/z calcd for C₇H₁₅F₃Si (M⁺) 184.0895, found 184.0943.

Tris(trimethylsilyl)trifluoromethylsilane (3h). The procedure was similar to the above examples. Into 2 g (83 mmol) of Mg turnings and 1 g (4.76 mmol) of 1a in 20 mL of DMF at -40 C was slowly added 3 g (10.6 mmol) of tris(timethylsilyl)silyl chloride in 10 mL of DMF. The reaction mixture was then stirred at -40 C for 1 h and between -40 and - 20 C for another 2 h, until all the 1a was consumed (monitored by ¹⁹F NMR). The reaction mixture was washed with ice-water, followed by extraction with pentane (20 mL x 4). The pentane phase was washed with cold 98% sulfuric acid (10 mL x 3) to remove most of the siloxane and silanol and washed with cold aqueous NaHCO₃ solution three times until pH paper indicated neutral pH. After drying over MgSO₄ and solvent removal, the crude product was further purified by silica gel chromatography (pentane as the eluent) to give 0.93 g (62% yield) of solid product 3h that sublimes at 50 C/10 Torr. ¹H NMR (500 MHz, CDCl₃): 0.26 (s, 27 H). ¹³C NMR (125 MHz, CDCl₃): 0.5 (s, CH₃); 136.8 (q, ¹J_C-F =328.0 Hz, CF₃). ¹⁹F NMR (470 MHz, CDCl₃): -41.4. ²⁹Si NMR (99 MHz, CDCl₃): -66.8 (q, ²J_Si-F = 27.5 Hz, 1 Si); -12.5 (q, ³J_Si-F = 4.6 Hz, 3Si). GC-MS (m/z): 316 (M⁺), 247 [(Me₃Si)₃Si⁺], 69 (CF₃⁺). High-resolution GC-MS (EI): m/z calcd for C₁₀H₂₇F₃Si₄ (M⁺) 316.1142, found 316.1110.

(Difluoromethyl)trimethylsilane (3i). Into a mixture of 4.8 g (200 mmol) of Mg turnings, 28.93 g (266 mmol) of TMSCl, and 100 mL of DMF at 0 C was added 12.80 g (66.7 mmol) of difluoromethyl phenyl sulfone (1i) in 10 mL of DMF slowly. The reaction mixture was stirred at 0 C for 90 min until ¹⁹F NMR showed that all the 1i was consumed. All of the low-boiling species was separated out by bulb to bulb distillation, followed by washing with ice-water (30 mL x 3) and drying over molecular sieves. Fractional distillation (using a 30 cm long distillation column) afforded 4.96 g of product, bp 52 C (lit.^2c 50 C), yield 76%. ¹H NMR (360 MHz, CDCl₃): 0.15 (s, 9H); 5.82 (t, ²J_H-F = 46.5 Hz, 1H). ¹³C NMR (90 MHz, CDCl₃): -5.4 (t, ³J_C-F = 2.8 Hz); 123.9 (t, ¹J_C-F = 254.7 Hz). ¹⁹F NMR (338 MHz, CDCl₃): -140.1 (d, ²J_F-H = 46.8 Hz).

(Difluoromethyl)triethylsilane (3j). Into a mixture of 5 g (26 mmol) of difluoromethyl phenyl sulfone (1i), 1.9 g of Mg turnings (78 mmol), and 150 mL of DMF at -40 C was slowly added 11.8 g (78 mmol) of chlorotriethylsilane. The reaction mixture was then stirred at temperatures between -40 and 10 C over a 4 h period until ¹⁹F NMR indicated that all the 1i was consumed. Similar workup as above and fractional distillation gave 2.2 g of product 3j,²⁷ bp 71 C/56 Torr, yield 51%. ¹H NMR (500 MHz, CDCl₃): 0.72 (q, ³J_H-H = 8.0 Hz, 6H); 1.02 (t, ³J_H-H = 8.0 Hz, 9H); 5.95 (t, ²J_H-F = 46.0 Hz, 1H). ¹³C NMR (125 MHz, CDCl₃): 0.6 (s, CH₂); 6.7 (s, CH₃); 124.3 (t, ¹J_C-F = 254.8 Hz). ¹⁹F NMR (470 MHz, CDCl₃): -137.6 (d, ²J_F-H = 45.8 Hz). ²⁹Si NMR (99 MHz, CDCl₃): 3.3 (t, ²J_Si-F = 24.8 Hz). GC-MS (m/z): 166 (M⁺); 115 (Et₃Si⁺); 51 (CF₂H⁺).

1,2-Bis(trimethylsilyl)-1,1,2,2-tetrafluoroethane (3l). Into a mixture of 0.42 g (17.5 mmol) of Mg turnings, 1.92 g (17.7 mmol) of TMSCl, and 10 mL of DMF was added 1.60 g (5.9 mmol) of bromodifluoromethyl phenyl sulfone 1l. The reaction mixture was stirred at 0 C for 30 min and then at room temperature for another 30 min until ¹⁹F NMR showed that all the 1l was consumed (the yield of 3l was 76% and byproduct TMSCF₂TMS, 18% by ¹⁹F NMR analysis). The reaction mixture was washed with ice-water followed by extraction with pentane (10 mL x 4). The pentane phase was washed with cold 98% sulfuric acid (10 mL x 3) to remove most of the siloxane and silanol. Then, the pentane solution was washed with cold aqueous NaHCO₃ solution three times until pH paper indicated a neutral pH. After drying over MgSO₄ and solvent removal, the crude product was further purified by fractional distillation and then recrystallization at -20 C to give 0.40 g of crystalline product 3l, mp 40~42 C, yield 55%. ¹H NMR (500 MHz, CDCl₃): 0.24 (s, 18H). ¹³C NMR (125 MHz, CDCl₃): -4.0 (m, CH₃); 126.6 (tt, ¹J_C-F = 265.0 Hz; ²J_C-F = 45.9 Hz). ¹⁹F NMR (470 MHz, CDCl₃): -122.3.

Compound 3l was also prepared by using PhSO₂CF₂O₂SPh (1n) or PhSO₂CF₂TMS (1m) as the starting material (see Scheme 4).

Phenyl (Trimethylsilyl)difluoromethyl Sulfide (3k). Into a mixture of 0.22 g (9.2 mmol) of Mg turnings, 1.99 g (18.3 mmol) of TMSCl, and 20 mL of DMF at room temperature was added 1.1 g (4.6 mmol) of bromodifluoromethyl phenyl sulfide 1k. The reaction was stirred at room temperature for another 1 h. Excess TMSCl was removed under vacuum (~10 mmHg). The residue was washed with ice-water and then extracted with dichloromethane (20 mL x 3). The organic phase was further washed with brine and water successively and dried over MgSO₄. After solvent removal, the crude product was further purified by silica gel chromatography (pentane as eluent) to give 905 mg (85% yield) of product 3k as a colorless liquid, bp 86~87 C/4 Torr. ¹H NMR (500 MHz, CDCl₃): 0.25 (s, 9H); 7.37 (m, 3H); 7.59 (d, 2H). ¹³C NMR (125 MHz, CDCl₃): -4.2; 126.3 (t, ³J_C-F = 4.1 Hz); 128.8; 129.3; 134.0 (t, ¹J_C-F = 300.1 Hz); 136.2. ¹⁹F NMR (470 MHz, CDCl₃): -88.1 (s). ²⁹Si NMR (99 MHz, CDCl₃): 7.7 (t, ²J_Si-F = 31.28 Hz). IR (neat): 3064; 2965; 2904; 1884; 1585; 1475; 1441; 1414; 1307; 1255; 1076; 1025; 962; 884; 850; 825; 744; 703; 690; 631; 607; 496 cm^-1. GC-MS (m/z): 232 (M⁺), 109 (PhS⁺), 73 (Me₃Si⁺). HRMS (DEI): m/z calcd for C₁₀H₁₄F₂SSi (M⁺) 232.0553, found 232.0545.

Phenyl (Trimethylsilyl)difluoromethyl Sulfone (1m). Phenyl (trimethylsilyl)difluoromethyl sulfide (3k) (2.0 g, 8.6 mmol) was oxidized with mCPBA (9.0 mmol) in 20 mL of CH₂Cl₂ initially at 0 C, followed by stirring at room temperature overnight. After filtration, the filtrate was washed with Na₂SO₃ solution (10 mL x 3), NaHCO₃ solution (10 mL x 2), and water sequentially. After drying over MgSO₄ and solvent removal, the crude product was distilled to afford 1.2 g (51% yield) of product 1m as a colorless liquid, bp 112~114 C/1 Torr. ¹H NMR (500 MHz, CDCl₃): 0.44 (s, 9H); 7.61 (t, 2H); 7.74 (t, 1H); 7.95 (d, 2H). ¹⁹F NMR (470 MHz, CDCl₃): -112.9. HRMS (DCI/NH₃): m/z calcd for C₁₀H₁₈F₂NO₂SSi (M + NH₄⁺) 282.0795, found 282.0787.

Acknowledgment

Support of our work in part by Loker Hydrocarbon Research Institute is gratefully acknowledged.