Vinyl Cation Stabilization by Silicon Enables a Formal Metal‐Free α‐Arylation of Alkyl Ketones

Abstract The ability of silicon to stabilize vinyl cationic species leads to a redox arylation of alkynes whereby the stringent limitations of reactivity and regioselectivity of alkyl‐substituted alkynes are lifted. This allows the synthesis of a range of α‐silyl‐α′‐arylketones under mild conditions in good to excellent yields and with high functional group tolerance, whereby the silicon moiety in the final products can either be removed for a formal acetone monoarylation transform, or capitalized upon for subsequent electrophilic substitutions at either side of the carbonyl group.


Experimental Procedures
General experimental: Unless otherwise stated, all glassware was flame-dried before use and all reactions were performed under an atmosphere of argon. All solvents were distilled from appropriate drying agents prior to use or directly taken from commercial sealed bottles under an atmosphere of argon. All reagents were used as received from commercial suppliers unless otherwise stated. Reaction progress was monitored by thin layer chromatography (TLC) performed on aluminum plates coated with silica gel F254 with 0.2 mm thickness. Chromatograms were visualized by fluorescence quenching with UV light at 254 nm or by staining using potassium permanganate. Flash column chromatography was performed using silica gel 60 (230-400 mesh, Merck and co.). Neat infra-red spectra were recorded using a Brucker Vertex 70 FT-IR spectrometer. Wavenumbers are reported in cm -1 . Mass spectra were obtained using a Brucker maXis UHR-TOF spectrometer, using electrospray ionization (ESI) and by Agilent 7200B GC/Q-TOF spectrometer, using electron impact (EI). All 1 H NMR and 13 C NMR spectra were recorded using a Bruker AV NEO 500, AV III 600 or AV III HD 700 spectrometer in CDCl3. Chemical shifts were given in parts per million (ppm, δ), referenced to the solvent peak of CDCl3, defined at δ = 7.26 ppm ( 1 H NMR) and δ = 77.16 ( 13 C NMR). Coupling constants are quoted in Hz (J). 1 H NMR splitting patterns were designated as singlet (s), doublet (d), triplet (t), quartet (q), pentet (p). Splitting patterns that could not be interpreted or easily visualized were designated as multiplet (m) or broad (br).

1) Synthesis of starting materials
a. Sulfoxides 4, 4,4'-Sulfinylbis(methoxybenzene) was prepared according to a literature procedure [1] on a 5 mmol scale and obtained as a white solid (1.08 g, 82% yield). The spectral properties are in agreement with those reported in the literature.

4,4'-Sulfinylbis(bromobenzene)
4,4'-Sulfinylbis(bromobenzene) was prepared according to a literature procedure [1] on a 10 mmol scale and was obtained (1.82 g, 50 % yield) as a white solid. The spectral properties are in agreement with those reported in the literature.

4,4'-Sulfinylbis(fluorobenzene)
4,4'-Sulfinylbis(fluorobenzene) was prepared according to a literature procedure [1] on a 10 mmol scale and was obtained (1.29 g, 54% yield) as a yellow oil. The spectral properties are in agreement with those reported in the literature.

4,4'-Sulfinyldibenzonitrile
4,4'-Sulfinyldibenzonitrile was prepared according to a literature procedure [1] on a 3.75 mmol scale and was obtained (460 mg, 42% yield over two steps) as a white solid. The spectral properties are in agreement with those reported in the literature.

Dibenzo[b,d]thiophene 5-oxide
Dibenzo[b,d]thiophene 5-oxide was prepared according to a literature procedure [2] and obtained as a white solid (1.13 g, 56% yield) The spectral properties are in agreement with those reported in the literature.

1-Methyl-4-(methylsulfinyl)benzene
1-Methyl-4-(methylsulfinyl)benzene was prepared according to a literature procedure [3] on a 5.8 mmol scale and obtained as a colourless oil (0.80 g, 90% yield). The spectral properties are in agreement with those reported in the literature. [4] (Benzylsulfinyl)benzene (Benzylsulfinyl)benzene was prepared according to a modified literature procedure. [5] A round-bottom-flask was charged with benzylphenylsulfide (3.0 mmol, 1.0 equiv.) and DCM (0,5 M). After cooling to 0 °C, m-CPBA (3.0 mmol, 1.0 equiv.) was added in portions and the reaction was stirred for 1 h. Aqueous 1 M NaOH (10 mL) was added, the layers were separated and the aqueous phase was extracted with DCM (2x 10 mL). The combined organic extracts were dried over anhydrous MgSO4 and concentrated under reduced pressure. The crude residue was purified by column chromatography (10-20% EtOAc in heptane). The title compound was obtained as a white solid (0.44 g, 68% yield). The spectral properties are in agreement with those reported in the literature. [6] (Cyclopropylsulfinyl)benzene (Cyclopropylsulfinyl)benzene was prepared following a similar procedure used for the synthesis of (benzylsulfinyl)benzene on a 3 mmol scale. The title compound was obtained as a colourless oil (0.42 g, 84% yield). The spectral properties are in agreement with those reported in the literature. [7] Thiochromane 1-oxide Thiochromane 1-oxide was prepared from thiochromane following a similar procedure used for the synthesis of (benzylsulfinyl)benzene on a 3.3 mmol scale. The title compound was obtained as a colourless oil (0.48 g, 88% yield). The spectral properties are in agreement with those reported in the literature. [9] 1-Chloro-4-(p-tolylsulfinyl)benzene 1-Chloro-4-(p-tolylsulfinyl)benzene was prepared according to a literature procedure [2] on a 16 mmol scale and obtained as a white solid (1.19 g, 34% yield over two steps). The spectral properties are in agreement with those reported in the literature.

b. Propargyl silanes
Triisopropyl (3-(trimethylsilyl) Triphenylphosphine (633 mg, 2.4 mmol, 1.5 equiv) was added to a solution of alcohol 1e' (432 mg, 1.6 mmol, 1 equiv) and CBr4 (640 mg, 1.9 mmol, 1.2 equiv) in DCM (3 mL) at 0 °C. The mixture was stirred 15 min at 0 °C then 2 hours at room temperature and concentrated under reduced pressure. Et2O was added, the mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (heptane/EtOAc 100:1 to 98:2) to afford 440 mg (83% yield) of bromide 1f. 1 Potassium phthalimide (251 mg, 1.36 mmol, 1.5 equiv) was added to a solution of bromide 1f (300 mg, 0.91 mmol, 1 equiv) in DMF (3 mL) at room temperature. The mixture was stirred overnight at room temperature, then diluted with water. The aqueous layer was extracted 3 times with EtOAc, the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (heptane/

2) Reaction between propargyl silanes and sulfoxides
a. Terminal propargyl silanes General procedure B: A solution of Tf2NH (5.6 mg, 0.02 mmol, 0.1 equiv) in MeNO2 or DCM (0.1 mL) was added to a solution of alkyne (39 mg, 0.2 mmol, 1 equiv) and sulfoxide (0.4 mmol, 2 equiv) in MeNO2 or DCM (0.9 mL) at room temperature. The mixture was stirred at room temperature for 2 hours and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted 3 times with DCM, the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (typically a gradient elution heptane-EtOAc from 99:1 to 95:5).

b. In situ protodesilylation 1-(2-(phenylthio)phenyl)propan-2-one (3a)
A solution of Tf2NH (5.6 mg, 0.02 mmol, 0.1 equiv) in DCM (0.1 mL) was added to a solution of 1a (39 mg, 0.2 mmol, 1 equiv) and diphenylsulfoxide (81 mg, 0.4 mmol, 2 equiv) in DCM (0.9 mL) at room temperature. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. MeOH (3 mL) and 1 M aqueous HCl (1 mL) were added, the mixture was stirred at rt for 2 hours then quenched with saturated aqueous NaHCO3. The aqueous layer was extracted 3 times with DCM, the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (64% yield).

c. α-branched propargyl silanes
When propargyl silanes bearing substituents αto the silicon were used, the main product of the reaction was a rearranged diene resulting from 1,2-silyl shift. This event has been described in the literature under similar conditions. [10] d. Internal propargyl silanes General procedure C: A solution of Tf2NH (5.6 mg, 0.02 mmol, 0.1 equiv) in MeNO2 (0.1 mL) was added to a solution of alkyne (0.2 mmol, 1 equiv) and diphenylsulfoxide (121 mg, 0.6 mmol, 3 equiv) in MeNO2 (0.9 mL) at room temperature. The mixture was stirred at room temperature for 6 hours and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted 3 times with DCM, the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (typically elution heptane-EtOAc 100:0 to 95:5).

e. Competition experiments
With a mixture of sulfoxides A solution of Tf2NH (5.6 mg, 0.02 mmol, 0.1 equiv) in DCM (0.1 mL) was added to a solution of alkyne (39 mg, 0.2 mmol, 1 equiv), pmethyl diphenyl sulfoxide (46 mg, 0.2 mmol, 1 equiv) and p-chloro diphenyl sulfoxide (54 mg, 0.2 mmol, 1 equiv) in DCM (0.9 mL) at room temperature. The mixture was stirred at room temperature for 2 hours and quenched with saturated aqueous NaHCO3. The aqueous layer was extracted 3 times with DCM, the combined organic layers were dried over MgSO4 and concentrated under reduced pressure.
This result suggests that the addition step of the sulfoxide onto the vinyl cation is faster for the most nucleophilic sulfoxide.

With an asymmetric sulfoxide
In this case, another mechanistic step is taken into consideration: this result indicates that the sulfonium rearrangement is faster onto the most electron-rich ring.
The results of competition experiments with a mixture of sulfoxides of different nucleophilicity as well as with an unsymmetrical diaryl sulfoxide with different aromatic substituents suggest that the overall reaction is faster as the sulfoxide gets more electron rich. However, we observed the opposite trend ( Figure 1 of the main manuscript), which suggests that the Bronsted basicity of the sulfoxide plays a role in the mechanism. The alkyne is protonated by the protonated sulfoxide, then the same sulfoxide adds to the vinyl cation, and this is followed by rearrangement and deprotonation. The sulfoxide plays the role of a proton carrier and only then it acts as a nucleophile. Hence the lower the basicity, the easier the proton transfer between the sulfoxide and the alkyne, hence the faster the reaction. The result of the intermolecular competition experiment with a mixture of sulfoxides shows that the most electron rich sulfoxide gets protonated preferentially. Even if it reacts more slowly, it still needs to be protonated for the reaction to be initiated. So the most basic sulfoxide is more likely to get captured because it is more likely to be protonated. The results of the mechanistic experiments suggest that the alkyne protonation is the rate determining step. Calculations with selenoalkynes suggest a similar mechanism. [11]

3-(2-(Phenylthio)phenyl)-1-(triisopropylsilyl)butan-2-one (6)
To a solution of NaHMDS (2.0 M in THF, 0.12 mL, 0.24 mmol, 1.2 equiv.) in anhydrous THF (1.5 mL) at -78 C was added dropwise a solution of 2a (79.7 mg, 0.2 mmol, 1 equiv.) in anhydrous THF (0.5 mL). The reaction mixture was was stirred at -78 °C for 30 min, then warmed up to 0 °C and stirred for 45 min. Then MeI (31.4 µL, 0.5 mmol, 2.5 equiv.) was added at 0 °C, the reaction mixture was stirred at 0 °C for further 60 minutes, then it was allowed to warm up to room temperature and stirred for 24 h. The reaction mixture was quenched with saturated aqueous solution of NaHCO3. The reaction mixture was extracted with DCM 3 times, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (heptane/EtOAc 97:3 to 95:5) to afford 70 mg (85%) of compound 6. 1 (7) To a solution of 2a (341 mg, 0.855 mmol) in methanol (10 mL) was added an excess of Raney 2800 Ni (washed with methanol three times just prior to use; Caution! Raney Ni is pyrophoric if allowed to dry out). The resulting mixture was stirred vigorously at room temperature for 48 h under an atmosphere of H2 (1atm). The progress of the reaction was monitored by 1 H NMR. The mixture was diluted with EtOAc and filtered over a pad of Celite®, and the filter cake was washed with copious amount of EtOAc.