α‐Functionalisation of Ketones Through Metal‐Free Electrophilic Activation

Abstract Triflic anhydride mediated activation of acetophenones leads to highly electrophilic intermediates that can undergo a variety of transformations when treated with nucleophiles. This electrophilic ketone activation gives access to α‐arylated and α‐oxyaminated acetophenones under metal‐free conditions in moderate to excellent yields and enables extension to the synthesis of arylated morpholines via generation of vinylsulfonium salts. Computational investigations confirmed the transient existence of intermediates derived from vinyl triflates and the role of the oxygen atoms at the para position of aromatic ring in facilitating their stabilisation.


.1 General experimental information
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. Triflic anhydride (trifluoromethanesulfonic acid anhydride) was distilled over phosphorus pentoxide prior to use. 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).

General procedures
General procedure A1 for one pot ketone activation and interception by aryl sulfoxide from activated acetophenones: To a flame dried Schlenk tube under argon with a stirring bar and solution of a ketone (1.0 equiv.), 2,6-di-tert-butyl-4-methylpyridine (1.05-1.1 equiv.) in DCE (0.1 M) was added triflic anhydride (1.1 equiv.) at room temperature (unless lower temperature is stated). The reaction mixture was stirred at room temperature for 30 min (for 4-methoxyacetophenone as a substrate) or other time stated (up to 120 min depending on the acetophenone usedreferred to later as activation time). To the reaction mixture at room temperature was then added the aryl sulfoxide (2.0 equiv.). The reaction mixture was stirred for 18 h at room temperature. Water was added to quench the reaction mixture. The reaction mixture was extracted with DCM (3x), dried over sodium sulfate, evaporated in vacuo and purified by normal phase flash column chromatography using a suitable mixture of solvents. Usual solvent mixtures for column chromatography were heptane-ethyl acetate, heptane-DCM or DCM-toluene (in the latter case, this eluent was used when the TLC separation between the starting material and product with other eluents was small).
General procedure A2 for one pot ketone activation and interception by aryl sulfoxide from unactivated acetophenones: To a flame dried Schlenk tube under argon equipped with a stirring bar and a solution of a ketone (1.0 equiv.), 2,6-di-tert-butyl-4-methylpyridine (1.05-1.1 equiv.) in DCE (0.1 M) at room temperature was added triflic anhydride (1.1 equiv.). The reaction mixture was stirred at room temperature for 15 h. To the reaction mixture at room temperature was added the

SUPPORTING INFORMATION
S4 aryl sulfoxide (2.0-3.0 equiv.). The reaction mixture was heated at 100 °C in a sealed tube for 24 h. The reaction mixture was allowed to cool down to room temperature, and water was added to quench the reaction mixture. Then it was extracted with DCM (3x), dried over sodium sulfate, evaporated in vacuo and purified by normal phase flash column chromatography using a suitable mixture of solvents. Usual solvent mixtures for column chromatography were heptane-ethyl acetate, heptane-DCM or DCM-toluene (in the latter case, this eluent was used when the TLC separation between the starting material and product with other eluents was small).
General procedure B1 for telescopic alpha arylation of activated ketones:

Optimisation of alpha-arylation of 4-methoxyacetophenone
General procedure A1 was employed for optimisation (using 0. 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.

N-(2-hydroxyethyl)-4-methylbenzenesulfonamide 12
Literature procedure was followed. [4] para-Toluenesulfonyl chloride (1.0 g, 5.5 mmol) was taken up in dichloromethane (12 mL). Ethanolamine (0.30 mL, 5.0 mmol) was added and the mixture was cooled to 0 °C. Triethylamine (0.77 mL, 5.5 mmol) was added dropwise and the reaction was stirred at RT (18 h). The reaction mixture was diluted with dichloromethane and poured onto water. The aqueous phase was extracted with dichloromethane and the organic extracts were combined and dried over Na2SO4. The solvent was removed and the crude yellow oil of target compound 12 (1.07 g, 100%) was deemed to be of sufficient purity to be used without further purification.
The data are in accordance with the literature data. [4]

2-(4-methoxyphenyl)-4-tosylmorpholine 13
Modified literature procedure was applied. [5] A suspension of N-(2-hydroxyethyl)-4-  Given the flexibility of the investigated molecules, wherever appropriate, the conformational space has been initially explored using the OPLS_2005 force field [6] and the systematic Monte Carlo conformers search routine implemented in MACROMODEL 11.5. [7] Further, to consider the different possibilities that individual fragments can adopt within a particular complex, (e.g. the complex of a cation with the negatively charged TfOcounterion), the electrostatic potential of the ions has been calculated applying a natural bond orbital (NBO) population analysis. The reciprocal positions of the fragments have been determined based on the calculated NBO charges. The so obtained complexes have been used to restrict further the conformational search and obtain the set of complexes that will be reoptimized using density functional theory (DFT) methods.
Accordingly, the structures located at force field level have then been subjected to a B3LYP-D3/def2-SVP [8][9][10][11][12][13] geometry optimization. The nature of all stationary points (minima and transition states) was verified through the computation of the vibrational frequencies.
The thermal corrections to the Gibbs free energy were combined with the single point energies calculated at the DLPNO-CCSD(T)/def2-TZVP [14,15] to yield DLPNO-CCSD(T)//DFT Gibbs free energies ("G298") at 298.15 K. All energies are reported in kcal mol -1 .