Unexpected rearrangements and a novel synthesis of 1,1-dichloro-1-alkenones from 1,1,1-trifluoroalkanones with aluminium trichloride

A novel reactivity of 1,1,1-trifluoroalkanones is reported, where the reaction with AlCl3 results in the formation of 1,1-dichloro-1-alkenones. The reaction scope was found to be broad, with various chain lengths and aryl substituents tolerated. For substrates containing an electron-rich aromatic ring, further reactions take place, resulting in bicyclic and/or rearrangement products.


S1
Upon treatment of (thio)ethers S2, S3 and S4 with AlCl3 under the standard conditions (see below), complex reaction mixtures were obtained, from which no clean products could be isolated (Scheme S1). Scheme S1: Reaction of (thio)ethers with AlCl3.

General information
All reagents bought from commercial sources were used as received without further purification.
Reactions carried out at 0 °C were conducted using a water/ice bath. Anhydrous solvents were purchased from commercial suppliers. MgSO4 was used as the drying reagent to dry organic phases. Normal phase column chromatography was carried out using a Biotage Isolera TM using CHROMABOND flash SiOH columns (Macherey-Nagel) with columns in sizes between 15 g to 40 g. The solvent system was ethyl acetate, heptane and methanol at various gradient systems. Reversed-phase column chromatography was carried out using Biotage R Ultra C18 SNAP 12 g column. The solvent system was water and acetonitrile at various gradient systems. If no method of purification is stated, then the product was deemed pure enough for use in subsequent steps without purification. The purity of all compounds was determined by 1 H NMR. All 1D and 2D NMR spectra were recorded using a Bruker AVII spectrometer with a Bruker TBI-probe. 1 H NMR spectra were recorded at 400 MHz or 600 MHz, 13 C NMR spectra were recorded at 100 or 150 MHz and 19 F NMR spectra were recorded at 376 MHz. CDCl3 was used as the solvent. All chemical shift values are referenced to TMS and reported in ppm to 1 Hz resolution. LCMS spectra were obtained by an Agilent LC spectrometer with a 3100 Mass Detector (SQD) using electron ionization (EI) technique. High resolution mass spectrometry (HRMS) was obtained by a Waters spectrometer with Q-ToF Premiers using electron spray ionization.

Experimental procedures and spectral data
General procedure A for the formation of 1,1,1-trifluoroalkanones 5 A dry 2-necked round-bottomed flask attached to a condenser was filled with magnesium (8 mmol, 2 equiv) under argon and stirred for 30 minutes. An iodine crystal was added. The mixture was warmed gently and stirred vigorously for 10 minutes. Dry diethyl ether (10 mL) was added followed by the dropwise addition of 1,1,1-trifluoro-4-iodo-butane (4 mmol, 2 equiv) at such a rate as to maintain a gentle reflux. After the addition was complete, the mixture was stirred at reflux for an additional 30 minutes. This solution of 4,4,4-trifluorobutylmagnesium iodide (10 mL, 2 equiv) was added to a solution of the corresponding benzonitrile (4 mmol, 1 equiv) and CuBr (0.2 mmol, 5.0 mol %) in dry THF (10 mL) at 0 °C under argon. The reaction was heated to 50 °C for 2 h. Upon completion the reaction was cooled to room temperature and quenched with 2M HCl (5 mL). The aqueous layer was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by automated flash column chromatography (40 g silica, 0-100% heptane/ethyl acetate). In some cases further purification by reversed-phase column chromatography was required (12 g silica, 0-100% water/acetonitrile).
The reaction was quenched with 2M HCl and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The resulting residue was purified by C18 reversed-phase column chromatography(0-100% water/acetonitrile) to obtain products 9 and 10.