Mechanistic Pathways in Amide Activation: Flexible Synthesis of Oxazoles and Imidazoles

The preparation of substituted aminooxazoles and aminoimidazoles from α-arylamides and α-aminoamides through triflic anhydride-mediated amide activation is reported. These reactions proceed via the intermediacy of nitrilium adducts and feature N-oxide-promoted umpolung of the α-position of amides as well as a mechanistically intriguing sequence that results in sulfonyl migration from nitrogen to carbon. Quantum-chemical mechanistic analysis sheds light on the intricacies of the process.


General 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. Triflic anhydride was distilled over P4O10 prior to use. All other reagents were used as received from commercial suppliers unless otherwise stated. Reaction progress was monitored by thin layer chromatography (TLC) performed on aluminium 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 infrared spectra were recorded using a Perkin-Elmer Spectrum 100 FT-IR spectrometer. Wavenumbers (νmax) are reported in cm -1 . Mass spectra were obtained using a Finnigan MAT 8200 or (70 eV) or an Agilent 5973 (70 eV) spectrometer, using electrospray ionization (ESI). All 1 H NMR and 13 C NMR spectra were recorded using a Bruker AV-400 or AV-600 spectrometer at 300K. 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 and 13 C splitting patterns were designated as singlet (s), doublet (d), triplet (t), quartet (q), sextet (sext), septet (sept). Splitting patterns that could not be interpreted or easily visualized were designated as multiplet (m) or broad (br).

General Procedure A (1a-d)
To a solution of the amine (1.00 equiv.), triethylamine (1.00 equiv.), hydroxybenzotriazole (HOBt, 1.00 equiv.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI*HCl, 1.00 equiv.) in dichloromethane (0.1 M), the corresponding carboxylic acid was added and the resulting solution was stirred at ambient temperature overnight (14 h). After this time, the organic solution was extracted sequentially with 0.5 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The washed solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography on silica gel (heptane/ethyl acetate) to afford the desired compound.

General Procedure B (1j-m)
To a solution of N-Boc-sarcosine (1.00 equiv.) in anhydrous DCM (0.1M), 1-hydroxybenzotriazole hydrate (HOBt, 1.00 equiv.), 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDCI*HCl, 1.00 equiv.) and triethylamine (1.00 equiv.) were added and stirred until complete dissolution. After this, the secondary amine was added and the solution was stirred for 12 h at 23 °C. The reaction was worked up by the addition of an aqueous solution of HCl (0.5M) in a ratio 4:1 with respect to the solvent. The organic phase was then washed with a saturated aqueous solution of NaHCO3 in a 4:1 ratio with respect to the solvent and then with brine. The washed solution was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was dissolved in DCM (0.1M) and trifluoroacetic acid (36.0 equiv.) was added. The resulting solution was stirred for 3 h at 23 °C. After this time, the acid was quenched by the dropwise addition of a saturated aqueous solution of NaHCO3. The organic phase was then separated and washed with brine, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude residue was used in the next steps without further purification.

S6
To a solution of the amide (1.00 equiv.) in DCM (0.1M), triethylamine (4.00 equiv.) was added, followed by the corresponding sulfonyl chloride (R 2 SO2Cl) (3.00 equiv.). The mixture was stirred until complete dissolution and then stirred for 3 h at 23 °C. Excess sulfonyl chloride was quenched by the addition of a saturated aqueous solution of NaHCO3 in a 4:1 ratio with respect to the solvent. The organic phase was separated and subsequently washed with brine. The organic phase was then dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The product was purified by flash column chromatography on silica gel (heptane/ethyl acetate) to afford the desired product.

N,N-Diethyl-2-phenylacetamide (1b)
Synthesized following general procedure A. All spectroscopic data were in good accordance with the data reported in the literature. 2 1 H-NMR included below.

N,N-Dimethyl-2-(4-(trifluoromethyl)phenyl)acetamide (1c)
Synthesized following general procedure A. All spectroscopic data were in good accordance with the data reported in the literature. 3 1 H-NMR included below.

Imidazoles
To a cooled (0 °C) solution of the corresponding amide (1.00 equiv.) and 2-nitropyridine (2.00 equiv.) in the appropriate nitrile (0.05M) over activated molecular sieves (3Å), triflic anhydride (2.00 equiv.) was added. The resulting mixture was allowed to stir at 0 °C for 15 min, after which the cooling bath was removed and the reaction mixture was stirred at 23 °C for 2 h. After this time, the mixture was filtered over celite and the molecular sieves were washed with DCM. The resulting filtrate was washed with a saturated aqueous solution of NaHCO3 (4:1 with respect to the solvent) and then with brine. The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography on silica gel (heptane/ethyl acetate) to afford the desired compound.
For nitriles solid at 0 °C, DCM was added to the reaction mixture. The corresponding ratios are given below.

X-Ray Analysis
The X-ray intensity data were measured on Bruker D8 Venture diffractometer equipped with multilayer monochromators, Cu K/a INCOATEC micro focus sealed tube and Kryoflex II cooling device. The structures were solved by direct methods and refined by full-matrix least-squares techniques. Nonhydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms were inserted at calculated positions and refined with a riding model respectively as rotating groups. The following software was used: Bruker SAINT software package 14 using a narrow-frame algorithm for frame integration, SADABS 15 for absorption correction, OLEX2 16 for structure solution, refinement, molecular diagrams and graphical user-interface, Shelxle 17 for refinement and graphical user-interface SHELXS-2013 18 for structure solution, SHELXL-2013 19 for refinement, Platon 20 for symmetry check. Experimental data and CCDC-Codes can be found in Table 1. Crystal data, data collection parameters, and structure refinement details are given in Tables 2, 3, 4 and 5. Molecular structures in "Ortep View" are displayed in Figure 1 and 2.