Synthesis of Novel Heterocycles by Amide Activation and Umpolung Cyclization

Herein, we report a metal-free synthesis of cyclic amidines, oxazines, and an oxazinone under mild conditions by electrophilic amide activation. This strategy features an unusual Umpolung cyclization mode and enables the smooth union of α-aryl amides and diverse alkylazides, effectively rerouting our previously reported α-amination transform.


General Information
Unless otherwise stated, all glassware was flame-dried before use and all reactions were performed under an atmosphere of argon with anhydrous solvents. Triflic anhydride was distilled over P2O5 prior to use. All other reagents were used as received from commercial suppliers unless otherwise stated. Reaction requiring higher temperature were heated in an oil bath. 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.). DMA mixture for column chromatography was made of DCM, MeOH, concentrated ammonia (90:10:1). Neat infra-red 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 1H NMR and 13C NMR spectra were recorded using a Bruker AV-400, AV-600 and AV-700 spectrometer at 300K. Chemical shifts were given in parts per million (ppm, δ) and coupling constants (J) are quoted in Hz, referenced to the solvent peak of CDCl3, defined at δ = 7.26 ppm (1H NMR) and δ = 77.16 (13C NMR). Coupling constants are quoted in Hz (J). 1H 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). Selected 13C NMR spectra were recorded using the attached proton test (APT) to facilitate the confirmation and assignment of the structure.   To a solution of the amine (1.0 eq.) and triethylamine (2.0 eq.) in DCM (0.1 M) at 0 °C, the corresponding acyl chloride (1.2 eq.) was added dropwise and the resulting reaction mixture was allowed to warm up to room temperature while stirring for 14 h. Afterwards, the reaction was quenched with a saturated aqueous solution of sodium bicarbonate and the biphasic system was separated. After extraction of the aqueous phase with DCM (2×), the organic phases were combined and dried over anhydrous sodium sulfate. The dried solution was filtered and concentrated under reduced pressure. The resulting crude material was purified by flash column chromatography on silica gel (heptane/ethyl acetate, 40:60) to afford the desired compound.
General Procedure B The acyl chloride was first prepared via addition of oxalyl chloride (3 eq.) to a mixture of carboxylic acid (1 eq.) and catalytic amount of N,N-dimethylformamide (0.1 eq.) in DCM (0.2 M) at room temperature. After stirring for 14 h, the solvent and excess of oxalyl chloride were removed under reduced pressure. The crude acyl chloride was directly dissolved in DCM (0.2 M) and pyrrolidine (5 eq.) was added. The mixture was stirred for 5 h at room temperature. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate. After separation, the organic layer was washed with HCl (1 M), NaHCO3 (sat.) and brine. The product was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The pure product was used without further purification.

General Procedure C
To a solution of carboxylic acid (1.0 eq.), HOBt (1.0 eq.) and EDCI (1.0 eq.) in DCM (0.5 M) were added the secondary amine (1.0 eq.) and triethylamine (1.0 eq.). The mixture was stirred for 16 h under argon atmosphere at room temperature. The mixture was diluted with EtOAc (5 DCM volumes). The organic layer was washed with HCl 1M. then a saturated solution of NaHCO3 then brine. The organic layer was dried over MgSO4, filtered and evaporated under reduced pressure.
General Procedure D HATU (1.2 eq.) was added to a solution of secondary amine (1.2 eq.), carboxylic acid (1 eq.) and triethylamine (2.4 eq.) in 0.4 M DMF. The reaction was stirred overnight at room temperature before quenching with 1M NaOH. The mixture was then extracted with ether, washed with sat. NH4Cl solution, dried over Na2SO4, and then evaporated.
Spectroscopic data are in agreement with the literature. 5
Spectroscopic data are in agreement with the literature.

2-bromo-1-(4-nitrophenyl)ethan-1-one S3
A solution of 6 mmol bromine (307 µL) in chloroform (2 mL) was slowly added to a solution of 5 mmol 4-nitroacetophenone (826 mg) in chloroform (5 mL) at 0° C under continuous stirring. The temperature of the reaction mixture was maintained at 0-5 °C during the addition. After stirring for 14 h at r.t., the solvent was removed under reduced pressure. The product was purified by recrystalization in EtOH (ca. 10 mL) to yield pure compound.
Spectroscopic data are in agreement with the literature. 7

Azide Synthesis
General Procedure E A solution of bromide (1 eq.) and NaN3 (1.5 eq.) in DMF (0.2 M) was stirred at 80 °C overnight. After 14 h, the reaction mixture was cooled to r.t., diluted with Et2O or EtOAc. The biphasic system was separated and the organic layer was washed with ice-cooled H2O (4x) and brine (1x). The pure product was obtained after drying over anhydrous Na2SO4 and evaporation of the solvent under reduced pressure to obtain the pure product which was used without further purifications.

General Procedure F
The corresponding halide was added to a solution of NaN3 (1.5 eq. or 3 eq.) in DMSO (0.5 M) at 0 °C and the reaction mixture was stirred at 23 °C for 10 min or 14 h. Ice-cooled H2O was added to the mixture and the mixture was extracted with diethyl ether (3x). The combined organic layers were washed with ice-cooled H2O (4x) and brine (1x), dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to obtain the pure product which was used without further purifications.

General Procedure G
The corresponding chloride was added to a suspension of NaN3 (1.5 eq.) in acetone (0.2 M) and stirred for 36 h. Afterwards, the mixture was filtered. The filtrate was evaporated under reduced pressure to obtain the pure product which was used without further purification.
Spectroscopic data are in agreement with the literature. 8 The product was prepared using procedure E with 1 mmol 2-Methylphenethyl bromide (169 µL) and 1.5 mmol sodium azide (97.5 mg) in DMF.
Spectroscopic data are in agreement with the literature. 9
Spectroscopic data are in agreement with the literature. 9

1-(2-azidoethyl)-4-fluorobenzene 2d
To a 0.5 M solution of NaN3 (1.1 eq., 2.2 mmol, 143 mg) in 4 mL DMSO was added p-Fluorophenethyl bromide (1.0 eq., 2 mmol, 0.28 mL), and the mixture was stirred at 80 °C and periodically monitored by TLC. When the reaction was completed, the mixture was quenched with water and stirred until it cooled down to room temperature and then extracted with Et2O. The organic layer was separated, washed with water and brine, and dried over Na2SO4. Filtration, concentration in vacuo, and purification of the residue by silica gel flash column chromatography gave the corresponding alkyl azide.
Spectroscopic data are in agreement with the literature. 9 Benzyl azide 2f The product was obtained using general procedure E from 10 mmol benzyl bromide (1.19 mL) and 15 mmol sodium azide (975 mg).
Spectroscopic data are in agreement with the literature. 10
Spectroscopic data are in agreement with the literature. 16 2-azidocyclohexan-1-one 7g The product was prepared using procedure F with 5 mmol 2-Chlorocyclohexanone (572 µL) and 7.5 mmol sodium azide (488 mg) in DMSO and stirring for 14 h.
Spectroscopic data are in agreement with the literature. 18 tert-butyl 2-azidoacetate 7i The product was prepared using procedure F with 5 mmol tert-butyl bromoacetate (729 µL) and 7.5 mmol sodium azide (488 mg) in DMSO and stirring for 14 h.
Spectroscopic data are in agreement with the literature. 19

Amidines, Oxazines and Oxazinones
General Procedure H To a mixture of amide (1.0 eq.), 2,4-dichloroquinoline (2.0 eq.) in anhydrous DCM (0.1 M), triflic anhydride (2.0 eq.) was added dropwise under vigorous stirring at 0 °C. After 15 min, the azide (1.1 eq.) was added and the mixture was stirred at r.t. for 14 h. The reaction was then quenched with a saturated aqueous solution of sodium bicarbonate for 1 h. After separation of the biphasic system and extraction of the aqueous phase with DCM (3×), the organic phases were combined and dried over anhydrous sodium sulfate. The dried solution was filtered and concentrated under reduced pressure.

X-ray Analysis
The X-ray intensity data were measured on Bruker D8 Venture diffractometer equipped with multilayer monochromators, Mo K/α INCOATEC micro focus sealed tubes and Oxford system. The structure was solved by direct methods and refined by full-matrix least-squares techniques. Non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms were inserted at calculated positions and refined with riding model. The following software was used: Bruker SAINT software package 20 using a narrow-frame algorithm for frame integration, SADABS 21 for absorption correction, OLEX2 22 for structure solution, refinement, molecular diagrams and graphical user-interface, Shelxle 23 for refinement and graphical user-interface SHELXS-2015 24 for structure solution, SHELXL-2015 25 for refinement, Platon 26 for symmetry check and π-π Interactions. Experimental data and CCDC-Codes (Available online: http://www.ccdc.cam.ac.uk/conts/retrieving.html) can be found in Table 1. Crystal data, data collection parameters and structure refinement details are given in Tables 2 to 5. Crystal structures and Packing views are visualized in Figures 1 to 4.