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An expeditious FeCl3-catalyzed cascade 1,4-conjugate addition/annulation/1,5-H shift sequence for modular access of all-pyrano-moiety-substituted chromenes

ortho-Alkynyl quinone methides are well-known four-atom synthons for direct [4 + n] cycloaddition in constructing useful oxa-heterocyclic compounds owing to their high reactivity as well as the thermodynamically favored aromatization nature of this process. Herein we report an operationally simple and eco-friendly protocol for the modular and regioselective access of (E)-4-(vinyl or aryl or alkynyl)iminochromenes from propargylamines and S-methylated β-ketothioamides in the presence of FeCl3, and particularly under undried acetonitrile and air atmosphere conditions. This method exhibits a broad substrate scope and displays nice functional group compatibility, thus providing an efficient access of 3,4-disubstituted iminochromenes.


General consideration
Unless otherwise specified, all reagents and starting materials were purchased from commercial sources and used as received without purification. The solvents were used directly without purification unless stated. The dried acetonitrile used in screening was distilled from calcium hydride under nitrogen using standard procedures. 1 All cascade reactions were performed in a resealable screw-capped Schlenk flask (approximately 20 mL volume) in the presence of Teflon-coated magnetic stirrer bar (4.5 mm × 12 mm). Thin layer chromatography was conducted on precoated silica gel 60 F254 plates. Flash chromatography was performed using 200-300 mesh silica gel with the indicated solvent system according to standard techniques.
Melting points were measured on an uncorrected Melting Point instrument. The 1 H and 13 C NMR spectra were recorded on a 400 MHz and 100 MHz NMR spectrometers, unless otherwise specified. Chemical shifts (δ) in parts per million were reported relative to the residual signals of chloroform (7.26 ppm for 1 H and 77.0 ppm for 13 C), and all 13 C NMR were recorded with proton broadband decoupling and indicated as 13 C{ 1 H} NMR. Multiplicities are described as s (singlet), d (doublet), t (triplet), q (quartet), or m (multiplet), and the coupling constants (J) are reported in Hertz (Hz).
HRMS analysis with a quadrupole time-of-flight mass spectrometer yielded ion mass/charge (m/z) ratios in atomic mass units.

General procedures for the synthesis of propargylamines 1
To a 25 mL round-bottom flask equipped with a magnetic stir bar were added pyrrolidine (1.2 mmol), aldehyde (1.0 mmol), acetylene (1.2 mmol), copper(I) iodide (10 mol%) and toluene (3 mL). The mixture was degassed and backfilled with nitrogen, and then stirred in an oil bath preheated to 100 °C for 5 h (monitored by TLC). After the reaction completed (as determined using TLC), the reaction mixture was cooled to room temperature, diluted with CH2Cl2 (10 mL) and filtered through a thin pad of silica gel.
The filter cake was washed with CH2Cl2, and the combined filtrate was concentrated in vacuum. The crude product was purified by flash column chromatography on silica gel to afford the corresponding propargylamines 2 .
Then, aryl isothiocyanates was added dropwise at 0 °C in an ice-water bath, and stirring was continued at room temperature for 1 h. Iodomethane (0.18 mL, 2.4 mmol) was then added dropwise, stirring for another 1 h. Upon completion of the reaction, the reaction mixture was extracted with CH2Cl2 (3 × 10 mL), and washed with brine. The organic layers were combined, dried over Na2SO4, filtered, and then evaporated under vacuum. The residue was purified using flash column chromatography with a silica gel (200-300 mesh), using ethyl acetate and petroleum ether (1:40, v/v) as the elution solvent to give corresponding N,S-keteneacetals 2.

General procedures for the synthesis of alkenyl-iminochromene 3
A mixture of propargylamines 1 (0.3 mmol), N,S-keteneacetals 2 (0.2 mmol), and FeCl3 (20-50 mol%) were added under air atmosphere to a resealable screw-capped Schlenk tube. Undried acetonitrile (2 mL) was then added. The tube sealed with a Teflon-coated cap and the resulting mixture was stirred in an oil bath preheated to 120 °C for 12 h (monitored by TLC). Upon completion of the reaction, the reaction mixture was cooled to room temperature, extracted with CH2Cl2 (3 × 10 mL), and washed with brine. The organic layers were combined, dried over Na2SO4, filtered, and then evaporated under a vacuum. The residue was purified using flash column chromatography with a silica gel (200-300 mesh), using ethyl acetate and petroleum ether (1:20, v/v) as the elution solvent to give desired products 3.

Large scale synthesis of compound 3aa
A mixture of 1a (
Undried acetonitrile (2 mL) was then added. The tube sealed with a Teflon-coated cap and the resulting mixture was stirred in an oil bath preheated to 120 °C for 12 h (monitored by TLC). Upon completion of the reaction, the reaction mixture was cooled to room temperature, extracted with CH2Cl2 (3 × 10 mL), and washed with brine. The organic layers were combined, dried over Na2SO4, filtered, and then evaporated under a vacuum. The residue was purified using flash column chromatography with a silica gel (200-300 mesh), using ethyl acetate and petroleum ether (1:20, v/v) as the elution solvent to give desired products 5.

General procedures for the synthesis of compound 9
To a solution of 4-vinyliminochromene 3 (0.2 mmol), in THF (2 mL) was added solid sodium borohydride (5-10 equiv.) and the mixture was stirred in an oil bath preheated to 80 °C under air atmosphere for 12 h (monitored by TLC). Upon completion of the reaction, the reaction mixture was cooled to room temperature, extracted with CH2Cl2 (3 × 10 mL), and washed with brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified using flash column chromatography with a silica gel (200-300 mesh), using ethyl acetate and petroleum ether (1:20, v/v) as the elution solvent to give desired product 9.

S32
15. X-ray crystallographic data of compound 5ga Figure S2. ORTEP drawing of compound 5ga (30% probability for the thermal ellipsoid). The purified compound 5ga is dissolved in a mixed solvent of ethyl acetate and petroleum ether, and placed in a dark cabinet to slowly evaporate. After several days, a colourless bulk crystal was obtained. The X-ray crystal-structure determinations were obtained on a Bruker Smart CCDC APEX-2 diffractometer (graphitemonochromated Mo Kα radiation, λ=0.71073 nm) at 296(2) K. Figure S3. ORTEP drawing of compound 9aa (30% probability for the thermal ellipsoid). The purified compound 9aa is dissolved in a mixed solvent of ethyl acetate and petroleum ether, and placed in a dark cabinet to slowly evaporate. After several days, a colourless bulk crystal was obtained. The X-ray crystal-structure determinations were obtained on a Bruker Smart CCDC APEX-2 diffractometer (graphitemonochromated Mo Kα radiation, λ=0.71073 nm) at 296(2) K.

Computational Details
Geometry optimizations were performed by DFT calculation with the with the B3PW91-D3 functional, 3,4 where the Stuttgart-Dresden-Bonn basis sets 5 were used for Fe with the effective core potentials employed for representing core electrons and the 6-31G(d) basis sets were used for all other atoms. We performed single-point calculations using 6-311+G(d,p) basis sets for non-metal atoms. Solvation effects of acetonitrile were evaluated with the PCM method. 6 All these calculations were carried out with Gaussian16 program. 7