Stereoselective synthesis of alkyl-, aryl-, vinyl- and alkynyl-substituted Z-enamides and enol ethers

Highly stereoselective synthesis of Z-enamides and enol ethers at room temperature via an umpolung/cross coupling strategy applicable to drugs and natural products.


1-[(Trimethylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one (TMS-EBX, 2b)
Following a slight modification of the reported procedure, 3 trimethylsilyl triflate (5.54 mL, 30.7 mmol, 1.10 equiv) was added to a suspension of 2-iodosylbenzoic acid 22 (7.36 g, 28.0 mmol, 1.00 equiv) in CH2Cl2 (85 mL) at RT. The resulting yellow mixture was stirred for 1 h, followed by the dropwise addition of bis(trimethylsilyl)acetylene (6.98 mL, 30.7 mmol, 1.10 equiv). The resulting suspension was stirred for 6 h at RT, during this time a white solid was formed. A saturated solution of NaHCO3 was then added and the mixture was stirred vigorously until completely solubilization of the white solid. The two layers were separated and the combined organic extracts were washed with sat. NaHCO3, dried over MgSO4, filtered and evaporated under reduce pressure.
The resulting oil was dissolved in dichloromethane (30 mL) and under vigorous stirring, saturated aq. NaHCO3 (30 mL) was added. The mixture was stirred for 15 minutes, the two layers were separated and the aqueous phase was extracted with additional portions of dichloromethane (3 x 25 mL). The combined organic layers were washed with brine (25 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (DCM:MeOH 9:1) to afford the desired compounds 2a-2j.
The resulting mixture was combined with the solid obtained by filtration and boiled in CH3CN (ca 300 mL). The mixture was cooled down, filtered and dried under high vacuum to afford 2j (6.08

General Procedure GPX for the Synthesis N-vBX and O-vBX.
Note: prior to the reaction, the glassware requires to be carefully cleaned with aqua regia to remove all metal traces; the commercially available starting material were purified through a short plug of silica prior to being used.

GP2:
In a glass vial, the correspondent sulfonamide or phenol (0.100 or 1.00 mmol, 1.00 equiv.) was dissolved in 12.5 mL of EtOH (0.08 M). Cs2CO3 (10 mol%, 10.0 µmol or 0.100 mmol) was added and the mixture stirred vigorously for 5'. Then the corresponding EBX 2a-2i was added in one portion (0.100 or 1.00 mmol, 1.00 equiv.) and the reaction was left stirring for 12 hours if not specifically specified otherwise. The reaction was stopped, the EtOH removed under reduced pressure and the crude purified via column chromatography using DCM:MeOH (20:1) as eluent. S17 S18