Iron(II)/Persulfate Mediated Newman–Kwart Rearrangement

Herein, we report that iron(II)/ammonium persulfate in aqueous acetonitrile mediates the Newman–Kwart rearrangement of O-aryl carbamothioates. Electron-rich substrates react rapidly under moderate heating to afford the rearranged products in excellent yields. The mild conditions, rapid reaction rates, and suitability for scale up offers immediate practical benefits to access functionalized thiophenols.


General considerations
Commercially available starting materials were purchased from Sigma-Aldrich, Alfa Aesar, TCI Europe, and Apollo Scientific and were used without further purification. Ammonium persulfate was purchased as for molecular biology and for electrophoresis (>98%) grade and the purity was checked by ICPMS (vide infra). Oxygen-18 enriched water (min 98%) was purchased from Rotem Industries Ltd. Solvents were obtained from Sigma-Aldrich; unless stated otherwise, reagent grade solvents were used for reactions and column chromatography and analytical grade solvents were used for recrystallizations. "Petrol" refers to petroleum ether having boiling point in the range of 40-60 °C. Reactions were heated using either a heating mantle or an oil bath; temperature was controlled with two independent thermocouples which calibration had been cross-checked with a mercury thermometer. Reaction progress was monitored by thin layer chromatography (TLC) on aluminium sheets coated with silica gel 60 F254 (Merck Millipore) and detection was carried out using UV light (325 nm and 254 nm) and/or chemical solutions. Crude reaction mixtures were purified either by recrystallization, by manual flash column chromatography on silica gel 60 (230-400 mesh, 0.040-0.063 mm; Merck Millipore), or by automated flash column chromatography (Biotage Isolera One). 1 H, 13 C, and 19 F Nuclear Magnetic Resonance (NMR) spectra were recorded on a Bruker Avance 300, 400, 600 or 700 at room temperature. 13 C NMR experiments were proton decoupled. 1 H and 13 C NMR spectra are reported relative to the internal reference of the relative deuterated solvent. Chemical shifts (δ) are reported in ppm and coupling constants (J) are given in Hertz (Hz). Multiplicity is described with ( High resolution mass spectrometry data were recorded on a Thermo Finnigan MAT900xp (CI, EI), Agilent 6510 QTOF (ESI), Waters LCT Premier spectrometers (ESI), or Thermo Exactive mass spectrometer with an Orbitrap (ESI, APCI). For the MS/MS experiments (ESI, APCI) an LTQ XL ion trap from Thermo Fisher was used. Inductively coupled plasma mass spectrometry was recorded on a PerkinElmer Nexion 350D. Melting points were taken either on a Gallenkamp or a Stuart SMP20 heating block and are uncorrected; when measured after recrystallization, the solvent is mentioned in brackets.

General procedures 1.2.1. General Procedure 1 for the synthesis of O-aryl carbamothioates using sodium hydride as the base
Into a flame-dried three-neck round-bottom flask, equipped with an argon inlet and a condenser, were added the phenol derivative (1 equiv.) and the anhydrous solvent (tetrahydrofuran or dimethylformamide, as indicated) (reaction concentration = 0.4 mol.L -1 ). The reaction vessel was degassed with argon and the solution cooled to 0 °C. Sodium hydride (60% w/w in mineral oil, 1.2 equiv.) was subsequently added portion-wise. Once all the dihydrogen was released, the solution was allowed to warm at room temperature and dimethylthiocarbamoyl chloride (1.1 equiv.) was added. The resulting suspension was heated at 70 °C under argon for the indicated time. The reaction was subsequently cooled to room temperature before a saturated aqueous solution of ammonium chloride was added. The resulting mixture was extracted with ethyl acetate. If no base-sensitive functionalities were present on the molecule, the combined organic layers were washed with a 1 M aqueous solution of sodium hydroxide to remove unreacted phenol, otherwise brine was used. The combined organic layers were dried over magnesium sulfate and solvents were removed under reduced pressure. The residue was purified using the indicated method.

General Procedure 2 for the synthesis of O-aryl carbamothioates using DABCO as the base
Into a flame-dried round-bottom flask, equipped with an argon inlet and a condenser, were added the phenol derivative (1 equiv.) and anhydrous THF (reaction concentration = 0.5 mol.L -1 ). To this were added 1,4diazabicyclo [2.2.2]octane (DABCO, 1.3 equiv.) and dimethylthiocarbamoyl chloride (1.3 equiv.). The resulting solution was heated at 50 °C under argon for the indicated time. The reaction was subsequently cooled to room temperature before most of the THF was removed under reduced pressure. The resulting mixture was diluted with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. If no base-sensitive functionalities were present on the molecule, the combined organic layers were washed with a 1 M aqueous solution of sodium hydroxide to remove unreacted phenol, else brine was used. The combined organic layers were dried over magnesium sulfate and solvents were removed under reduced pressure. The residue was purified using the indicated method.

General Procedure 3 for the synthesis of S-aryl carbamothioates via the Iron(II)/APS-mediated NKR
A screw-cap vial (14 mL) was charged with the O-aryl carbamothioate (1 equiv.), ammonium persulfate (1 equiv.), Mohr's salt (5 mol%), and CH3CN/H2O (3:1, reaction concentration = 0.083-0.17 mol.L -1 ). The vial was capped and the reaction was heated at the indicated temperature under maximum stirring (1200 rpm) for the indicated time. After cooling to room temperature, the crude reaction mixture was diluted with brine and then extracted with chloroform. The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified using the indicated method.

O-(3',5'-dimethoxy-5-methyl-[1,1'-biphenyl]-2-yl) dimethylcarbamothioate (1a)
Appearance A dry round-bottom flask was charge with 4-ethoxyphenol (1.38 g, 10 mmol) and anhydrous DMF (20 mL). The resulting solution was cooled to 0 °C in an ice bath and sodium hydride (60% in mineral oil, 440 mg, 11 mmol) was added portionwise under a strong flow of nitrogen. The resulting suspension was stirred for 30 min at 0 °C and then allowed to warm to room temperature, after which diethylthiocarbamoyl chloride (1.96 g, 13 mmol) was added. The reaction was then heated to 40 °C for 15 h under an inert atmosphere and vigorous stirring. The reaction was subsequently allowed to cool to room temperature after which the reaction was quenched with water (50 mL) and then extracted with diethyl ether (300 mL). The organic layer was separated and washed successively with water (50 mL), 1M aqueous sodium hydroxide (2×50 mL), water (50 mL), and brine (50 mL). The organic layer was dried over magnesium sulfate and evaporated to dryness to give a yellow oil. Purification by automated flash column chromatography (SiO2 Büchi FlashPure 40 g; 10%→25% EtOAc in petrol) afforded the title compound as a white solid (1.47 g, 58%).    A dry round-bottom flask was charged with sodium phenolate (2.00 g, 17.2 mmol) and anhydrous tetrahydrofuran (40 mL) and the resulting solution was cooled to 0 °C. Dimethylthiocarbamoyl chloride (2.55 g, 20.6 mmol) was subsequently added and the reaction was warmed to 70 °C and stirred at this temperature for 18 h under inert atmosphere. The reaction was subsequently allowed to cool to room temperature after which the reaction was quenched with water (50 mL) and then extracted with diethyl ether (200 mL). The organic layer was separated and washed successively with water (50 mL), 1M aqueous sodium hydroxide (2×50 mL), water (50 mL), and brine (50 mL). The organic layer was dried over magnesium sulfate and solvents were evaporated under reduced pressure. The residue was purified by automated flash column chromatography (SiO2 Büchi FlashPure 80 g; 10%→30% EtOAc in petrol) to afford the title compound as a clear oil (1.30 g, 42%). O- (3',5'-dimethoxy-5-methyl-[1,1'-biphenyl]-2-yl) dimethylcarbamothioate 1a (331 mg, 1 mmol) was treated according to general procedure 3 (reaction time = 2 h, temperature = 65 °C). Purification by automated flash column chromatography (SiO2 Büchi FlashPure 40 g; 20%→60% diethyl ether in petrol) afforded the title compound as a pale orange solid (250 mg, 75%).

5-(4-(4-((Benzo[d][1,3]dioxol-5-ylmethyl)amino)thieno[2,3-d]pyrimidin-5-yl)phenyl)-2,4-dimethoxy-8-methyl-5H-dibenzo[b,d]thiophen-5-ium trifluoromethanesulfonate (7)
Appearance: Off-white amorphous powder Chemical Formula: C36H28F3N3O7S3 Molecular Weight: 767.81 Yield: 72% Biaryl thioether 6 (124 mg, 0.20 mmol) and sodium trifluoromethanesulfonate (69 mg, 0.40 mmol) were dissolved in acetonitrile (6 mL) and the resulting solution was cooled to 0 °C. Into a separate vial, calcium hypochlorite (technical grade 65% wt., 31 mg, 0.14 mmol) and 1M aqueous acetate buffer (4 mL, pH 4.2) were added and briefly stirred at room temperature until full solubilization. The resulting solution was added dropwise over 10 min into the round-bottomed flask at 0 °C under vigorous stirring. At the end of the addition, the reaction was allowed to warm to room temperature and was stirred for a further 5 min at room temperature. The reaction was subsequently diluted with 1M aqueous solution of sodium hydroxide (9 mL). The resulting crude reaction mixture was extracted with dichloromethane (3×35 mL) and the combined organic layers were washed with a 1M aqueous solution of sodium triflate (10 mL). The combined organic layers were dried over magnesium sulfate and the solvents removed in vacuo. The residue was taken up in dichloromethane (2 mL) and added dropwise to a stirred solution of diethyl ether (7 mL); an off-white precipitate immediately formed. The precipitate was allowed to settle and the supernatant was discarded. The remaining powder was subsequently triturated twice in diethyl ether (2×5 mL) to afford the title compound as a pure off-white amorphous powder (110 mg, 72%).   Batch ❷, contaminated in iron, mediated NKR rearrangement in the absence of any added metal. All experiments described in the article and Supporting Information were carried-out using batch ❶, electrophoresis grade (> 98%), which did not react unless a metal catalyst was added.  (20 mg, 5 mol%). The flask was evacuated and refilled with nitrogen (three times). Anhydrous and degassed acetonitrile (12 mL) was injected after which the flask was sealed and allowed to stir (1200 rpm) at 65 °C for 1 h. The reaction was cooled to room temperature, and then diluted with brine (5 mL) and extracted with chloroform (3×50 mL). The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by automated flash column chromatography (SiO2 Büchi FlashPure 25 g; 5%→100% [5% EtOAc in CHCl3] in petrol) to afford 18 O-1o as a white solid (137 mg, 65%) which was analysed by 1 H & 13 C NMR spectroscopy and Tandem mass spectrometry MS-MS ( Figure S2).  A screw-cap vial (14 mL) was charged with 1o (226 mg, 1.0 mmol), ammonium persulfate (456 mg, 2.0 mmol), Mohr's salt (20 mg, 5 mol%), and CH3CN (12 mL). The vial was capped and the reaction was heated at 65 °C under maximum stirring (1200 rpm) for 2 h. After cooling to room temperature, most of the acetonitrile was removed under reduced pressure. The residue was diluted with brine (10 mL) and then extracted with chloroform (3×10 mL). The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by automated flash column chromatography (SiO2 Büchi FlashPure 12 g; 15%→50% EtOAc in petrol). The isolated pure fraction (185 mg) was analysed by NMR ( Figure S5 & S6, bottom back line) and the resulting spectra were compared to those of an authentic standard of 4-nitrophenyl dimethylcarbamate 3o synthesized by a previously published procedure ( Figure S5 & S6, top green line). 7 This confirmed the isolated fraction to be 4nitrophenyl dimethylcarbamate (185 mg, 88%).     A screw-cap vial (14 mL) was charged with 1b (106 mg, 0.5 mmol), 1d (126 mg, 0.5 mmol), ammonium persulfate (228 mg, 1.0 mmol), Mohr's salt (20 mg, 5 mol%), and CH3CN/H2O (3:1, 12 mL). The vial was capped and the reaction was heated at 45 °C under maximum stirring (1 200 rpm) for 1 h. After cooling to room temperature, the crude reaction mixture was diluted with brine (5 mL) and then extracted with chloroform (3 × 50 mL). The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure to give a yellow oil (0.221 g) which was analysed via 1 H NMR spectroscopy ( Figure  S7) and HRMS. A screw-cap vial (14 mL) was charged with 1b (106 mg, 0.5 mmol), ammonium persulfate (114 mg, 0.5 mmol), Mohr's salt (10 mg, 5 mol%), and CH3CN/H2O (3:1, 6 mL, pre-warmed to 45 °C). The vial was capped and the reaction was heated at 45 °C under maximum stirring (1 200 rpm). At the desired time-point, the reaction was cooled to -78 °C in a dry ice/acetone bath. A sample of the reaction mixture (1.0 mL) was added to water (0.2 mL) in a screw-cap vial (14 mL). To this was added CHCl3 (10 mL) and mixed well. This mixture was dried over MgSO4 and then filtered through a cotton plug in a syringe (20 mL). The organic solvents were removed under reduced pressure and the residue was dried under high-vacuum before 1 H NMR spectroscopy analysis. This protocol was repeated for each timepoint.