Continuous Synthesis of Carbamates from CO2 and Amines

We present a novel approach for the continuous preparation of carbamates. The simple yet fast synthetic route relies on directly utilizing carbon dioxide and, in contrast with the literature-known methods, only employs 1,8-diazabicyclo[5.4.0]undec-7-ene as an additive. The applicable amines’ diversity offers considerable flexibility to the synthetic protocol. Additionally, the continuous method’s applicability significantly decreases the reaction time typically required for CO2-based carbamate synthesis and allows for straightforward and precise gas introduction. The mild reaction conditions and omission of the need for column chromatography render the process less time-demanding and environmentally more benign, providing the desired compounds in yields of 45 to 92%. Moreover, the modified procedure can potentially be applied in the selective synthesis of oxazolidinones from aziridines.


General remarks
Unless otherwise noted, all chemicals purchased from commercial suppliers were used without further purification.Petroleum ether is 40-60 b.p. unless stated otherwise.
Chemical shifts are reported in parts per million (ppm) from Me4Si and were calibrated to the residual solvent signal (e.g., CDCl3, 1 H: 7.26 ppm, 13 C: 77.0 ppm).Coupling constants are reported in hertz (Hz).The assignments are based on comparison with reported spectra.
High-resolution mass spectrometry (HRMS) was carried out using an Agilent 1100/1200 HPLC with a 6230 AJS ESI-TOF MS.GC-MS was carried out using a Thermo Scientific DSQ II with a BGB5 column.
Infrared (IR) spectra were recorded with the aid of a Perkin-Elmer Spectrum65 FT IS spectrometer with absorption maxima (νmax) quoted in wavenumbers (cm -1 ).
Continuous-flow experiments were performed using a Vapourtec ® E-Series flow chemistr y device using a standard 10-mL coil reactor.

Set-up of the continuous-flow experiments
. Set-up of the device in continuous -mode operation

General procedure for the continuous synthesis of carbamates
. Reaction for the continuous synthesis of carbamates with various starting materials A 30-mL vial with septum was charged with the corresponding amine (1.0 eq., 4.29 mmol), the corresponding alkyl bromide (2.0 eq., 8.58 mmol), and DBU (2.0 eq., 8.58 mmol).The reactants were dissolved in 5 mL acetonitrile.The solvent bottle was charged with MeCN.The reactor was heated up to the desired temperature (70 °C).Pump A was used as a back-pressure regulator (BPR, 3 bar).Pump B was connected to the vial with the reaction mixture; pump C was connected to the gas tube, where the CO2 was introduced.Carbon dioxide was supplied from a gas cylinder.The gas flow rate was set with a mass flow controller (6 mL/min).The tubes were primed with the reagent mixture and acetonitrile, respectively.The reactor (10-mL coil reactor) was initially rinsed by a CO2/MeCN flow for several minutes.Then, the reaction mixture was supplied to the reactor (pump B: 0.25 mL/min; pump C: 6 mL/min).After the entire volume of the reaction mixture was pumped through the reactor, the vial was rinsed with pure MeCN, and the residue was pumped through the reactor.The product was collected for 50 minutes.Following rotary evaporation of the solvent the crude product was recovered, which was bound to silica and, subsequently, subjected to column chromatography on silica gel.Alternatively, the products could be purified via acidic treatment: the crude residue was taken up in dichloromethane, washed thrice with 1.5 M HCl solution, dried over anhydrous Na2SO4, filtered, and concentrated.

4.
General procedure for the synthesis of aziridines (2-bromo-1-phenylethyl)dimethylsulfonium bromide was prepared according to the standard literature procedure. 12Aziridines were prepared according to the literature procedure; 13 the alkylsulfonium bromide (1.0 eq., 10 mmol) was dissolved in 20 mL distilled water.To this, the solution of the corresponding amine (3.0 eq., 30 mmol) in 10 mL water was added dropwise.
The reaction mixture was stirred overnight at room temperature.After completion, the mixture was quenched with 20 mL brine, extracted with diethyl ether (3 x 20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo.The crude products were subjected to column chromatography on neutral aluminum oxide (Brockmann Grade IV).
1-butyl-2-phenylaziridine (4a) 14 Column chromatography (petroleum ether/Et2O 20:1, R f = 0.61) afforded the product as colorless liquid (1.56 g, 8.9 mmol, 89%).A 30-mL vial with septum was charged with the corresponding aziridine (1.0 eq., 0.73 mmol), FeBr3 (20 mol%, 0.146 mmol), and TBAB (20 mol%, 0.146 mmol).The reactants were dissolved in 5 mL acetonitrile.The solvent bottle was charged with MeCN.Pump A was used as a back-pressure regulator (BPR, 5 bar).Pump B was connected to the vial with the reaction mixture; pump C was connected to the gas tube, where the CO2 was introduced.Carbon dioxide was supplied from a gas cylinder.The gas flow rate was set with a mass flow controller (8 mL/min).The tubes were primed with the reagent mixture and acetonitrile, respectively.The reactor (10-mL coil reactor) was initially rinsed by a CO2/MeCN flow for several minute s.
Then, the reaction mixture was supplied to the reactor (pump B: 0.25 mL/min; pump C: 8 mL/min).After the whole volume of the reaction mixture was pumped through the reactor, the vial was rinsed with pure MeCN, and the residue was pumped through the reactor.The product was collected for 50 minutes.Following rotary evaporation of the solvent the crude product was recovered, which was bound to silica gel and subjected to column chromatography on silica gel. 14lumn chromatography (petroleum ether/Et2O 2:1, R f = 0.55) afforded the product as colorless liquid (101 mg, 4.6 mmol, 63%).