Supporting Information for DOI: /s Georg Thieme Verlag KG Stuttgart New York Thieme

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1 Supporting Information for DI: /s Georg Thieme Verlag KG Stuttgart ew York 2017 Thieme

2 Base catalyzed transcarbamoylation Benoît Rhoné a,b,c Vincent Semetey a,b a PSL Research University, Chimie ParisTech - CRS, Institut de Recherche de Chimie Paris, 11 rue pierre et Marie Curie, Paris, France. b Laboratoire Physico Chimie Curie, Institut Curie, PSL Research University, 75005, Paris, France. c Sorbonne Universités, UPMC Univ Paris 06, Paris, France. Materials and methods All solvents used were dry solvents purchased from Sigma-Aldrich or were dried from solvent purification system (Innovative technology). All reagents were purchased from Sigma-Aldrich and used without further purification. 1 and 13 C MR spectra were recorded with a Bruker Avance III spectrometer (300 Mz for 1 MR spectra, respectively). DMS-d6 or CDCl3 was used as the solvent and tetramethylsilane (TMS) as the internal standard. Chemical shifts (δ) and coupling constants (J) are given in parts per million and in ertz, respectively. PLC was monitored using a P Agilent 1050 series PLC with diode array detector. PLC analysis was performed on a Vydac 218TP column (C18, 5 µm, 4.6 mm i.d. x 250 mm) by using a linear gradient of A (0.1% TFA in 2) and B (MeC containing 0.1% TFA) at a flow rate of 1.2 ml/min with UV detection at 254 nm. All solvents were PLC grade. The volume of sample injected was set at 5 μl. Procedure for the synthesis of methyl phenylcarbamate Phenyl isocyanate (2 g, 17 mmol) was added dropwise to 10 ml of dry methanol at ambient temperature. Dibutyltin dilaurate (5 µl, mmol) was added and the reaction mixture was stirred at 50 C for 3 h. The methanol was evaporated under reduced pressure to give a colourless liquid (2.6g, 100% yield) that cristallised after 2h at ambient temperature. White solid. PLC tr 13.9 min (linear gradient, 0-60% B, 20 min). 1 MR (300 Mz, DMS-d6): δ (ppm) 9.61 (s, 1 ), 7.44 (d, J = 8.4 z, 2 ), 7.26 (t, J = 8.1 z, 2 ), 6.98 (t, J = 8 z, 1 ), 3.65 (s, 3 ). Procedure for the synthesis methyl -cyclohexylcarbamate Cyclohexyl isocyanate (2 g, 16 mmol) was added dropwise to 10 ml of dry methanol at ambient temperature. Dibutyltin dilaurate (5 µl, mmol) was added and the reaction mixture was stirred at 50 C for 6 h. The methanol was evaporated under reduced pressure to give a colourless liquid (2.55 g, 100% yield) that cristallised after 2h at ambient temperature. 1 MR (DMS-d6, 300 Mz): δ (ppm) 7.02 (s, 1), 3.47 (s, 3), 3.21 (m, 1), 1.67 (t, 4), 1.50 (d, 1), 1.14 (m, 5). Procedure for the synthesis of methyl -ethylcarbamate Ethyl isocyanate (2 g, 28 mmol) was added dropwise to 10 ml of dry methanol at ambient temperature. Dibutyltin dilaurate (5 µl, mmol) was added and the reaction mixture was stirred at 50 C for 4 h. The methanol was evaporated under reduced pressure to give a colourless liquid (2.9g, 100% yield). Colorless liquid. 1 MR (CDCl3, 300Mz): δ (ppm) 4.64 (br. S, 1), 3.67 (s, 3), (m, 2), 1.14 (t, J = 7.2 z, 3). Corresponding author. Tel.: ; vincent.semetey@chimie-paristech.fr 1

3 General procedure for the transcarbamoylation reaction of an urethane and an alcohol. R 1 + R 2 - R 1 + Me- Me R The urethane 1 (0.66 mmol) was dissolved in dry toluene (2 ml). The alcohol (3 equiv, 1.98 mmol) and the base (1.2 equiv, 0.79 mmol) were added and the reaction mixture was heated at 60 C with continuous agitation during 20h. To isolate the pure product, water (10 ml) and ethyl acetate (10 ml) were added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and the solvent was evaporated. The residue was purified by silica column chromatography eluting with a 10-50% ethyl acetate/cyclohexane gradient. The fractions were concentrated under reduced pressure to give the desired product 2. Butyl -phenylcarbamate: White solid (115 mg, 90% yield). PLC tr 16.1 min (linear gradient, 0-60% B, 20 min). 1 MR (300 Mz, DMS-d6): δ (ppm) 9.57 (s, 1 ), 7.43 (d, J = 7.5 z, 2 ), 7.24 (t, J = 7.5 z, 2 ), 6.95 (t, J = 6 z, 1 ), 4.05 (t, J = 6.8 z, 2 ), (m, 2 ), (m, 2 ), 0.89 (t, J = 7.3 z, 3 ). ctyl -phenylcarbamate: White solid (135 mg, 82% yield). PLC tr 18.9 min (linear gradient, 0-60% B, 20 min). 1 MR (CDCl3, 300Mz): δ (ppm) 7.38 (d, J = 7.5 z, 2), 7.31 (t, J = 7.5 z, 2), 7.06 (t, J = 7.5 z, 1), 7.06 (br. s., 1), 4.16 (t, J = 6.8 z, 2), (m, 2), (m, 10), (m, 3). 2-methoxyethyl -phenylcarbamate: White solid.(120 mg, 93% yield). PLC tr 14.5 min (linear gradient, 0-60% B, 20 min). 1 MR (CDCl3, 300Mz): δ (ppm) (m, 4), (m, 1), (m, 1), 4.33 (t, J = 4.5 z, 2), 3.65 (t, J = 4.5 z, 2), 3.42 (s, 3). Propyl -phenylcarbamate: White solid. PLC tr 15.7 min (linear gradient, 0-60% B, 20 min). 1 MR (DMS-d6, 300 Mz): δ (ppm) 9.60 (s, 1), 7.43 (d, J = 7.5 z, 2), 7.24 (t, J = 7.5 z, 2), 6.95 (t, J = 7.5 z, 1), 4.00 (t, J = 7.5 z, 2), (m, 2), 0.91 (t, J = 7.5 z, 3). Isopropyl -phenylcarbamate: 2

4 White solid. 1 MR (CDCl3, 300 Mz): δ (ppm) (m, 4), (m, 1), 6.53 (br. s., 1), 5.02 (septet, J = 6.4 z, 1), 1.30 (d, J = 6.4 z, 6). Butyl -cyclohexylcarbamate: 1 MR (DMS-d6, 300 Mz): δ (ppm) 6.95 (d, J = 7.3 z, 1), 3.88 (t, J = 6.6 z, 2), 3.20 (d, J = 7.3 z, 1), (m, 4), (m, 4), (m, 6), 0.86 (t, J = 7.3 z, 3). 2-methoxyethyl -cyclohexylcarbamate: White solid. 1 MR (CDCl3, 300 Mz): δ (ppm) 4.68 (br. s., 1), (t, J = 4.5 z, 2), (t, J = 4.5 z, 2), 3.47 (br. s., 1), (m, 3), (m, 2), (m, 3), (m, 2), (m, 3). Butyl -ethylcarbamate: Colorless oil. 1 MR (CDCl3, 300Mz): δ (ppm) 4.69 (br. s, 1), 4.05 (t, J = 6.9 z, 2), 3.21 (m, 2), (m, 2), 1.38 (dq, J = 7.3 z, 2), 1.13 (t, J = 6.9 z, 3), 0.93 (t, J = 7.3 z, 3). 2-methoxyethyl -ethylcarbamate Colorless oil. 1 MR (CDCl3, 300Mz): δ (ppm) 4.77 (br. s, 1), 4.22 (t, J = 6.9 z, 2), 3.58 (t, 2), 3.22 (m, 4), 1.13 (t, J = 6.9 z, 3). 3

5 Calculations of conversions The conversions calculated by PLC (aromatic urethane) were performed by integrating the area of product and starting material peaks (A(starting material), A(product)) see for example Figure S1) and applying the following equation: AA (pppppppppppppp) Conversion (%) = x 100 AA (ssssssssssssssss mmmmmmmmmmmmmmmm) The conversions calculated by MR (aliphatic urethane and aromatic urethane) were performed by comparison of the integration values of key signals of both urethanes (starting material and product). For example, for the transcarbamoylation reaction between methyl -phenylcarbamate and butanol affording butyl -phenylcarbamate, two MR signals were used : -C3 (Me) for the starting material and -C2-C2-C2-C3 (Bu) for the product (see Figure S2). Me Bu (3 equiv.), K (1.2 equiv.), Bu The conversion of product was calculated following this equation: CCCC3 pppppppppppppp () Conversion (%) = x 100 CCCC3 ssssssssssssssss mmmmmmmmmmmmmmmm () ote : Conversions determined by both MR or PLC and yields were found to be very similar (Table S1). Table S1. Entry Carbamate Conversion a Isolated yield 1 PhC2Bu b 60% 56% 2 PhC2Bu c 95% 90% 3 PhC2(C2)7C3 d 85% 82% 4 PhC2(C2)2C3 e 97% 93% a Determined by PLC and MR analysis. b Reaction conditions: PhC2Me (1 equiv., 0.3 M in toluene), butanol (3 equiv.), K (1.2 equiv.), 60 C, 4h. c Reaction conditions: PhC2Me (1 equiv., 0.3 M in toluene), butanol (3 equiv.), K (1.2 equiv.), 60 C, 20h. d Reaction conditions: PhC2Me (1 equiv., 0.3 M in toluene), octanol (3 equiv.), K (1.2 equiv.), 60 C, 20h. e Reaction conditions: PhC2Me (1 equiv., 0.3 M in toluene), 2-methoxyethanol (3 equiv.), K (1.2 equiv.), 60 C, 20h. 4

6 Figure S1. PLC trace of the transcarbamoylation reaction between methyl -phenylcarbamate and butanol over time. Less polar butyl -phenylcarbamate is formed while more polar methyl -phenylcarbamate is consumed. o trace of side products is observed. 5

7 Figure S2. (A) MR of the crude resulting from the transcarbamoylation reaction between methyl -phenylcarbamate and butanol. Two key signals (-C3 for the starting material and -C2-C2-C2-C3 for the product) were used to determine the conversion (60%) (B) MR of the isolated butyl -phenylcarbamate obtained from the same reaction (yield = 56%). A B 6