(R)-tert-butyl (1-(1H-indol-3-yl)propan-2-yl)carbamate synthesis

Yield:847199-90-0 63%

Reaction Conditions:

Stage #1: indolewith methylmagnesium chloride;copper(l) chloride in tetrahydrofuran;dichloromethane at -20 - -15; for 0.333333 h;Inert atmosphere;
Stage #2: (R)-4-methyl-2,2-dioxo-1,2,3-oxathiazolidine-3-carboxylic acid tert butyl ester in tetrahydrofuran;dichloromethane at -10; for 2.5 h;Inert atmosphere;Temperature;Reagent/catalyst;

Steps:

5

[0530] To a mixture of indole (7.4 g, 63.2 mmol, 1.5 equiv.) and CuCl (5.4 g, 54.7 mmol, 1.3 equiv.) in DCM (60 ml) was added MeMgCl (3.0 M in THF, 18.7 mL, 56 mmol, 1.33 equiv.) at - 15°C under N₂over 10 min. The resulting light yellow mixture was stirred at -20°C for 10 min, and then a solution of tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (10.0 g, 42.1 mmol, 1.0 equiv.) in DCM (40 ml) was added dropwise at -10°C under N2 over 30 min. The mixture was stirred at -10°C for 2 hours or until the reaction was complete as judged by TLC (PE/EA = 5/1, disappearance of tert-butyl (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide) or by GC. The reaction was quenched by adding 10% citric acid (100 mL) while maintaining the internal temperature ₂SO₄(10 g). The resulting mixture was stirred at room temperature for 30 min then filtered. The cake was washed with DCM (50 mL x 2). The filtrate and wash were combined and concentrated under vacuum at 30°C to provide crude tert-butyl (R)-(1-(1H-indol-3-yl)propan-2- yl)carbamate (16.9 g, 40.9 LCA%). Heptane (200 ml) was added to the crude tert-butyl (R)-(1- (1H-indol-3-yl)propan-2-yl)carbamate, and the mixture was stirred at room temperature for 1 hour, during which time, off-white solid precipitated gradually. The solid was collected by filtration, and the cake was washed with heptane (17 mL x 3). The solid was dried under high vacuum at 25 °C to provide 7.0 g of tert-butyl (R)-(1-(1H-indol-3-yl)propan-2-yl)carbamate (25.5 mmol, 97 A%, 99 wt%).¹H NMR (400 MHz, DMSO-d6) d 10.76 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.32 (dt, J = 8.1, 1.0 Hz, 1H), 7.09 (d, J = 2.3 Hz, 1H), 7.05 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 6.96 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), 3.76-3.69 (m, 1H), 2.86 (dd, J = 13.9, 5.8 Hz, 1H), 2.64 (dd, J = 14.1, 7.7 Hz, 1H), 1.37 (s, 9H), 1.00 (d, J = 6.6 Hz, 3H).

References:

WO2019/245974,2019,A1 Location in patent:Paragraph 0411; 0526; 0530; 0531; 0532; 0534