Reaction Steps
To a mixture of 4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid ethyl ester (2.4 mmol) in 10 mL 1,4-dioxane is added di-tert-butyl dicarbonate (2.9 mmol), followed by a solution of K2CO3 (2.9 mmol) in 5 mL H2O. After stirring at RT for 16 hours 50 mL ethyl acetate and 50 mL H2O are added to the mixture. The organic layer is separated and the aqueous layer is extracted several times with EtOAc. The organic layers are combined, dried over Na2SO4 and evaporated in vacuo yielding 4-Oxo-4,5,6,7-tetrahydro-indole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester, 700 mg, as a dark yellow/brown oil (95%). 1H NMR (CDCl3) 1.38 (t, 3H), 1.62 (s, 9H), 2.11-2.19 (m, 2H), 2.50-2.58 (m, 2H), 3.17 (t, 2H), 4.37 (q, 2H), 7.70 (s, 1H). Step 2: To the solution of 4-oxo-4,5,6,7-tetrahydro-indole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (33 mmol) in 140 mL THF is added dropwise a solution of phenyltrimethylammonium bromide (33 mmol) in 56 mL THF. After stirring at RT for an additional 1½ hours the mixture is poured onto 200 mL 5% NaHCO3 solution, and is then extracted several times with EtOAc. The organic layers are combined, dried over Na2SO4 and evaporated in vacuo. The dark brown oil is chromatographed using ethyl acetate 1: hexanes 10 as a mobile phase to yield 5-bromo-4-oxo-4,5,6,7-tetrahydro-indole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester, 5 g, as a white solid (40%). 1H NMR (CDCl3)1.39 (t, 3H), 1.62 (s, 9H), 2.42-2.51 (m, 2H), 3.20-3.38 (m, 2H), 4.35 (q, 2H), 4.58 (t, 1H), 7.79 (s, 1H). Step 3: To a solution of 5-bromo-4-oxo-4,5,6,7-tetrahydro-indole 1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (0.78 mmol) in 10 mL CH3OH is added thioacetamide (1.55 mmol). After stirring under refluxing for 16 hours the solvent is removed in vacuo. The brown oil is chromatographed using EtOAc 1: hexane 1, followed by 5% MeOH in CH2Cl2 as mobile phases to yield 2-methyl-5,6-dihydro-4H-thiazolo[4,5-e]indole-8-carboxylic acid ethyl ester as a white solid (34%). 1H NMR (DMSO-d6) 1.27 (t, 3H), 2.60 (s, 3H), 2.78 (t, 2H), 2.96 (t, 2H), 4.19 (q, 2H), 7.21 (s, 1H), 11.44 (s, 1H).
