Bromine → Ethyl 2-methyl-4,5,6,7-tetrahydrobenzo[d]thiazole-4-carboxylate

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Reaction Steps

To a solution of 15 g (88 mmol) of ethyl 2-oxocyclohexanecarboxylate in 40 mL of anhydrous diethyl ether cooled to 0° C. was added 4.5 mL (88 mmol) of bromine dropwise over 15 min. After complete addition the mixture was allowed to warm to ambient temperature over 90 min. The mixture was next diluted with 100 mL of ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was taken up in 100 mL of ethanol and 6.6 g (88 mmol) of thioacetamide was added. The mixture was stirred at ambient temperature for 1 h, then at reflux overnight. After evaporation of all volatiles in vacuo the residue was partitioned between a saturated aqueous sodium bicarbonate solution and dichloromethane. The layers were separated and the organic phase was dried over magnesium sulfate and evaporated in vacuo. The crude residue was purified by MPLC (Biotage Horizon: FLASH 65i) eluent: 100% Hexanes (500 ml), gradient 0 to 25% EtOAc in hexanes (1200 ml) then 25% EtOAc in hexanes (1200 ml) to give the title compound as a pale orange oil. 1H NMR (500 MHz, CDCl3) δ: 4.22 (q, J=7.1, 2H), 3.84 (t, J=5.5, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 2.65 (s, 3H), 2.18 (m, 1H), 2.11-1.95 (m, 2H), 1.85 (m, 1H), 1.29 (t, J=7.1, 3H).

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