Thioacetamide → 2-methyl-5,6-dihydro-4H-thiazolo[4,5-e]indole-8-carboxylic acid ethyl ester

HRID 497406Notes

Reaction equation

HRID 497406 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=O)[CH:12](Br)[CH2:11][CH2:10][C:9]=2[N:8](C(OC(C)(C)C)=O)[CH:7]=1)=[O:5])[CH3:2].[C:24]([NH2:27])(=[S:26])[CH3:25]>CO>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13]3[N:27]=[C:24]([CH3:25])[S:26][C:12]=3[CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]

Participants

4

Reactant 2

HCID 2723949ThioacetamideHCID 208723925-Bromo-4-oxo-4,5,6,7-tetrahydro-indole 1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester

Product 1

HCID 206056232-methyl-5,6-dihydro-4H-thiazolo[4,5-e]indole-8-carboxylic acid ethyl esterYield 34%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

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).

Workup

  1. temperatureunder refluxing for 16 hours the solvent
  2. customis removed in vacuo
  3. customThe brown oil is chromatographed

Sources & evidence

ORD record
ord-2ef915d5d716442685dc56b6d0aed01f
Source dataset
uspto-grants-2005_09
Patent number
US06949562B2

Reaction notes

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