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A solution of thiophene2-carboxylic acid (1.00 g, 7.8 mmol), diphenylphosphoryl azide (2.15 g, 7.80 mmol) and triethylamine (1.1 mL, 7.8 mmol) in tert-butanol (20 mL) was heated at reflux for 5 hours, at which time thin layer chromatography (DCM/Hexanes) indicates the reaction is complete. The reaction mixture was cooled to room temperature, poured into water and extracted with diethyl ether (3.x.). The combined ether extracts were washed with brine, dried over anhydrous sodium sulfate, and then concentrated to afford a beige solid. Purification by column chromatography (SiO2, DCM/Hexanes) afforded compound 113 as a white solid 1.07 g (69percent). 1H-NMR (400 MHz, DMSO-d6)δ 6.87(dd, 1H), 6.77 (m, 1H), 6.5 (dd, 1H), 1.46 (s, 9H).
69%
for 5 h; Heating / reflux
Example 113; A solution of thiophene2-carboxylic acid (1.00 g, 7.8 mmol), diphenylphosphoryl azide (2.15 g, 7.80 mmol) and triethylamine (1.1 mL, 7.8 mmol) in tert-butanol (20 mL) was heated at reflux for 5 hours, at which time thin layer chromatography (DCM/Hexanes) indicates the reaction is complete. The reaction mixture was cooled to room temperature, poured into water and extracted with diethyl ether (3.x.). The combined ether extracts were washed with brine, dried over anhydrous sodium sulfate, and then concentrated to afford a beige solid. Purification by column chromatography (SiO2, DCM/Hexanes) afforded compound 113 as a white solid 1.07 g (69percent). 1H-NMR (400 MHz, DMSO-d6)δ 6.87 (dd, 1H), 6.77 (m, 1H), 6.5 (dd, 1H), 1.46 (s, 9H).
50%
at 90℃; for 4 h;
To a solution of thiophenecarboxylic acid (0.5 g, 3.90 mmol) in tBuOH (10 ml) was added Et3N (0.571 ml, 4.10 mmol) and DPPA (0.883 ml, 4.10 mmol). The solution was heated at 90 °C for 4 hours. The reaction mixture was cooled to RT and the solvent was removed in vacuo. The residue was treated with benzene and then the solution was washed with 5percent citric acid, and sat'd NaHCO3. Solid was filtered off and the filtrate was washed with brine. The organic layer was dried (MgSO4), concentrated in vacuo and the residue was purified by silica gel column chromatography (EtOAc/hexanes) to obtain tert-butyl thiophen-2-ylcarbamate (0.39 g, 50percent yield). 1H NMR (400 MHz, DMSO-d6): δ 10.4 (brs, 1H), 6.84 (dd, J = 1.6, and 5.2 Hz, 1H), 6.75 (dd, J = 4.0, and 5.6 Hz, 1H), 6.48 (dd, J= 1.6, and 4.0 Hz, 2H), 1.45 (s, 9H); MS (ESI) m/z: 222.0 (M+22+H+).
Reference：
[1] Journal of Medicinal Chemistry, 1991, vol. 34, # 5, p. 1594 - 1605
[2] Patent: US2007/105864, 2007, A1, . Location in patent: Page/Page column 151
[3] Patent: US2007/117804, 2007, A1, . Location in patent: Page/Page column 77
[4] Journal of Medicinal Chemistry, 2002, vol. 45, # 20, p. 4513 - 4523
[5] Journal of Medicinal Chemistry, 2007, vol. 50, # 20, p. 4898 - 4908
[6] Patent: WO2010/51373, 2010, A1, . Location in patent: Page/Page column 100
[7] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 21, p. 5567 - 5571
With hydrogenchloride; In ethanol; at 105.0℃; for 24.0h;Inert atmosphere;
To a solution of tert-butyl thiophen-2-ylcarbamate (3.0 g, 15 mmol) and 2-bromomalonaldehyde (2.57 g, 17 mmol) in EtOH (30 mL) was added concentrated HC1 (7.5 mL) under N2. The reaction mixture was heated to 105 oC for 24 h. After cooling to rt, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 2% MeOH in DCM to give 5-bromothieno[2,3-b]pyridine as a yellow solid (90 mg, 3%). 1H NMR (300 MHz, CDC13 8.60 (d, J = 2.1 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H), 7.55-7.60 (m, 1H), 7.19-7.22 (m, 1H). LC-MS (ESI) mlz 215 (M+H)+.
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