| 63% |
With aluminum (III) chloride; In dichloromethane; at -5 - 20℃; for 3.33333h;Inert atmosphere; |
EXAMPLE 1; 2-(l-(6,7-bis(difluoro methoxy)naphthalen-2-yl)-2-methylpropyl)-2H-tetrazole (1)To a stirred solution of A (40 g, 0.21 mol) in CH2CI2 (600 mL) was added isobutyryl chloride (34 mL, 0.31 mol) at -5 C, followed by portion- wise addition of AICI3 (56.8 g, 0.42 mol) over a period of 20 min under N2 atmosphere. The reaction was allowed to slowly warm to RT and stirred for 3h; the reaction mixture was poured into ice-cold water (200 mL) and the organic layer was separated. The aqueous layer was then extracted with CH2CI2 (2 x 100 mL); combined organic extracts were washed with 5% NaHC03 solution (100 mL), water (100 mL), brine (100 mL) and dried over anhydrous Na2S04. After filtration and evaporation under reduced pressure, the crude material was washed with w-hexane to afford B (35 g, 0.13 mol, 63%) as off-white solid. 1H NMR (200 MHz, CDC13): delta 8.34 (s, 1 H), 7.90 (dd, / = 8.6,1.8 Hz, 1 H), 7.73 (d, / = 8.6 Hz, 1 H), 7.26 (s, 1 H), 7.14 (s, 1 H), 4.03 (s, 6 H), 3.79-3.63 (m, 1 H), 1.27 (d, / = 7.0 Hz, 6H). MS (ESI): mlz 259 [M+H]+.To a stirred solution of B (18 g, 69 mmol) in CH2C12 (180 mL) was added BBr3 (87.2 g, 348 mmol) drop wise at -40 C. After completion of addition, stirring was continued for addition 1 h at -40 C and 1 h at RT. The reaction mixture was poured into cold water and aqueous layer was then extracted with CH2CI2 (2 x 200 mL). Combined organic extracts were washed with water (100 mL), brine (100 mL) and dried over anhydrous Na2S04. After filtration and evaporation of solvent under reduced pressure, the crude material was purified by column chromatography (Si02, 100-200 mesh) to afford C (9.0 g, 39 mmol, 56%) as brown color solid. 1H NMR (200 MHz, CDC13): delta 8.29 (s, 1 H), 7.88 (dd, / = 8.8, 1.6 Hz, 1 H), 7.68 (d, / = 8.6 Hz, 1 H), 7.36 (s, 1 H), 7.26 (s, 1 H), 5.88 (br s, 2 H), 3.79-3.63 (m, 1 H), 1.27 (d, / = 6.8 Hz, 6 H).To a stirred solution of C (10.0 g, 0.043 mol) in DMF (100 mL) were added sodium 2-bromo-2,2- difluoroacetate (42.6 g, 0.21 mol) (the Na salt was prepared by treating ester with 1.0 eq of NaOH in EtOH: H20 (2:1) at RT for 16. Then solvent was evaporated and residue was co-distilled with toluene (3 times) to obtain the salt.) and K2C03 (36 g, 0.26 mol) and the mixture was stirred at 80- 90 C for 48 h. The reaction mixture was poured into cold water and aqueous layer was then extracted with CH2C12 (3 x 100 mL). Combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over anhydrous Na2S04. After filtration and evaporation of solvent under reduced pressure, the crude material was purified by column chromatography (Si02, 100- 200 mesh) to afford D (3.0 g, 0.009 mol, 21%) as a solid. 1H NMR (500 MHz, CDC13): delta 8.40 (s, 1 H), 8.05 (dd, / = 8.5, 1.5 Hz, 1 H), 7.86 (d, / = 9.0 Hz, 1 H), 7.79 (s, 1 H), 7.68 (s, 1 H), 6.67 (t, JF.H = 73 Hz, 1 H), 6.65 (t, JF>H = 73 Hz, 1 H), 3.72-3.65 (m, 1 H), 1.27 (d, / = 7.0 Hz, 6 H). To a stirred solution of D (0.65 g, 1.96 mmol) in MeOH (10 mL) was added NaBH4 (0.15 g, 3.9 mmol) at 0 C and the resulting mixture was stirred for additional 30 min at 0 C. The reaction mixture was quenched with ice-cold water and the aqueous layer was then extracted with EtOAc (2 x 50 mL). Combined organic extracts were washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude material was purified by column chromatography (Si02, 100-200 mesh) using gradients of EtOAc/hexane to afford E (0.58 g, 1.74 mmol, 89%) as a semi solid. 1H NMR (200 MHz, CDC13): delta 7.80-7.72 (m, 2 H), 7.64 (s, 2 H), 7.50 (dd, / = 8.4, 1.8 Hz, 1 H), 6.63 (t, JF>H = 72 Hz, 2 H), 4.58-4.53 (m, 1 H), 2.10-2.00 (m, 1 H), 1.95 (d, / = 3.0 Hz, 1 H), 1.00 (d, / = 6.8 Hz, 3 H), 0.84 (d, / = 6.8 Hz, 3 H).To a stirred solution of E (0.8 g, 2.4 mmol) in acetonitrile (15 mL) was added thionyl chloride (0.27 mL, 3.61 mmol) at 0 C and the resulting reaction mixture was stirred for additional 30 min at 0 C. The reaction mixture was quenched with water (20 mL) and the aqueous layer was then extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with 5% NaHC03 solution (50 mL), water (50 mL), brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to afford F (0.8 g, 2.28 mol, 95%) as solid. 1H NMR (200 MHz, CDCI3): delta 7.81-7.72 (m, 2 H), 7.65 (s, 2 H), 7.53 (dd, / = 8.6,1.8 Hz, 1 H), 6.62 (t, JF>H = 74 Hz, 2 H), 4.75 (d, / = 8.0 Hz, 1 H), 2.38-2.28 (m, 1 H), 1.14 (d, / = 6.4 Hz, 3 H), 0.87 (d, / = 6.8 Hz, 3 H).To a stirred solution of F (0.3 g, 0.85 mmol) in DMF (5 mL) were added K2C03 (0.47 g, 3.41 mmol) and IH-tetrazole (0.18 g, 2.56 mmol) at RT. The reaction mixture was heated at 90 C for 36 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL); combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over anhydrous Na2S04. After filtration and evaporation of solvent under reduced pressure, the crude mater... |
| 30% |
With aluminum (III) chloride; In dichloromethane; at 0 - 20℃; for 3.33333h;Inert atmosphere; |
To a mixture of D (8.5 g, 45.2 mmol) and isobutyryl chloride (6.9 g, 65.5 mmol) in DCM (45 mL) was added AICI3 (10.1 g, 76.3 mmol) portion- wise at 0 C to -5 C over a period of 20 min under N2 atmosphere. After completion of addition, the reaction mixture was allowed to warm to room temperature and stirred for 3 h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with cold water (100 mL) and 1 N HC1 (50 mL) and then aqueous layer was extracted with DCM (2 x 200 mL). Combined organic extracts were washed with 1 M NaOH solution (100 mL), water (100 mL), brine (100 mL) and dried over anhydrous Na2S04. After filtration and evaporation under reduced pressure, the crude material was recrystallized from ethyl acetate/hexane (1:3) to afford compound-E (3.5 g, 30%) as light yellow colored solid. 1H NMR (200 MHz, CDC13): ? 8.34 (s, 1 H), 7.93 (d, J = 10.4 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.23 (s, 1 H), 7.15 (s, 1 H), 4.03 (s, 6 H), 3.73-3.63 (m, 1 H), 1.29 (d, J = 1.0 Hz, 6H). MS (ESI): m/z 259 [M++l]. |
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