Ethyl Acetate → 2-(1-(6-Bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-yl)propan-2-ol

Participants

Reaction Conditions

Reaction Steps

1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidine-3-carboxylic acid (≈600 mg, 2 mmol) was dissolved in MeOH (100 mL) and H2SO4 (2 drops) were added. A reflux condenser was fitted and the reaction gently refluxed for 24 h. At this time the reaction was diluted with EtOAc (200 mL) and extracted with water (3×100 mL). The crude material was fused to SiO2 and purified by flash column chromatography (DCM) to give essentially a quantitative yield (2.08 mmol). The ester (650 mg, 2.08 mmol) was dissolved in THF (20 mL) and cooled to 0° C. To this was added MeMgBr (6 mL, 6 mmol). After 30 min at low temperature the reaction was brought to RT and followed by TLC. When the reaction was deemed complete the mixture was cooled back to 0° C. and cautiously quenched with aqueous NH4Cl. The mixture was then extracted into EtOAc (3×100 mL), dried with MgSO4 and concentrated in vacuo. The crude material was fused to SiO2 and purified by flash column chromatography (20% Acetone in Hex) to give 474 mg of 2-(1-(6-bromobenzo[c][1,2,5]oxadiazol-4-yl)azetidin-3-yl)propan-2-ol (73% yield). 1H NMR (500 MHz, CDCl3) δ=7.20 (s, 1H), 5.89 (s, 1H), 4.26 (m, 4H), 2.87 (m, 1H), 1.38 (s, 1H), 1.26 (s, 6H). To a stirring solution of the tertiary alcohol (223 mg, 0.71 mmol) dissolved in THF (10 mL) and cooled to 0° C. was added NaH (600 mg, 20 mmol). Once the initial bubbling had subsided MeI (1.14 g, 8 mmol) was added dropwise and the reaction mixture was left to come to RT. After 18 h the reaction was cooled back to 0° C. and NH4Cl was cautiously added. The reaction mixture was extracted with EtOAc (3×50 mL), washed with brine, (1×50 mL) and concentrated in vacuo. The crude material was then purified by flash column chromatography (10% Acetone in Hex). To a solution of the ether (193 mg, 0.6 mmol) in DME (4 mL)/Na2CO3 (2M, 0.9 mL) was added 3-formyl-phenylboronic acid (133 mg, 0.9 mmol) and Pd(P(Ph)3)4 (40 mg). The flask was then fitted with a reflux condenser, purged with argon and heated to 110° C. O/N. The reaction was worked up by pouring into 1 M NaOH (150 mL) and vacuum isolating the resultant solids. The crude aldehyde was purified by plugging through SiO2 (20% EtOAc in Hex) to give 184 mg of material which was used as is. To a stirring solution of aldehyde (400 mg, 1.4 mmol) and Rupert's reagent (483 mg, 3.3 mmol) in DCM (13 mL) at 0° C. was added TBAF (0.1 mL, 1 M THF, 0.2 mmol). After 30 min at low temperature the cold bath was removed and the reaction was allowed to come to RT. After stirring overnight an excess of TBAF was added and the reaction was diluted with DCM. The organic phases were washed with saturated NH4Cl, brine, and then dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (30% EtOAc in Hex) to give 90 mg (41% yield). 1H NMR (500 MHz, CDCl3) δ=7.72 (s, 1H), 7.66 (m, 1H), 7.50 (m, 2H), 7.11 (s, 1H), 6.01 (s, 1H), 5.11 (m, 1H), 4.25 (m, 4H), 3.24 (s, 3H), 2.96 (m, 1H)

Provenance & Evidence