Pyrrolidine → 6-Bromo-4-(pyrrolidin-1-yl)benzo[c][1,2,5]oxadiazole

HRID 520805Notes

Reaction equation

HRID 520805 reaction equation
Br[C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[C:4]([Br:11])[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[Br:11][C:4]1[CH:3]=[C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:10]2[C:6]([CH:5]=1)=[N:7][O:8][N:9]=2

Participants

6

Reactant 3

HCID 31268PyrrolidineHCID 81531DiisopropylethylamineHCID 152095134,6-dibromobenzo[c][1,2,5]oxadiazole

Product 1

HCID 900432016-Bromo-4-(pyrrolidin-1-yl)benzo[c][1,2,5]oxadiazoleYield 75%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
100 °C

Procedure

4,6-dibromobenzo[c][1,2,5]oxadiazole (0.3122 g, 1.12 mmol), pyrrolidine (0.10 mL, 1.12 mmol) and DIPEA (0.20 mL, 1.12 mmol) were dissolved in NMP (2 mL) under argon and stirred in a sealed tube at 100° C. overnight. Upon cooling to room temperature, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with H2O (5×), 1 N HCl (aq), saturated NaHCO3 (aq) and brine before drying with Na2SO4, filtering and concentrating to give the crude 6-bromo-4-(pyrrolidin-1-yl)benzo[c][1,2,5]oxadiazole (0.2247 g, 75% yield). The crude material (0.1964 g, 0.73 mmol) and 3-acetylbenzeneboronic acid (0.1558 g, 0.95 mmol) were added to a tube. The tube was evacuated and purged with argon (3×). 2 M Na2CO3 (1.1 mL, 2.21 mmol) and DME (1.6 mL) were added and the solution was degassed for 15 minutes. Pd(PPh3)4 (0.0422 g, 0.0365 mmol) was quickly added and the tube was heated at 100° C. overnight. Upon cooling to room temperature, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with H2O (5×), saturated NaHCO3 (aq) and brine before drying with Na2SO4, filtering and concentrating. The crude material was dissolved in methanol (12 mL) and cooled to 0° C. NaBH4 (0.0552 g, 1.46 mmol) was added and the mixture was stirred at 0° C. for 3 hours. The reaction mixture was quenched with saturated NaHCO3. This thick mixture was diluted with water and extracted with DCM (5×). The extracts were then dried (Na2SO4), filtered and concentrated. The crude material was purified via chromatography (30% EtOAc/Hexane) to afford 0.2029 g (90% yield, over 2 steps) of TRV-1310. 1H NMR (CDCl3) δ=7.65 (s, 1H), 7.55 (d, J=7.0 Hz, 1H), 7.47-7.42 (m, 2H), 7.07 (s, 1H), 6.11 (s, 1H), 5.00-4.99 (m, 1H), 3.81 (s, 4H), 2.12-2.09 (m, 4H), 1.92 (d, J=3.0 Hz, 1H), 1.56 (d, J=6.5 Hz, 3H).

Workup

  1. temperatureUpon cooling to room temperature
  2. extractionextracted with EtOAc
  3. washThe combined organic layers were washed with H2O (5×), 1 N HCl (aq), saturated NaHCO3 (aq) and brine
  4. dry with materialbefore drying with Na2SO4
  5. filtrationfiltering
  6. concentrationconcentrating

Sources & evidence

ORD record
ord-f3195837f2424c5b80df2b6f4d7c154a
Source dataset
uspto-grants-2016_05
Patent number
US09328078B2

Reaction notes

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