Benzyl Alcohol → 5-(2-(Benzyloxy)-4-bromo-6-fluorophenyl)-1,3,4-thiadiazol-2-amine

HRID 579361Notes

Reaction equation

HRID 579361 reaction equation
[H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:17]=[C:16](F)[C:15]([C:19]2[S:23][C:22]([NH2:24])=[N:21][N:20]=2)=[C:14]([F:25])[CH:13]=1>C1COCC1>[CH2:3]([O:10][C:16]1[CH:17]=[C:12]([Br:11])[CH:13]=[C:14]([F:25])[C:15]=1[C:19]1[S:23][C:22]([NH2:24])=[N:21][N:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1

Participants

5

Reactant 3

HCID 244Benzyl AlcoholHCID 24758Sodium hydrideHCID 801326305-(4-Bromo-2,6-difluorophenyl)-1,3,4-thiadiazol-2-amine

Product 1

HCID 867271855-(2-(Benzyloxy)-4-bromo-6-fluorophenyl)-1,3,4-thiadiazol-2-amineYield 37.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
50 °C

Procedure

A stirred suspension of NaH (60% dispersion in mineral oil, 151 mg, 3.77 mmol) in THF (10 mL) was cooled under nitrogen in an ice bath. To this suspension was added a solution of benzyl alcohol (0.372 mL, 3.59 mmol) in THF (5 mL) drop-wise. On completion of addition, the resulting suspension was stirred at ice bath temperature for 5 minutes, then room temperature for 10 minutes, before being slowly added to a stirred, ice-bath cooled suspension of 5-(4-bromo-2,6-difluorophenyl)-1,3,4-thiadiazol-2-amine (1 g, 3.42 mmol) in THF (20 mL). The resulting yellow/brown suspension was stirred at ice bath temperature for 15 minutes, room temperature for 1 hour then heated at 50° C. for 18 hours. The reaction was quenched by addition of saturated NH4Cl(aq) (30 mL), diluted with water (30 mL), and extracted with EtOAc (100 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was concentrated onto silica gel and the crude material was purified by flash chromatography using an 80 g silica cartridge running an EtOAc/heptane gradient to afford the title compound as a pale yellow solid (488 mg, 37% yield). LC-MS: Rt 1.19 min; MS m/z 282.0 M+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ 7.27-7.47 (m, 9H), 5.28 (s, 2H).

Workup

  1. temperaturewas cooled under nitrogen in an ice bath
  2. additionOn completion of addition
  3. waitroom temperature for 10 minutes
  4. additionbefore being slowly added to a stirred, ice-bath
  5. temperaturecooled
  6. stirringThe resulting yellow/brown suspension was stirred at ice bath temperature for 15 minutes
  7. customThe reaction was quenched by addition of saturated NH4Cl(aq) (30 mL)
  8. additiondiluted with water (30 mL)
  9. extractionextracted with EtOAc (100 mL)
  10. customThe organic phase was separated
  11. dry with materialdried over MgSO4
  12. filtrationfiltered
  13. concentrationThe filtrate was concentrated onto silica gel
  14. customthe crude material was purified by flash chromatography

Sources & evidence

ORD record
ord-ca102c4661c74a1ca58873dc53bcbde9
Source dataset
uspto-grants-2015_05
Patent number
US09040712B2

Reaction notes

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