Pentamethylbenzene → 6-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-ol

HRID 625087

Reaction equation

HRID 625087 reaction equation
C([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22]([O:26][CH3:27])[S:21]4)[O:17][C:13]=2[CH:12]=[C:11]([O:28][CH3:29])[CH:10]=1)C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1>ClCCl>[CH3:29][O:28][C:11]1[CH:12]=[C:13]2[O:17][C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22]([O:26][CH3:27])[S:21]4)=[CH:15][C:14]2=[C:9]([OH:8])[CH:10]=1

Participants

4

Reactant 2

HCID 12784PentamethylbenzeneHCID 722017086-(4-(Benzyloxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole

Product 1

HCID 722017096-Methoxy-2-(2-methoxyimidazo[2,1-b][1,3,4]thiadiazol-6-yl)benzofuran-4-olYield 81.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
-78 °C

Procedure

A mixture of 6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-methoxyimidazo[2,1-b][1,3,4]thiadiazole (Example 1G, 1.250 g, 3.06 mmol) and pentamethylbenzene (3.17 g, 21.4 mmol) in dichloromethane (200 mL) was cooled to −78° C. under a nitrogen atmosphere and then treated immediately (to avoid crystallization) with 8 mL (8 mmol) of a 1 M solution of boron trichloride in dichloromethane added dropwise over 3 min. The resulting mixture was stirred at −78° C. for 1 h. The reaction mixture was then quenched by the addition of a solution of sodium bicarbonate (6 g) in water (100 mL) added in one portion. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1 h. The solid formed was filtered, washed successively with water (50 m) and dichloromethane (50 mL). The filter cake was allowed to soak with anhydrous ethanol (15 ml) and then sucked dry. The white solid obtained was then dried under vacuum for 24 h to give 0.788 g (80% yield) of pure title material (>95% by hplc). The combined filtrate and washings were diluted with dichloromethane (600 mL) and stirred in a warm water bath till the organic phase was clear with no apparent solid in suspension. The organic phase was collected, dried over anhydrous magnesium sulfate and rapidly filtered while still warm. The filtrate was evaporated and the residue (product and hexamethylbenzene) was triturated with toluene (20 mL), the solid collected and washed with toluene (20 mL) to give 0.186 g (19% yield, 99% combined yield) of title material as a tan solid (>95% by hplc). LC (Method E): 1.444 min. HRMS (ESI) calcd for C14H12N3O4S [M+H]+ m/z 318.0543, found 318.0578. 1H NMR (DMSO-d6, 600 MHz) δ 3.71 (s, 3H), 4.16 (s, 3H), 6.21 (d, J=1.87 Hz, 1H), 6.61 (broad s, 1H), 6.95 (s, 1H), 8.29 (s, 1H), 9.96 (s, 1H).

Workup

  1. additiontreated immediately
  2. custom(to avoid crystallization) with 8 mL (8 mmol) of a 1 M solution of boron trichloride in dichloromethane
  3. additionadded dropwise over 3 min
  4. customThe reaction mixture was then quenched by the addition of a solution of sodium bicarbonate (6 g) in water (100 mL)
  5. additionadded in one portion
  6. customThe cooling bath was removed
  7. stirringthe resulting mixture was stirred at room temperature for 1 h
  8. customThe solid formed
  9. filtrationwas filtered
  10. washwashed successively with water (50 m) and dichloromethane (50 mL)
  11. customsucked dry
  12. customThe white solid obtained
  13. customwas then dried under vacuum for 24 h

Sources & evidence

ORD record
ord-cb17d560b9e44d1093e63ff073603928
Source dataset
uspto-grants-2016_04
Patent number
US09303065B2

Linked notes

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