Sodium Carbonate → 3-Methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenol

HRID 579311Notes

Reaction equation

HRID 579311 reaction equation
C([Si]([O:8][C:9]1[CH:14]=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[C:11]([O:24][CH3:25])[CH:10]=1)(C)C)(C)(C)C.Br[C:27]1[S:31][C:30]([N:32]([CH3:43])[CH:33]2[CH2:38][C:37]([CH3:40])([CH3:39])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]2)=[N:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][O:24][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[C:27]1[S:31][C:30]([N:32]([CH3:43])[CH:33]2[CH2:38][C:37]([CH3:39])([CH3:40])[NH:36][C:35]([CH3:42])([CH3:41])[CH2:34]2)=[N:29][N:28]=1

Participants

8

Reactant 3

HCID 10340Sodium CarbonateHCID 86710628Tert-butyl(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane2×HCID 867271295-Bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine2×

Product 1

HCID 1363413373-Methoxy-4-(5-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)-1,3,4-thiadiazol-2-yl)phenol

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

To a stirred suspension of tert-butyl(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)dimethylsilane (Intermediate 3) (3.28 g, 9.00 mmol) and 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Intermediate 4) (1 g, 6.00 mmol) in dioxane (48 mL) under nitrogen was added Pd(PPh3)4 (0.347 g, 0.30 mmol) followed by a solution of Na2CO3 (1.272 g, 12.00 mmol) in water (12 mL). The resulting mixture was refluxed at 120° C. for 18 hours. The reaction mixture was cooled to room temperature, then diluted with EtOAc (150 mL) and washed with water (100 mL). The organic phase was separated and the aqueous phase re-extracted with EtOAc (150 mL). The combined organics were dried over MgSO4, filtered, and the filtrate concentrated in vacuo to afford an oily brown residue. The residue was suspended in EtOAc (10 mL) and sonicated, then the resulting suspension was filtered under vacuum to afford the crude product as an off-white solid. The crude mixture was purified by flash chromatography using 3% [7M NH3 in MeOH]/DCM as the eluent to afford the title compound as a pale yellow glass-like solid (0.534 g, 23% yield). LC-MS: Rt 0.75 min; MS m/z 377.3 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.99 (br. s., 1H), 7.88 (d, J=8.59 Hz, 1H), 6.54 (d, J=2.53 Hz, 1H), 6.50 (dd, J=8.34, 2.27 Hz, 1H), 4.34-4.25 (m, 1H), 3.86 (s, 3H), 2.94 (s, 3H), 1.59 (dd, J=11.62, 3.03 Hz, 2H), 1.40 (t, J=12.38 Hz, 2H), 1.26 (br. s., 1H), 1.20 (s, 6H), 1.08 (s, 6H).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. washwashed with water (100 mL)
  3. customThe organic phase was separated
  4. extractionthe aqueous phase re-extracted with EtOAc (150 mL)
  5. dry with materialThe combined organics were dried over MgSO4
  6. filtrationfiltered
  7. concentrationthe filtrate concentrated in vacuo
  8. customto afford an oily brown residue
  9. customsonicated
  10. filtrationthe resulting suspension was filtered under vacuum
  11. customto afford the crude product as an off-white solid
  12. customThe crude mixture was purified by flash chromatography

Sources & evidence

ORD record
ord-307eee1dcdce48fcae10f7b004b1dd67
Source dataset
uspto-grants-2015_05
Patent number
US09040712B2

Reaction notes

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