Pivalic acid → 4-methyl-6-(1,3-thiazol-5-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine

HRID 2402370Notes

Reaction equation

HRID 2402370 reaction equation
C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC.Br[C:27]1[N:32]=[C:31]([NH:33][C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][N:35]=2)[CH:30]=[C:29]([CH3:44])[CH:28]=1.[S:45]1[CH:49]=[CH:48][N:47]=[CH:46]1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C(C)(C)C>CC(N(C)C)=O.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[CH3:44][C:29]1[CH:28]=[C:27]([C:49]2[S:45][CH:46]=[N:47][CH:48]=2)[N:32]=[C:31]([NH:33][C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][N:35]=2)[CH:30]=1

Participants

8

Reactant 5

HCID 6417Pivalic acidHCID 9256ThiazoleHCID 11430Potassium CarbonateHCID 11371790Bis(adamantan-1-yl)(butyl)phosphaneHCID 86680795HCID 86680795, compound

Product 1

HCID 709773814-methyl-6-(1,3-thiazol-5-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amineYield 43.2%

Reagents, catalysts & solvents 2

HCID 61538Palladium, di-mu-chlorobis(eta3-2-propenyl)di-CatalystHCID 31374DimethylacetamideSolvent2×

Procedure

In a dry flask, allylpalladium(II) chloride dimer (1.333 g, 3.64 mmol) and butyldiadamantylphosphine (5.23 g, 14.57 mmol) were taken-up in degassed dimethylacetamide (50 mL). The vessel was evacuated and backfilled with argon (3 times), and then stirred at rt for 10 minutes. Additional degassed dimethylacetamide (50 mL), 6-bromo-4-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (12.1 g, 36.4 mmol), thiazole (10.36 mL, 146 mmol), potassium carbonate (15.11 g, 109 mmol), and pivalic acid (6.34 mL, 54.6 mmol) were added. The vessel was evacuated and backfilled with argon (3 times) and stirred under argon at 130° C. overnight. The reaction mixture was then diluted with EtOAc (500 mL), cooled to rt, filtered through Celite®, and concentrated. Water was added to the crude product mixture and the resulting precipitate was collected via filtration and subjected to silica gel flash chromatography (ethyl acetate-hexanes). Purification yielded 4-methyl-6-(1,3-thiazol-5-yl)-N-[4-(trifluoromethyl)pyridin-2-yl]pyridin-2-amine (5.29 g, 15.72 mmol, 43% yield) as a yellow solid. MS ESI calcd for C15H11F3N4S [M+H]+ 337, found 337. 1H NMR (600 MHz, DMSO) δ 10.21 (s, 1H), 9.14 (s, 1H), 8.59 (s, 1H), 8.52 (s, 1H), 8.47 (d, J=5.1 Hz, 1H), 7.43 (s, 1H), 7.20 (d, J=5.1 Hz, 1H), 7.11 (s, 1H), 2.30 (s, 3H) ppm.

Workup

  1. customThe vessel was evacuated
  2. additionwere added
  3. customThe vessel was evacuated
  4. stirringstirred under argon at 130° C. overnight
  5. additionThe reaction mixture was then diluted with EtOAc (500 mL)
  6. temperaturecooled to rt
  7. filtrationfiltered through Celite®
  8. concentrationconcentrated
  9. additionWater was added to the crude product mixture
  10. filtrationthe resulting precipitate was collected via filtration
  11. customPurification

Sources & evidence

ORD record
ord-09adde890d4b42e1b1d81aa2375480a8
Source dataset
uspto-grants-2014_08
Patent number
US08796310B2

Reaction notes

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