2-Amino-4-methylpyridine → 4-methyl-N-(thiazol-2-yl)pyridine-2-amine

HRID 1685287Notes

Reaction equation

HRID 1685287 reaction equation
[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.N[C:10]1[S:11][CH:12]=[CH:13][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH:3]=1

Participants

7

Reactant 3

HCID 15332-Amino-4-methylpyridineHCID 21552-AminothiazoleHCID 10340Sodium Carbonate

Product 1

HCID 146685484-methyl-N-(thiazol-2-yl)pyridine-2-amineYield 67.2%

Reagents, catalysts & solvents 3

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)Catalyst2×HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
130 °C

Procedure

A suspension of 4-methyl-2-aminopyridine (5.10 g, 40.0 mmol), 2-aminothiazole (4.81 g, 48 mmol, 1.2 eq), sodium carbonate (5.94 g, 56.0 mmol, 1.4 eq) and XANTPHOS (0.278 g, 0.48 mmol, 0.012 eq) in THF (100 mL, bubbled with argon for 5 minutes) was bubbled again with argon for 5 additional minutes. Tris(dibenzylideneacetone)dipalladium (0) (0.146 g, 0.16 mmol, 0.004 eq) was then added to the suspension which was heated at 130° C. for 2 days. Additional quantities of XANTPHOS (0.278 g) and tris(dibenzylideneacetone)dipalladium (0) (0.146 g) were added again and the reaction was heated at 130° C. for 4 more days. The mixture was cooled down to RT and filtered. The resulting solid was suspended in water and stirred for 1 hour. After filtration, the resulting solid was dried under vacuum overnight. The THF filtrate was evaporated and the residue was combined to the previously isolated solid. This was precipitated from MeOH to give the title compound (5.14 g, 67%) as a solid. The mother liquor was evaporated and the residue purified by silica gel chromatography (50% ethyl acetate/dichloromethane to 100% ethyl acetate) and afforded the title material (0.825 g, 11%) as a solid, 1H NMR (400 MHz, CDCl3) δ (ppm): 2.36 (3H, s), 6.71 (1H, s), 6.75 (1H, br d, J=5.1 Hz), 6.84 (1H, d, J=3.5 Hz), 7.43 (1H, d, J=3.5 Hz), 8.24 (1H, d, J=5.3 Hz). LC/MS (M+H)+: 192. HPLC ret. time (Condition A): 1.285 min.

Workup

  1. customwas bubbled again with argon for 5 additional minutes
  2. temperaturethe reaction was heated at 130° C. for 4 more days
  3. temperatureThe mixture was cooled down to RT
  4. filtrationfiltered
  5. filtrationAfter filtration
  6. customthe resulting solid was dried under vacuum overnight
  7. customThe THF filtrate was evaporated
  8. customThis was precipitated from MeOH

Sources & evidence

ORD record
ord-60c3397c55174132b21c3ac0c744d4d8
Source dataset
uspto-grants-2012_04
Patent number
US08148400B2

Reaction notes

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