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Cesium carbonate → 4-methyl-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine

HRID 1039877
Notes
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Reaction equation

HRID 1039877 reaction equation
[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:12]=[C:11]([CH3:24])[CH:10]=2)[N:3]=1.Br[C:26]1[S:30][CH:29]=[N:28][CH:27]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([C:26]3[S:30][CH:29]=[N:28][CH:27]=3)[CH:12]=[C:11]([CH3:24])[CH:10]=2)[N:3]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 4

HCID 10796Cesium carbonateHCID 5460595-BromothiazoleHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 584562194-methyl-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine

Product 1

HCID 584561954-methyl-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine
Yield 55.5%

Reagents, catalysts & solvents 1

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
100 °C

Procedure

A microwave vial was charged with Intermediate 18 (218 mg, 0.670 mmol), 5-bromo-1,3-thiazole (59.9 μL, 0.670 mmol), Pd2(dba)3 (30.7 mg, 0.034 mmol), X-Phos (32.0 mg, 0.067 mmol) and cesium carbonate (437 mg, 1.341 mmol). The system was purged and flushed with Ar(g) four times before adding dioxane (918 μL) and water (92 μL). Again, the system was purged and flushed five times before sealing the vial and heating at 100° C. LCMS showed ˜60% desired product, ˜35% de-borolated product and remaining unreacted starting material. The reaction mixture was diluted with ethyl acetate, filtered through a celite plug and concentrated. The resultant residue was purified by column chromatography on silica gel (Biotage, 0-20% ethyl acetate in hexanes) to afford 4-methyl-N-[3-methyl-5-(1,3-thiazol-5-yl)phenyl]pyrimidin-2-amine (105 mg, 0.372 mmol, 55.5%). MS ESI: [M+H]+ m/z 283.0. 1H NMR (500 MHz, DMSO-D6) δ 9.60 (s, 1H), 9.04 (s, 1H), 8.35 (d, J=6.6, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 7.54 (s, 1H), 7.10 (s, 1H), 6.75 (d, J=6.3, 1H), 2.37 (s, 3H), 2.30 (s, 3H).

Workup

  1. customThe system was purged
  2. customflushed with Ar(g) four times
  3. additionbefore adding dioxane (918 μL) and water (92 μL)
  4. customAgain, the system was purged
  5. customflushed five times
  6. additionThe reaction mixture was diluted with ethyl acetate
  7. filtrationfiltered through a celite plug
  8. concentrationconcentrated
  9. customThe resultant residue was purified by column chromatography on silica gel (Biotage, 0-20% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-a5906a2b0ade4d3a9ad9a86ba0801718
Source dataset
uspto-grants-2013_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08551984B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes