Dimethylacetamide → 2-(Bicyclo[1.1.1]pentan-1-ylamino)-4-(methylthio)pyrimidine-5-carbonitrile

HRID 2280838Notes

Reaction equation

HRID 2280838 reaction equation
[C:1]12([NH:6][C:7]3[N:12]=[C:11]([S:13][CH3:14])[C:10](Br)=[CH:9][N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.C[C:17]([N:19](C)C)=O>C(OCC)(=O)C.O.[Zn].[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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]>[C:1]12([NH:6][C:7]3[N:12]=[C:11]([S:13][CH3:14])[C:10]([C:17]#[N:19])=[CH:9][N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2

Participants

9

Reactant 2

HCID 31374DimethylacetamideHCID 70982096N-(bicyclo[1.1.1]pentan-1-yl)-5-bromo-4-(methylthio)pyrimidin-2-amine

Product 1

HCID 709828862-(Bicyclo[1.1.1]pentan-1-ylamino)-4-(methylthio)pyrimidine-5-carbonitrileYield 55.8%

Reagents, catalysts & solvents 6

HCID 11186Zinc cyanide (Zn(CN)2)CatalystHCID 23994ZincCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

N-(Bicyclo[1.1.1]pentan-1-yl)-5-bromo-4-(methylthio)pyrimidin-2-amine (1250 mg, 4.37 mmol), zinc dust (71.4 mg, 1.092 mmol), zinc cyanide (333 mg, 2.84 mmol), 1,1′-bis-(diphenylphosphino)-ferrocene (196 mg, 0.349 mmol), tris(dibenzylideneacetone)dipalladium(0) (200 mg, 0.218 mmol), and DMA (8.35 mL) were combined and heated overnight at 90° C. under a nitrogen atmosphere. The reaction mixture was diluted with 125 mL ethyl acetate and 50 mL water and filtered through a pad of Celite. The layers of the filtrate were separated and the aqueous layer was extracted with 75 mL ethyl acetate. The combined ethyl acetate layers were washed with 2×50 mL brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The crude oil was purified by silica gel chromatography (0%-30% ethyl acetate in hexanes). The product containing fractions were combined and concentrated to afford 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-(methylthio)pyrimidine-5-carbonitrile (566 mg, 2.436 mmol, 55.8% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.81-9.08 (m, 1H), 8.31-8.57 (m, 1H), 2.55-2.63 (m, 3H), 2.11 (s, 7H). MS (ESI) m/z 233.3 [M+1]+.

Workup

  1. filtrationfiltered through a pad of Celite
  2. customThe layers of the filtrate were separated
  3. extractionthe aqueous layer was extracted with 75 mL ethyl acetate
  4. washThe combined ethyl acetate layers were washed with 2×50 mL brine
  5. dry with materialdried over anhydrous magnesium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated to an oil
  8. customThe crude oil was purified by silica gel chromatography (0%-30% ethyl acetate in hexanes)
  9. additionThe product containing fractions
  10. concentrationconcentrated

Sources & evidence

ORD record
ord-107d7dbdd12b45f1a1037867b46699b5
Source dataset
uspto-grants-2015_09
Patent number
US09139534B2

Reaction notes

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