Hydrochloric Acid → tert-Butyl 6-amino-2-chloro-4,5-dimethylnicotinate

HRID 1482061Notes

Reaction equation

HRID 1482061 reaction equation
[Cl:1][C:2]1[N:14]=[C:13](Cl)[C:12]([CH3:16])=[C:11]([CH3:17])[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].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.C([O-])([O-])=O.[Cs+].[Cs+].C(=[NH:79])(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])=O.[Na+].Cl.[OH-].[Na+]>O1CCOCC1.CCOC(C)=O.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]>[NH2:79][C:13]1[C:12]([CH3:16])=[C:11]([CH3:17])[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([Cl:1])[N:14]=1

Participants

11

Reactant 7

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 14798Sodium HydroxideHCID 136809Benzophenone imineHCID 517045Sodium AcetateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 118316314tert-Butyl 2,6-dichloro-4,5-dimethylnicotinate

Product 1

HCID 118308920tert-Butyl 6-amino-2-chloro-4,5-dimethylnicotinateYield 62.1%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

tert-Butyl 2,6-dichloro-4,5-dimethylnicotinate (1.9 g, 6.9 mmol, 1 equiv), Pd2(dba)3 (0.63 g, 0.69 mmol, 0.1 equiv), xantphos (0.80 g, 1.38 mmol, 0.2 equiv), and Cs2CO3 (5.4 g, 16.5 mmol, 2.4 equiv) was slurried in dioxane (deoxygenated by bubbling nitrogen through it for 10 min) added. Benzophenone imine (1.4 mL, 8.3 mmol, 1.2 equiv) was added and the mixture was heated at 90° C. for 2 h. Upon cooling to ambient temperature, the reaction was diluted with EtOAc and washed with water, dried (Na2SO4), and concentrated in vacuo. The crude product was taken up in MeOH (80 mL) and NaOAc (1.69, 20.6 mmol, 3 equiv) and hydroxlamine hydrochloride (0.96 g, 13.8 mmol, 2 equiv) was added. After 18 h, the reaction was added to 1 N NaOH and extracted with DCM (×2). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc/hex) to afford the product (1.1 g, 62%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 4.57 (br. s., 2H), 2.24 (s, 3H), 2.03 (s, 3H), 1.60 (s, 9H); LCMS (ESI, M+1): 257.15.

Workup

  1. additionadded
  2. temperatureUpon cooling to ambient temperature
  3. washwashed with water
  4. dry with materialdried (Na2SO4)
  5. concentrationconcentrated in vacuo
  6. extractionextracted with DCM (×2)
  7. dry with materialThe combined DCM extracts were dried (Na2SO4)
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified by flash column chromatography (0-100% EtOAc/hex)

Sources & evidence

ORD record
ord-b074540ca43442d39feb25e509970f3d
Source dataset
uspto-grants-2016_08
Patent number
US09409922B2

Reaction notes

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