3,5-Dibromopyridine → Tert-butyl 2-[(5-bromopyridin-3-yl)amino]-3-methylbutanoate

HRID 510176Notes

Reaction equation

HRID 510176 reaction equation
Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.Cl.[C:10]([O:14][C:15](=[O:21])[C@@H:16]([CH:18]([CH3:20])[CH3:19])[NH2:17])([CH3:13])([CH3:12])[CH3:11].CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:6]1[CH:7]=[C:2]([NH:17][CH:16]([CH:18]([CH3:20])[CH3:19])[C:15]([O:14][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:21])[CH:3]=[N:4][CH:5]=1

Participants

7

Reactant 4

HCID 693693,5-DibromopyridineHCID 634876Binap, (A+-)-HCID 23676156Sodium t-butoxideHCID 45108216H-D-Val-OtBu hydrochloride

Product 1

HCID 89495408Tert-butyl 2-[(5-bromopyridin-3-yl)amino]-3-methylbutanoateYield 69.1%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
90 °C

Procedure

To a nitrogen degassed mixture of 3,5-dibromopyridine (5.0 g, 21.11 mmol), D-Valine t-butylester HCl (Aldrich Chemical, 4.43 g, 21.11 mmol) and sodium tert-butoxide (6.09 g, 63.3 mmol), in Toluene (200 ml) was added BINAP (2.63 g, 4.22 mmol) followed by tris(dibenzylideneacetone)-dipalladium(0) (Strem Chemical, 1.933 g, 2.111 mmol). The reaction was sealed and heated at 90° C. for 1 hr. The reaction was cooled, quenched into brine (100 mL), aqueous KHSO4 (20 mL) and ethyl acetate (200 mL). Aqueous sodium bicarbonate was added to adjust the pH to 8.0 and the organic layer removed. The aqueous layer was washed with ethyl acetate (100 mL). The combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered thru a pad of silica and the filtrate concentrated to oil. The oil was chromatographed on silica eluting with 5-30% ethyl acetate/hex to give 4.8 gm of compound I-2a, 69%.

Workup

  1. customTo a nitrogen degassed
  2. customThe reaction was sealed
  3. temperatureThe reaction was cooled
  4. customquenched into brine (100 mL), aqueous KHSO4 (20 mL) and ethyl acetate (200 mL)
  5. additionAqueous sodium bicarbonate was added
  6. customthe organic layer removed
  7. washThe aqueous layer was washed with ethyl acetate (100 mL)
  8. washThe combined organic extracts were washed with brine (100 mL)
  9. dry with materialdried over sodium sulfate
  10. filtrationfiltered
  11. concentrationthe filtrate concentrated to oil
  12. customThe oil was chromatographed on silica eluting with 5-30% ethyl acetate/hex

Sources & evidence

ORD record
ord-8e57b07723a3472a81352d2a59121307
Source dataset
uspto-grants-2015_08
Patent number
US09096598B2

Reaction notes

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