Iodine → N-(6-chloro-3-iodopyridin-2-yl)pivalamide

HRID 1011242Notes

Reaction equation

HRID 1011242 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.CCCCC.[I:25]I>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])[C:5]([I:25])=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 807IodineHCID 8003PentaneHCID 13154248N-(6-Chloropyridin-2-yl)-2,2-dimethylpropanamideHCID 178418306HCID 178418306, compound

Product 1

HCID 45480364N-(6-chloro-3-iodopyridin-2-yl)pivalamideYield 68.5%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of N-(6-chloropyridin-2-yl)pivalamide (15.8 g, 74.2 mmol) in anhydrous THF (150 mL) at −78° C. under a nitrogen atmosphere, is added 1.7 M t-butyllithium in pentane (96 mL, 163 mmol, 2.2 eq.) dropwise (dropping funnel) over 0.5 h. The reaction mixture is then stirred at −78° C. for 3 h before iodine (22.6 g, 89 mmol, 1.2 eq.) in THF (60 mL) is slowly added in one portion. After 10 min., the cooling bath is removed and the reaction is allowed to warm to rt and stirred for 2 h. Hydrochloric acid (1 M, 75 mL) is then added to the reaction mixture. The reaction mixture is concentrated in vacuo (rotary evaporator) to remove the THF, the resulting mixture is extracted with ethyl acetate (800 mL). The phases are separated and the organic layer is washed with aqueous 1 M Na2S2O3 (100 mL), brine (300 mL×2), water (300 mL), dried over MgSO4, and evaporated. The crude product is recrystallized from DCM/hexanes (1:4) and the solid that forms collected by filtration to provide N-(6-chloro-3-iodopyridin-2-yl)pivalamide as a white crystalline solid (17.2 g). The filtrate is evaporated and the residue chromatographed on a silica gel column (hexanes/EtOAc, 9/1) to provide an additional product (2.5 g). Overall 19.7 g (78% yield) of N-(6-chloro-3-iodopyridin-2-yl)pivalamide is obtained. 1H NMR (300 MHz, DMSO-d6), δ 9.86 (s, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 1.23 (s, 9H). LCMS-ESI (m/z): calcd for C10H12Cl1N2O 337.9; [M+H]+ found 339.0.

Workup

  1. additionis slowly added in one portion
  2. customthe cooling bath is removed
  3. additionHydrochloric acid (1 M, 75 mL) is then added to the reaction mixture
  4. concentrationThe reaction mixture is concentrated in vacuo (rotary evaporator)
  5. customto remove the THF
  6. extractionthe resulting mixture is extracted with ethyl acetate (800 mL)
  7. customThe phases are separated
  8. washthe organic layer is washed with aqueous 1 M Na2S2O3 (100 mL), brine (300 mL×2), water (300 mL)
  9. dry with materialdried over MgSO4
  10. customevaporated
  11. customThe crude product is recrystallized from DCM/hexanes (1:4)
  12. filtrationthe solid that forms collected by filtration

Sources & evidence

ORD record
ord-3e628858cfad439e86d973a577375d26
Source dataset
uspto-grants-2011_07
Patent number
US07977352B2

Reaction notes

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