Bromoform → 2-(Dibromomethyl)-6-methoxy-5-methyl-3-nitropyridine

HRID 2088507Notes

Reaction equation

HRID 2088507 reaction equation
CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[CH:11][N:10]=1.[CH:19](Br)([Br:21])[Br:20]>C1COCC1>[Br:20][CH:19]([Br:21])[C:11]1[C:12]([N+:16]([O-:18])=[O:17])=[CH:13][C:14]([CH3:15])=[C:9]([O:8][CH3:7])[N:10]=1

Participants

5

Reactant 3

HCID 5558BromoformHCID 23665647Potassium tert-butoxideHCID 407869042-Methoxy-3-methyl-5-nitropyridine

Product 1

HCID 445964852-(Dibromomethyl)-6-methoxy-5-methyl-3-nitropyridineYield 94%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a 3 neck, 22 L round bottom flask equipped with a mechanical stirrer and an addition funnel was added potassium t-butoxide (450 g, 4.00 mol) and THF (4 L). The mixture was stirred vigorously and a solution of 2-methoxy-3-methyl-5-nitropyridine (100 g, 0.595 mol) from Part I and bromoform (195.4 g, 0.773 mol) in 500 mL of dry THF was added dropwise at such a rate that the temperature did not rise above −74° C. (3 h addition time). The reaction mixture was stirred at −78° C. for an additional 15 min. The reaction mixture was then quenched by the dropwise addition of a mixture of methanol (400 ml) and conc. HCl (600 mL) while maintaining the temperature below −68° C. Water (1 L) was then added and the aqueous layer was extracted with EtOAc (3×4 L). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by column chromatography on silica gel (0%→7% ethyl acetate in hexanes) to give 2-(dibromomethyl)-6-methoxy-5-methyl-3-nitropyridine (190.0 g, 94% yield) as a red-brown solid: mp 58.7-61.2° C. 1H NMR (300 mHz, CDCl3) δ 8.04 (s, 1H), 7.60 (s, 1H), 4.15 (s, 3H), 2.26 (s, 1H); LRMS, (ESI) m/e 339.0 [(M+H)+, calcd for C8H9N2O3Br2, 338.9].

Workup

  1. customTo a 3 neck, 22 L round bottom flask equipped with a mechanical stirrer and an addition funnel
  2. customdid not rise above −74° C.
  3. addition(3 h addition time)
  4. stirringThe reaction mixture was stirred at −78° C. for an additional 15 min
  5. customThe reaction mixture was then quenched by the dropwise addition of a mixture of methanol (400 ml) and conc. HCl (600 mL)
  6. temperaturewhile maintaining the temperature below −68° C
  7. additionWater (1 L) was then added
  8. extractionthe aqueous layer was extracted with EtOAc (3×4 L)
  9. washThe combined organic layers were washed with brine
  10. dry with materialdried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customThe product was purified by column chromatography on silica gel (0%→7% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-e4a2f9a4a8294197b9a63f4f651dda19
Source dataset
uspto-grants-2013_05
Patent number
US08436000B2

Reaction notes

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