Sodium Carbonate → 5-Methyl-3-(3-nitro-4-pyridinyl)-2-cyclohexen-1-one

HRID 2192564Notes

Reaction equation

HRID 2192564 reaction equation
[CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:3]1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 27357814-Chloro-3-nitropyridineHCID 592265515-Methyl-2-cyclohexene-1-one-3-boronic acid pinacol ester

Product 1

HCID 592265435-Methyl-3-(3-nitro-4-pyridinyl)-2-cyclohexen-1-oneYield 48%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone (1.0 equiv.) in degassed dioxane (0.5 M) and 2M Na2CO3 (2 equiv.) was added 4-chloro-3-nitropyridine (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.). The reaction was placed under a reflux condenser and heated in an oil bath to 110° C. for 1 h. Cooled to room temperature, filtered through a pad of Celite, washed the pad with ethyl acetate and concentrated the filtrate under vacuo. The residue was further pumped at 80° C. on a rotary evaporator for one hour to remove boronate by-products (M+H=101) via sublimation. The residue was partitioned between brine and ethyl acetate, and the layers were separated, the aqueous phase was further extracted with ethyl acetate (4×), the organics were combined, dried over sodium sulfate, filtered, and concentrated. The crude was purified via silica gel chromatography loading in DCM and eluting with 2-50% ethyl acetate and hexanes. The pure fractions were concentrated in vacuo to yield an orange oil. The oil was placed under high vacuum (˜500 mtorr) with seed crystals overnight to yield an orange solid. The solid was further purified via trituration in hexanes to yield 5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enone (48% 2 steps). LC/MS=233.2 (M+H); Rt=0.69 min, LC=2.70 min. 1H-NMR (400 MHz, CdCl3) δ ppm: 9.31 (s, 1H), 8.88 (d, J=5.1, 1H), 7.30 (d, J=5.1, 1H), 6.00 (d, J=2.4, 1H), 2.62 (dd, J=16.4, 3.5, 1H), 2.53-2.34 (m, 3H), 2.23 (dd, J=16.1, 11.7, 1H), 1.16 (d, J=6.3, 3H).

Workup

  1. customThe reaction was placed under a reflux condenser
  2. temperatureCooled to room temperature
  3. filtrationfiltered through a pad of Celite
  4. washwashed the pad with ethyl acetate
  5. concentrationconcentrated the filtrate under vacuo
  6. customThe residue was further pumped at 80° C. on a rotary evaporator for one hour
  7. customto remove boronate by-products (M+H=101) via sublimation
  8. customThe residue was partitioned between brine and ethyl acetate
  9. customthe layers were separated
  10. extractionthe aqueous phase was further extracted with ethyl acetate (4×)
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customThe crude was purified via silica gel chromatography loading in DCM
  15. washeluting with 2-50% ethyl acetate and hexanes
  16. concentrationThe pure fractions were concentrated in vacuo
  17. customto yield an orange oil
  18. customwas placed under high vacuum (˜500 mtorr) with seed crystals overnight
  19. customto yield an orange solid
  20. customThe solid was further purified via trituration in hexanes

Sources & evidence

ORD record
ord-6bb0ef8171284eadb6fd0dbc8a69dcd8
Source dataset
uspto-grants-2012_12
Patent number
US08329732B2

Reaction notes

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