Chlorotrimethylsilane → HCID 89456521, compound

HRID 1915763Notes

Reaction equation

HRID 1915763 reaction equation
[CH3:1][N:2]1[C:6]([N:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1.CCN(CC)CC.Cl[Si:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[CH3:1][N:2]1[C:6]([N:7]2[CH2:8][CH:9]=[C:10]([O:13][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:11][CH2:12]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1

Participants

5

Reactant 3

HCID 6397ChlorotrimethylsilaneHCID 8471TriethylamineHCID 71743244HCID 71743244, compound

Product 1

HCID 89456521HCID 89456521, compoundYield 59%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

Three identical solutions of piperidin-4-one hydrochloride hydrate (1.84 g, 12.0 mmol), 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (1.3 g, 8.0 mmol) and potassium fluoride (1.86 g, 32 mmol) in dry DMSO (20 mL) were heated in a microwave at 100° C. for 12 hr. The mixtures were combined, poured into water (700 mL) and extracted into EtOAc (3×100 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a yellow solid (1.97 g, 36%). To a solution of this ketone in DMF (40 mL) was added NEt3 (3.05 mL, 21.9 mmol) and chlorotrimethylsilane (1.55 mL, 12.3 mmol). The reaction vessel was sealed and the mixture heated at 90° C. for 16 hr. The mixture was cooled and the product extracted into EtOAc (2×50 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% Et2O/isohexane) gave 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-4-(trimethylsilyloxy)-1,2,3,6-tetrahydropyridine as a yellow gum (1.53 g, 59%). This gum was dissolved in MeCN (130 mL) and cooled to 0° C. A solution of SelectFluor® (1.99 g, 5.61 mmol) in 2:1 MeCN:DMF (10 mL) was added dropwise over 20 min and the mixture stirred at between −5° C. and 0° C. for 2 hr. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and water (40 mL). The product was extracted into EtOAc (50 mL) and DCM (50 mL), and the combined organic layers passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 3-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-one as a pale yellow solid (1.23 g, 99%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 5.04 (ddd, J=48.3, 8.2, 5.7 Hz, 1H), 3.89 (s, 3H), 3.77-3.64 (m, 2H), 3.64-3.51 (m, 1H), 3.50-3.43 (m, 1H), 2.88-2.72 (m, 2H).

Workup

  1. customThe reaction vessel was sealed
  2. temperatureThe mixture was cooled
  3. extractionthe product extracted into EtOAc (2×50 mL)
  4. customThe combined organic layers were passed through a phase separation cartridge
  5. concentrationconcentrated under reduced pressure
  6. customPurification via silica gel column chromatography (0-100% Et2O/isohexane)

Sources & evidence

ORD record
ord-cda6a64af43b4816a250180a445c8fc7
Source dataset
uspto-grants-2013_12
Patent number
US08614206B2

Reaction notes

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