Toluene → 1-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-(2-pyridyl)prop-1-en-1-yl)piperidine

HRID 1386803Notes

Reaction equation

HRID 1386803 reaction equation
[I-].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:52][C:53]([F:64])([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=1)[CH:54](OC)O>C1COCC1>[C:2]([O:6][C:7]([N:9]1[CH2:10][CH2:11][CH:12]([CH:15]=[CH:54][C:53]([F:64])([F:52])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[CH2:13][CH2:14]1)=[O:8])([CH3:3])([CH3:4])[CH3:5]

Participants

6

Reactant 4

HCID 1140TolueneHCID 3251421Potassium bis(trimethylsilyl)amideHCID 181875122,2-Difluoro-2-(2-pyridyl)-1-methoxyethanolHCID 18187633((1-(tert-Butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide

Product 1

HCID 539385881-(t-Butoxycarbonyl)-4-(3,3-difluoro-3-(2-pyridyl)prop-1-en-1-yl)piperidineYield 0.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A suspension of ((1-(t-butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide (5.29 g, 9.00 mmol, from EXAMPLE 155, Step C) in THF (70 mL) was stirred at RT for 40 min. A toluene solution of potassium bis(trimethylsilyl)amide (18 mL, 0.5 M, 9.0 mmol) was added, giving an orange suspension. After 40 min., crude 2,2difluoro-2-(2-pyridyl)-1-methoxyethanol (940 mg, 4.97 mmol) was added in THF (20 mL). After an additional 50 min., the mixture was quenched by the addition of saturated aq. NH4Cl (10 mL). The mixture was partitioned between EtOAc (100 mL) and H2O (100 ml), and the aqueous layer was extracted with EtOAc (3×100 mL). The organic layers were washed in succession with saturated aq. NaCl (100 mL), dried (Na2SO4), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 90:10 v/v to 80:20 v/v hexanes/EtOAc, gave 1.18 mg of the title compound (approximately 95:5 cis/trans mixture) as an oil which soldified upon standing. For the title compound: 1H NMR (500 MHz, CDCl3) S 8.68 (d, J=5, 1H), 7.84 (td, J=8, 2, 1H), 7.70 (d, J=8, 1H), 7.39 (dd, J=8, 5, 1H), 5.93 (td, J=14, 11, 1H), 5.70 (ddt, J=11, 10, 2, 1H), 4.17-3.99 (bs, 2H), 2.80-2.62 (m, 3H), 1.58 (d, J=12,22H), 1.46 (s, 9H), 1.26 (qd, J=12, 4, 2H); ESI-MS 339 (M+H); HPLC A: 4.28 min.

Workup

  1. customgiving an orange suspension
  2. waitAfter 40 min.
  3. waitAfter an additional 50 min.
  4. customthe mixture was quenched by the addition of saturated aq. NH4Cl (10 mL)
  5. customThe mixture was partitioned between EtOAc (100 mL) and H2O (100 ml)
  6. extractionthe aqueous layer was extracted with EtOAc (3×100 mL)
  7. washThe organic layers were washed in succession with saturated aq. NaCl (100 mL)
  8. dry with materialdried (Na2SO4)
  9. customdecanted
  10. customevaporated
  11. customPurification by flash column chromatography on silica gel
  12. washeluting with 90:10 v/v to 80:20 v/v hexanes/EtOAc

Sources & evidence

ORD record
ord-09a6de40b2474782b9617c0881455378
Source dataset
uspto-grants-2001_07
Patent number
US06265434B1

Reaction notes

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