Trimethyl phosphonoacetate → (E)-Methyl 5-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)pent-2-enoate

HRID 1855052Notes

Reaction equation

HRID 1855052 reaction equation
[Li+].[Cl-].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].C1CCN2C(=NCCC2)CC1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][C:32]1[CH:33]=[C:34]([C:38]23[CH2:45][CH2:44][C:41]([CH2:46][CH2:47][CH:48]=O)([CH2:42][CH2:43]2)[CH2:40][O:39]3)[CH:35]=[CH:36][CH:37]=1>CC#N>[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][C:32]1[CH:33]=[C:34]([C:38]23[CH2:45][CH2:44][C:41]([CH2:46][CH2:47]/[CH:48]=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])([CH2:42][CH2:43]2)[CH2:40][O:39]3)[CH:35]=[CH:36][CH:37]=1

Participants

6

Reactant 4

HCID 80029Trimethyl phosphonoacetateHCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 433294Lithium ChlorideHCID 904083923-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)propanal

Product 1

HCID 90409249(E)-Methyl 5-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)pent-2-enoateYield 86%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
0 °C

Procedure

To a 0° C. suspension of LiCl (55.4 mg, 1.306 mmol) in MeCN (2 mL) under N2 was added trimethyl phosphonoacetate (0.188 mL, 1.306 mmol) and DBU (0.197 mL, 1.31 mmol). The reaction was stirred at 0° C. for 30 minutes, and then 3-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)propanal (300 mg, 0.871 mmol) was added. The reaction was stirred at rt for 2 h and concentrated in vacuo. The residue was diluted with Et2O, washed with 1 N aq. HCl, satd aq. NaHCO3, brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 30% EtOAc:hexanes) to afford the title compound (300 mg, 86% yield) as a white solid. LCMS, [M+NH4]+=418.2. 1H NMR (500 MHz, CDCl3) δ 7.23 (t, J=8.0 Hz, 1H), 7.14-7.11 (m, 1H), 7.03-6.93 (m, 3H), 5.86 (dt, J=15.7, 1.5 Hz, 1H), 5.45 (t, J=3.2 Hz, 1H), 3.94 (ddd, J=11.3, 9.9, 3.0 Hz, 1H), 3.84 (s, 2H), 3.75 (s, 3H), 3.65-3.59 (m, 1H), 2.23-2.15 (m, 2H), 2.09-1.98 (m, 5H), 1.89-1.84 (m, 2H), 1.75-1.58 (m, 8H), 1.37-1.31 (m, 2H).

Workup

  1. stirringThe reaction was stirred at rt for 2 h
  2. concentrationconcentrated in vacuo
  3. additionThe residue was diluted with Et2O
  4. washwashed with 1 N aq. HCl
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude oil was purified by flash chromatography on SiO2 (0 to 30% EtOAc:hexanes)

Sources & evidence

ORD record
ord-fc4c8068058e4e7fb62788804890c77d
Source dataset
uspto-grants-2015_02
Patent number
US08962660B2

Reaction notes

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