Isocaproaldehyde → Methyl {(2S,4R)-1-[(1S)-4-methyl-1-(3-methylbutyl)pent-4-en-2-yn-1-yl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate

HRID 1942292Notes

Reaction equation

HRID 1942292 reaction equation
C[CH:2]([C@@H:6]1[CH2:11][CH2:10][NH:9][C@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH2:7]1)[C:3]([O-:5])=[O:4].[CH3:22][CH:23]([CH3:28])[CH2:24][CH2:25][CH:26]=O.N#N.[CH3:31][C:32]([C:34]#[CH:35])=[CH2:33].[CH3:36]O>O.[Au](Br)(Br)Br>[CH3:22][C:23](=[CH2:28])[C:24]#[C:25][C@@H:26]([N:9]1[CH2:10][CH2:11][C@@H:6]([CH2:2][C:3]([O:5][CH3:36])=[O:4])[CH2:7][C@H:8]1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][CH:13]=1)[CH2:35][CH2:34][CH:32]([CH3:31])[CH3:33]

Participants

8

Reactant 5

HCID 129IsocaproaldehydeHCID 887MethanolHCID 947NitrogenHCID 62323IsopropenylacetyleneHCID 86617999(+)-methyl{(2S,4R)-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate2×

Product 1

HCID 59201188Methyl {(2S,4R)-1-[(1S)-4-methyl-1-(3-methylbutyl)pent-4-en-2-yn-1-yl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate

Reagents, catalysts & solvents 2

HCID 82525Gold tribromideCatalystHCID 962WaterSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of (+)-methyl{(2S,4R)-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (Intermediate 2, 3.02 g, 10.0 mmol), 4-methylpentanal (2.1 g, 20.9 mmol) and gold (III) bromide (440 mg, 1 mmol) were combined in water (10 ml) in a 20 ml microwave vial. After the mixture was deoxygenated by evacuate/fill N2, 2-methylbut-1-en-3-yne (1.9 ml, 20.4 mmol) was added. The reaction was stirred and heated a 70° C. in the microwave for 30 min. The mixture was diluted with MeOH and loaded onto 5 SCX cartridges (10 g). Each cartridge was washed with MeOH (50 ml) then 2M NH3 in MeOH (2×50 ml). The ammonia-methanol fractions were combined and evaporated. The residue was taken up in EtOAc and washed with brine (×1), then dried (Na2SO4), filtered and evaporated. The residue was combined with the product from a repeat experiment on the same scale and purified by chromatography (silica, 10% Et2O/isohexane) to give the alkyne (9.1 g) a light yellow oil. 1H NMR (500 MHz, CDCl3): δ 0.83 (6H, d, J 6.6), 1.07-1.22 (2H, m), 1.27-1.45 (3H, m), 1.51-1.58 (2H, m), 1.77-1.85 (2H, m), 1.91 (3H, s), 1.93-2.02 (1H, m), 2.19-2.29 (2H, m), 2.40-2.46 (1H, m), 2.94-2.98 (1H, m), 3.18 (1H, t, J 7.6), 3.50 (1H, dd, J 2.7, 11.2), 3.65 (3H, s), 5.19 (1H, m), 5.25 (1H, s), 7.45 (2H, d, J 7.4), 7.56 (2H, d, J 8.2); M/Z (ES+) 420 (MH+).

Workup

  1. customAfter the mixture was deoxygenated
  2. additionwas added
  3. washEach cartridge was washed with MeOH (50 ml)
  4. customevaporated
  5. washwashed with brine (×1)
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. customevaporated
  9. custompurified by chromatography (silica, 10% Et2O/isohexane)

Sources & evidence

ORD record
ord-dbcd96eea4d34ba991d0adb384f2ce5e
Source dataset
uspto-grants-2013_03
Patent number
US08389547B2

Reaction notes

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