Reaktion #1108376

Reaktionsgleichung

2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine

lipoic acid

DiPEA

CDI

→

chroman amide

Lösungsmittel

THF

THF

EtOAc

EtOAc

Reaktionsbedingungen

Aufarbeitung

1. 1
   Waschenwashed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each)
2. 2
   TrocknenThe remaining organics were dried over anhydrous sodium sulfate
3. 3
   Filtrationfiltered
4. 4
   Einengenconcentrated in vacuo
5. 5
   workup.DISSOLUTIONThe unpurified residue was dissolved in 2 mL methanol at 40° C
6. 6
   workup.ADDITIONConcentrated HCl (approx. 30 μL) was added to the solution
7. 7
   workup.STIRRINGstirring
8. 8
   workup.WAITcontinued for 1 hr
9. 9
   SonstigeAt the completion of the reaction
10. 10
    Waschenwashed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each)
11. 11
    TrocknenThe remaining organics were dried over anhydrous sodium sulfate
12. 12
    Filtrationfiltered
13. 13
    Einengenconcentrated in vacuo
14. 14
    SonstigePurification
15. 15
    Waschenby silica gel chromatography (gradient elution 30→70% EtOAc/Heptane)

Vorschrift

Racemic lipoic acid (100 mg, 500 μmol) and CDI (87 mg, 540 μmol) was taken up and stirred in THF (1.1 mL) at 23° C. After 45 min, the yellow solution was added dropwise to a suspension of the hydrochloride salt of 2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine (150 mg, 450 μmol), in THF (1.1 mL) containing DiPEA (90 μL, 540 μmol). After stirring for an additional 3.5 hrs, the mixture was diluted in EtOAc (40 mL), washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each). The remaining organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The unpurified residue was dissolved in 2 mL methanol at 40° C. Concentrated HCl (approx. 30 μL) was added to the solution and stirring continued for 1 hr. At the completion of the reaction, the mixture was diluted in EtOAc (40 mL), washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each). The remaining organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient elution 30→70% EtOAc/Heptane) afforded the desired chroman amide as a colorless oil, 140 mg. 1H NMR (CDCl3, 400 MHz) 6.05 (m, 1H), 3.55 (m, 1H), 3.30 (q, 2H), 3.20-3.05 (m, 2H), 2.81 (t, 2H), 2.63 (t, 2H), 2.42 (m, 1H), 2.20 (m, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 1.90 (m, 1H), 1.75 (t, 2H), 1.70-1.40 (m, 6H), 1.25 (s, 6H) ppm. CAN-mediated oxidation of the intermediate amide using the procedure described above produced 5-(1,2-dithiolan-3-yl)-N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)pentanamide as a yellow oil that was purified by silica gel chromatography (gradient elution 30→70% EtOAc/Heptane). 1H NMR (CDCl3, 400 MHz) 5.88 (m, 1H), 3.54 (m, 1H), 3.30 (m, 2H), 3.16-3.08 (m, 2H), 2.67 (m, 4H), 2.43 (m, 1H), 2.14 (t, 2H), 1.95 (s, 6H), 1.88 (m, 1H), 1.73-1.58 (m, 4H), 1.44 (m, 3H), 1.26 (s, 6H) ppm.

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