Reaktion #498462

Reaktionsgleichung

(S)-1,2,3,6-tetrahydro-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]pyridine

THF

n-butyl lithium

THF

HCl

→

15

Ausbeute 70.0%

(−)-(1R,4S,5S)-5-[3-(1-methylethoxy)phenyl]-2,4-di-methyl-2-azabicyclo[3.3.1]nonan-7-one

Ausbeute 70.0%

Reaktionsbedingungen

Aufarbeitung

1. 1
   Temperaturis maintained
2. 2
   workup.ADDITIONfollowed by an addition of 1.1 eq
3. 3
   workup.STIRRINGby stirring for 2 h
4. 4
   Sonstigeshould be kept below −30° C. during cannulation
5. 5
   Extraktionextracted twice with ethyl ether
6. 6
   workup.WAITto stand for 15 min
7. 7
   workup.ADDITIONfollowed by addition of 50% NAOH to pH 14 and extraction (3×) with ethyl ether
8. 8
   WaschenThe ether is then washed (1N NaOH, H2O)
9. 9
   Sonstigethe solvent removed under vacuum
10. 10
    workup.DISSOLUTIONThe resulting residue of product and water is dissolved in MeOH (30 mL/g)
11. 11
    Sonstigenitrogen is bubbled through the solution for 5 min
12. 12
    workup.ADDITIONTo this is added concentrated HCl (2 mL/g)
13. 13
    Sonstigeto stand at room temperature until the reaction
14. 14
    Waschenelution with 50% (80% CHCl3:18% CH3OH:2% NH4OH) in CHCl3
15. 15
    workup.ADDITIONTo this mixture was added 50% NaOH
16. 16
    Sonstigethe methanol is removed under aspirator vacuum
17. 17
    ExtraktionThe aqueous residue is then extracted several times with 3:1 (methylene chloride:THF)
18. 18
    Waschenwashed twice with water and once with brine
19. 19
    Trocknendried over sodium sulfate
20. 20
    Sonstigeevaporated to an oil
21. 21
    SonstigeThis material was purified by flash chromatography on silica gel using 25-50% (80% CHCl3:18% CH3OH:2% NH4OH) in CHCl3

Vorschrift

To a solution of (S)-1,2,3,6-tetrahydro-1,3-dimethyl-4-[3-(1-methylethoxy)phenyl]pyridine (14) (1 eq) dissolved in THF (20 mL/g) and cooled to −10° C. was added n-butyl lithium (1.6M in hexanes) slowly until a red color is maintained followed by an addition of 1.1 eq. This material is stirred for 1 h at 10° C. and then cannulated quickly into a solution of Okahara's reagent (distilled to high purity) in THF (15 mL/g, 1.1 eq) at −78° C. followed by stirring for 2 h. The temperature should be kept below −30° C. during cannulation. This material is then poured into 2N HCl and extracted twice with ethyl ether. The aqueous layer is allowed to stand for 15 min followed by addition of 50% NAOH to pH 14 and extraction (3×) with ethyl ether. The ether is then washed (1N NaOH, H2O) and the solvent removed under vacuum. The resulting residue of product and water is dissolved in MeOH (30 mL/g) and nitrogen is bubbled through the solution for 5 min. To this is added concentrated HCl (2 mL/g), and the mixture is allowed to stand at room temperature until the reaction is complete as indicated by TLC (TLC condition: SiO2; elution with 50% (80% CHCl3:18% CH3OH:2% NH4OH) in CHCl3. Detection: 5% phosphomolybdic acid in ethanol. To this mixture was added 50% NaOH to adjust the pH to ˜10 and the methanol is removed under aspirator vacuum. The aqueous residue is then extracted several times with 3:1 (methylene chloride:THF). The organic extracts are combined and washed twice with water and once with brine, dried over sodium sulfate and evaporated to an oil. This material was purified by flash chromatography on silica gel using 25-50% (80% CHCl3:18% CH3OH:2% NH4OH) in CHCl3 to give 15 in 70% yield from 14. 1H NMR 7.24 (t,1,J=7.5 Hz), 6.77 (m, 3), 4.55 (m, 1), 3.49 (s, 1), 2.91 (dd,2,J=17 Hz and 16.5 Hz), 2.60 (m, 2), 2.35 (m, 5), 2.05 (m, 3), 1.35 (m, 6), 0.78 (d,3,J=6.8 Hz).

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