Reaction #1702084

Reaction equation

Methyl 5-(3,3-Dimethyl-but-1-ynyl)-3-[(1-methoxy-1-oxo-1λ5phosphinan-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylate

KHMDS

Trans-4-methylcyclohexanecarbonyl chloride

→

title compound

Yield 6.6%

methyl 5-(3,3-Dimethyl-but-1-ynyl)-3-[(1-methoxy-1-oxo-1 λ5-phosphinan-4-yl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylate

Yield 6.6%

Solvents

THF

Conditions

Workup

1. 1
   workup.STIRRINGstirring
2. 2
   workup.WAITwas continued at −78° C. for a further 5 min
3. 3
   Temperatureto warm to room temperature
4. 4
   TemperatureThe reaction mixture was cooled to 0° C.
5. 5
   Otherquenched with saturated aqueous NH4Cl
6. 6
   Otherpartitioned between water and ethyl acetate
7. 7
   ExtractionThe aqueous phase was extracted with ethyl acetate
8. 8
   WashThe combined organic layers were washed with brine
9. 9
   Dryingdried over magnesium sulfate
10. 10
    Filtrationfiltered
11. 11
    Concentrationconcentrated
12. 12
    OtherThe residue was purified by silica gel column chromatography
13. 13
    Otherfurther purified by HPLC (Gemini column
14. 14
    Otherwater, 5 min
15. 15
    Otherwater, 18 min
16. 16
    Other100% acetonitrile, 6 min
17. 17
    workup.ADDITIONboth solvents containing 0.1% trifluoroacetic acid),

Procedure

Methyl 5-(3,3-Dimethyl-but-1-ynyl)-3-[(1-methoxy-1-oxo-1λ5phosphinan-4-yl)-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylate (420 mg, 1.1 mmol) was dissolved in 2 mL of THF and cooled to −78° C. with a dry ice-acetone bath. A solution of KHMDS (2.6 mL, 0.5 M in toluene) was added slowly, and the mixture was stirred for 5 min. Trans-4-methylcyclohexanecarbonyl chloride (210 mg, 1.3 mmol) was added dropwise and stirring was continued at −78° C. for a further 5 min. The mixture was then allowed to warm to room temperature. The reaction mixture was cooled to 0° C. and quenched with saturated aqueous NH4Cl, and then partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography using 10% MeOH in EtOAc Hexanes as eluent and then further purified by HPLC (Gemini column; 5% acetonitrile:water, 5 min; 5-100% acetonitrile:water, 18 min; 100% acetonitrile, 6 min; both solvents containing 0.1% trifluoroacetic acid), resulting in the title compound (37 mg) and recovered starting material (210 mg). MS (m/z): 508.2 [M+H]+; HPLC retention time: 4.949 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).

Source