Reaction #1702099

Reaction equation

5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(ethoxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid

TMSI

2,6-lutidine

→

5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(hydroxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid

Yield 36.3%

Solvents

acetonitrile

Conditions

Workup

1. 1
   TemperatureThis solution was cooled in an ice bath
2. 2
   Othersome precipitate was formed
3. 3
   Otherresulting in a clear solution
4. 4
   OtherThe ice bath was removed
5. 5
   workup.ADDITIONAdditional TMSI (50 μL) and 2,6-lutidine (50 μL) were added
6. 6
   workup.WAITAfter 45 minutes the reaction was determined by LC/MS
7. 7
   TemperatureThe reaction was cooled in an ice bath
8. 8
   workup.ADDITIONadditional 2,6-lutidine (100 μL) was added
9. 9
   TemperatureThe reaction was warmed to room temperature
10. 10
    Concentrationconcentrated under vacuum

Procedure

5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(ethoxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (108 mg, 0.225 mmol) was dissolved in acetonitrile (3 mL). This solution was cooled in an ice bath and TMSI (160 μL, 1.12 mmol) was added dropwise. The reaction turned yellow and some precipitate was formed. After approximately 1 minute 2,6-lutidine (156 μL, 1.35 mmol) was added, resulting in a clear solution. The ice bath was removed and the reaction was stirred at room temperature for 2 hours. Additional TMSI (50 μL) and 2,6-lutidine (50 μL) were added. After 45 minutes the reaction was determined by LC/MS to be complete. The reaction was cooled in an ice bath and additional 2,6-lutidine (100 μL) was added, followed by MeOH (2 mL). The reaction was warmed to room temperature and concentrated under vacuum. 5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(hydroxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (37 mg, 36%) was isolated from the residue by reverse phase HPLC. MS (m/z): 453.93 [M+H]+; 31P NMR (161.9 MHz, CD3OD): d 49.909.

Source