Reaction #1702106

Reaction equation

(1S)-4-Methyl-cyclohex-3-ene-1-carboxylic acid chloride

5-(3,3-dimethyl-but-1-ynyl)-3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester

EtOAc

EtOAc

→

5-(3,3-dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester

Yield 56.0%

Solvents

dichloroethane

—

hexanes

—

hexanes

Conditions

Workup

1. 1
   Othersealed with
2. 2
   Othera cap
3. 3
   Temperaturethe temperature was increased to 90° C.
4. 4
   TemperatureThe reaction mixture was further heated to 100° C.
5. 5
   workup.STIRRINGstirred 24 h
6. 6
   Otherpartitioned between water and ethyl acetate:hexanes (1:1)
7. 7
   OtherThe layers were separated
8. 8
   Extractionthe aqueous layer was extracted again with ethyl acetate:hexanes (1:1)
9. 9
   DryingThe combined organic layers were dried over sodium sulfate
10. 10
    Filtrationfiltered
11. 11
    Concentrationconcentrated

Procedure

(1S)-4-Methyl-cyclohex-3-ene-1-carboxylic acid chloride (1.8 mmol), 5-(3,3-dimethyl-but-1-ynyl)-3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester (336 mg, 0.89 mmol) and DMAP (217 mg, 1.8 mmol) were dissolved in dichloroethane (2.2 mL), sealed with a cap and heated to 80° C. After 2 h, the temperature was increased to 90° C., and the solution was stirred 16 h. The reaction mixture was further heated to 100° C., stirred 24 h and partitioned between water and ethyl acetate:hexanes (1:1). The layers were separated and the aqueous layer was extracted again with ethyl acetate:hexanes (1:1). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Flash chromatography (5% EtOAc:hexanes 5 min then 5-40% EtOAc:hexanes, 20 min, 24 g column) afforded 250 mg (56% yield of the desired 5-(3,3-dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as a white foam.

Source