Reaction #1702100

Reaction equation

[5-(3,3-Dimethyl-but-1-ynyl)-thiophen-3-yl]-(1,4-dioxa-spiro[4.5]dec-8-yl)-amine

diisopropylethylamine

(COCl)2

(1S,6S)-4,6-dimethyl-cyclohex-3-ene-carboxylic acid

→

(1S,6S)-4,6-dimethyl-cyclohex-3-ene-carboxylic acid [5-(3,3-dimethyl-but-1-ynyl)-thiophen-3-yl]-(1,4-dioxa-spiro[4.5]dec-8-yl)-amide

Yield 92.3%

Solvents

1,2-dichloroethane

CH2Cl2

DMF

CH2Cl2

Conditions

Workup

1. 1
   Concentrationconcentrated
2. 2
   Concentrationconcentrated
3. 3
   TemperatureThe solution was warmed to room temperature
4. 4
   workup.STIRRINGstirred overnight
5. 5
   Washtwice washed with saturated NH4Cl(aq)
6. 6
   Dryingdried over MgSO4
7. 7
   Filtrationfiltered
8. 8
   Concentrationconcentrated
9. 9
   Otherpurified by silica gel column chromatography
10. 10
    Washeluting with a mixture of 0-75% EtOAc/hexanes

Procedure

(1S,6S)-4,6-dimethyl-cyclohex-3-ene-carboxylic acid (3.04 g, 19.7 mmol) was dissolved in CH2Cl2 (30 mL) and DMF (20 μL) was added. The solution was cooled to 0° C. and (COCl)2 (3.7 mL, 39 mmol) was added slowly. The reaction was stirred in an ice bath for 2 hours and then concentrated. The residue was taken up in hexanes and concentrated; this hexanes coevaporation was repeated once more. To the residue was added [5-(3,3-Dimethyl-but-1-ynyl)-thiophen-3-yl]-(1,4-dioxa-spiro[4.5]dec-8-yl)-amine (4.16 g, 13 mmol), diisopropylethylamine (4.5 mL, 26 mmol), and 1,2-dichloroethane (40 mL) at 0° C. The solution was warmed to room temperature and stirred overnight. The reaction was diluted with CH2Cl2, twice washed with saturated NH4Cl(aq), dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography, eluting with a mixture of 0-75% EtOAc/hexanes, to give (1S,6S)-4,6-dimethyl-cyclohex-3-ene-carboxylic acid [5-(3,3-dimethyl-but-1-ynyl)-thiophen-3-yl]-(1,4-dioxa-spiro[4.5]dec-8-yl)-amide (5.6 g, 12 mmol) as a single isomer.

Source