反应详情

A 2-L, 3-neck, rb flask equipped with a mechanical overhead stirrer, a 250-mL addition funnel, and a thermocouple w/N2-inlet adapter was charged with thieno[3,2-b]pyridin-7-ol (144 g, 952 mmol), chloroform (700 mL) and anhydrous N,N-dimethylformamide (100 ml, 1297 mmol). The heterogeneous mixture was cooled in an ice bath with stirring, then oxalyl dichloride (166 ml, 1905 mmol) was added dropwise via the addition funnel. Towards the end of the addition, the exotherm had diminished so the remaining reagent was added more quickly, which resulted in rapid off-gassing and the eruption of a portion of the contents out of the vessel. Upon complete addition, the mixture was allowed to stir out for 2 h, at which point LC-MS analysis indicated only about 10% conversion to the desired product (71556-13-A). The ice bath was removed, and the mixture was heated to reflux with a mantle. The heterogeneous mixture quickly turned homogeneous upon reaching temperature, and LC-MS indicated complete conversion after 1 h @ reflux (71556-13-B). After standing at ambient temp over the weekend, an orange solid had formed from the dark brown supernate. The mixture was cooled in an ice bath, then diluted with MTBE (800 mL), resulting in the exothermic precipitation of copious amounts of a dense, mustard-brown solid. The solid was isolated by vacuum filtration and washed with MTBE until the filtrate was colorless to yield the solid and a cloudy, bright orange filtrate. The solid product was then carefully partitioned between DCM (1 L) and sat'd aq. NaHCO3 (1 L). The phases were mixed and the light brown aqueous layer was back extracted with DCM (500 mL). The combined organic layers were washed with sat'd brine, then dried over anhydrous Na2SO4. MTBE (500 mL) was added, then concentrated by about 200 mL, then hexane (500 mL) was added to form a dark brown precipitate. The mixture was further concentrated by 100 mL, then cooled in an ice bath. The mixture was then filtered and washed with hexane/MTBE (200 mL). The filtrate was then concentrated to dryness to yield the title compound as a light brown oil that crystallized to a dark rust colored, oily solid (97.7 g, 60.5% yield).

1. temperatureThe heterogeneous mixture was cooled in an ice bath
2. additionTowards the end of the addition
3. additionwas added more quickly
4. customwhich resulted in rapid off-gassing and the eruption of a portion of the contents out of the vessel
5. additionUpon complete addition
6. stirringto stir out for 2 h, at which point LC-MS analysis
7. customThe ice bath was removed
8. temperaturethe mixture was heated
9. temperatureto reflux with a mantle
10. customafter 1 h
11. temperature@ reflux (71556-13-B)
12. customAfter standing at ambient temp over the weekend
13. customan orange solid had formed from the dark brown supernate
14. temperatureThe mixture was cooled in an ice bath
15. customresulting in the exothermic precipitation of copious amounts of a dense, mustard-brown solid
16. customThe solid was isolated by vacuum filtration
17. washwashed with MTBE until the filtrate
18. customto yield the solid
19. customThe solid product was then carefully partitioned between DCM (1 L)
20. additionThe phases were mixed
21. extractionthe light brown aqueous layer was back extracted with DCM (500 mL)
22. washThe combined organic layers were washed with sat'd brine
23. dry with materialdried over anhydrous Na2SO4
24. additionMTBE (500 mL) was added
25. concentrationconcentrated by about 200 mL
26. additionhexane (500 mL) was added
27. customto form a dark brown precipitate
28. concentrationThe mixture was further concentrated by 100 mL
29. temperaturecooled in an ice bath
30. filtrationThe mixture was then filtered
31. washwashed with hexane/MTBE (200 mL)
32. concentrationThe filtrate was then concentrated to dryness