反应详情

Potassium hydroxide (aq 10% b/w) (152.3 mL, 272 mmol) was added dropwise over 50 minutes to a 0° C. solution of diethyl cyclobutane-1,1-dicarboxylate (49.52 g, 247 mmol) in 95% ethanol (220 mL). Stirring was continued overnight while allowing the ice bath to warm to r. t. LC/MS after 1 hr indicated a 79.4% complete reaction, ca. 86% after overnight. Additional 10% aq KOH was added (0.11 eq, 15.26 mL, total now 1.21 eq) in small portions over 2 minutes, and stirring was continued for 1 hr. LC/MS after 37 min indicated 96% complete reaction. More 10% aq KOH solution was added in small portions over 2 minutes (0.11 eq, 15.26 mL, total now 1.32 eq), and stirring was continued for 37 minutes. LC/MS after 27 min indicated a complete reaction, with minimal formation of the dicarboxylic acid side product (5.5%). The reaction flask was immersed in an ice bath and acidified by the slow addition of 20% HCl, (ca. 220 mL). Most of the ethanol was removed under high vacuum with minimal heat (Bath less than 50° C.). Brine was added (100 mL), followed by 3 extractions with EtOAc (250 mL each). The combined EtOAc layers were washed with 100 mL of brine, dried over Na2SO4, and concentrated under vacuum to yield the title compound as an oil which after standing under vacuum became a white solid. LC/MS: m/e 173.14 (M+H), 195.12 (M+H+ Na), 155.11 (M+H-18, water). This material was used in the next step without additional purification.

1. temperatureto warm to r
2. waitLC/MS after 1 hr indicated
3. customa 79.4% complete reaction, ca. 86% after overnight
4. stirringstirring
5. waitwas continued for 1 hr
6. waitLC/MS after 37 min indicated
7. custom96% complete reaction
8. stirringstirring
9. waitwas continued for 37 minutes
10. waitLC/MS after 27 min indicated
11. customa complete reaction
12. customThe reaction flask was immersed in an ice bath
13. customMost of the ethanol was removed under high vacuum
14. temperaturewith minimal heat (Bath less than 50° C.)
15. additionBrine was added (100 mL)
16. extractionfollowed by 3 extractions with EtOAc (250 mL each)
17. washThe combined EtOAc layers were washed with 100 mL of brine
18. dry with materialdried over Na2SO4
19. concentrationconcentrated under vacuum