Bromine → 2-Oxindole-5-carboxylic acid

Indole-5-carboxylic acid 5.00 g (31.0 mmol) solution in ethanol 99% 120 mL and tert-butanol 180 mL in a 1 L RB flask was cooled on ice bath to +5° C. Meanwhile, a solution of lithium bromide 9.0 g (103.6 mmol) in neat acetic acid 60 mL was placed into an addition funnel. Neat bromine 5.0 mL (16.0 g; 100.1 mmol) was then charged to this LiBr solution and the resulting bromine+LiBr solution was dropwise added into the vigorously stirred indolecarboxylic acid solution at +5° C. over a 90 min period. (After a complete addition the addition funnel was then washed with EtOH (2×5 mL) and the washings were added to the reaction mix). At the end of the bromine addition the cooling bath was let to expire and the reaction mix was stirred at +5 to +15° C. bath for 1 hour and at 15° C. for additional 15 min. The reaction mixture was then diluted with additional acetic acid 100 mL. Zn dust 20 g [Aldrich; <10 μM] (306 mmol) was added in one portion (gas evolution) and the mixture was stirred in an open flask on ambient water bath overnight (16 hours). The next day, the precipitated solids were collected by filtration, washed with ethanol and dried by suction. The solid (containing a mix of the product, unreacted Zn metal and Zn salts) was transferred into a large beaker on a hotplate, suspended in boiling methanol (300 mL) and filtered. The extraction with boiling methanol was repeated twice more, to separate the unreacted Zn metal from the product. The combined methanolic filtrates were evaporated to dryness. Separately, the acetic acid+LiBr-containing filtrates from the reaction mix were concentrated to a small volume on rotovap and the produced salt-rich residue was diluted with water 0.6 L and acidified with 6M HCl to about pH=1.5. This mixture was then combined with the evaporation residue obtained from the methanolic filtrates. The solids in the flask were re-suspended by a brief sonication (5 min) and the slurry was cooled down on ice bath, then placed into a freezer (−20° C.) for 4 hours. The precipitated product was collected by filtration, washed with ice-cold water, dried by suction and on highvac. Y=5.23 g (95%) of a light tan solid. 1H-NMR (d6-DMSO, 400 MHz): 12.58 (br s, 1H), 10.72 (s, 1H), 7.82 (dd, 8.3 Hz, 1.6 Hz, 1H), 7.75 (s, 1H), 6.88 (d, 8.3 Hz, 1H), 3.54 (s, 2H)

1. addition(After a complete addition the addition funnel
2. washwas then washed with EtOH (2×5 mL)
3. additionthe washings were added to the reaction
4. additionmix)
5. additionAt the end of the bromine addition the cooling bath
6. additionthe reaction mix
7. waitat 15° C. for additional 15 min
8. additionThe reaction mixture was then diluted with additional acetic acid 100 mL
9. stirringthe mixture was stirred in an open flask on ambient water bath overnight (16 hours)
10. filtrationThe next day, the precipitated solids were collected by filtration
11. washwashed with ethanol
12. customdried by suction
13. additionThe solid (containing
14. additiona mix of the product, unreacted Zn metal and Zn salts)
15. filtrationfiltered
16. extractionThe extraction with boiling methanol
17. customto separate the unreacted Zn metal from the product
18. customThe combined methanolic filtrates were evaporated to dryness
19. additionSeparately, the acetic acid+LiBr-containing filtrates from the reaction
20. additionmix
21. concentrationwere concentrated to a small volume on rotovap
22. additionthe produced salt-rich residue was diluted with water 0.6 L
23. customobtained from the methanolic filtrates
24. customThe solids in the flask were re-suspended by a brief sonication (5 min)
25. temperaturethe slurry was cooled down on ice bath
26. waitplaced into a freezer (−20° C.) for 4 hours
27. filtrationThe precipitated product was collected by filtration
28. washwashed with ice-cold water
29. customdried by suction

ORD record

ord-21039d5a8daf40e384bcabfd253def91

Source dataset

uspto-grants-2015_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09162981B2