Chemical Properties
clear colorless liquid
Uses
Ethyl 2-Bromoisovalerate (cas# 609-12-1) is a compound useful in organic synthesis.
Synthesis
A. General procedure for the synthesis of ethyl 2-bromoisovalerate from ethanol and 2-bromo-3-methylbutyric acid (CAS: 10323-40-7):
1. 2-Bromo-3-methylbutyric acid (3 g, 16.5 mmol) was dissolved in ethanol (200 ml) and concentrated sulfuric acid (4 ml) was added.
2. The reaction was carried out under reflux conditions for 36 hours, after which the reaction mixture was cooled to room temperature and neutralized with saturated aqueous sodium carbonate solution.
3. After distillation to remove ethanol, the reaction mixture was extracted with dichloromethane (100 ml). The organic phase was dried with magnesium sulfate and the solvent was evaporated to give ethyl 2-bromo-3-methylbutyrate (1.91 g, 55% yield).
4. Zinc powder (31.5 g, 0.48 mol) was suspended in tetrahydrofuran (300 ml) and heated to reflux.
5. A small amount of ethyl 2-bromo-3-methylbutyrate was added to initiate the reaction and reflux was continued for 45 min.
6. 3,5-dimethylphenylacetonitrile (13.2 g, 91 mmol) was added under magnetic stirring, followed by dropwise addition of the remaining ethyl 2-bromo-3-methylbutyrate (total 19.1 g, 91 mmol).
7. After maintaining reflux for 15 min, the reaction mixture was cooled and tetrahydrofuran (500 ml) and 50% aqueous potassium carbonate (100 ml) were added.
8. After vigorous stirring for 45 min, the organic phase was separated and the aqueous phase was washed with tetrahydrofuran (2 x 100 ml).
9. The combined organic phases were treated with 10% aqueous hydrochloric acid (300 ml) for 45 minutes.
10. After removal of tetrahydrofuran by decompression distillation, the residue was washed with dichloromethane (300 ml), the organic phase was washed with saturated sodium bicarbonate solution (100 ml), dried over magnesium sulfate and concentrated.
11. The residue was purified by distillation (134 °C, 10^-1 mmHg) to afford ethyl 3-methyl-2-(3,5-dimethylphenylacetyl)butanoate (13.2 g, 52% yield).
12. Sodium metal (23.8 g, 1.034 mol) was dissolved in anhydrous ethanol (500 ml) to give a clarified solution.
13. Thiourea (54.35 g, 714 mmol) and ethyl 3-methyl-2-(3,5-dimethylphenylacetyl)butyrate (13.14 g, 47.6 mmol) were added to the solution.
14. After refluxing the reaction for 6 hours, it was concentrated under vacuum at 40-50 °C.
15. Concentrated hydrochloric acid (100 ml) was added to the residue and the solution was adjusted to pH 4 with acetic acid.
16. The obtained 6-(3,5-dimethylbenzyl)-5-isopropyl-2-thiouracil was dissolved in 10% aqueous chloroacetic acid (200 ml), refluxed for 24 hrs and then cooled to room temperature and the precipitate was isolated by filtration.
17. The precipitate was washed with cold ethanol followed by ether and dried under vacuum at 40 °C to give 6-(3,5-dimethylbenzyl)-5-isopropyluracil (7 g, 54% yield) with a melting point of 213-214 °C.
References
[1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 41, p. 7574 - 7578
[2] Chemical and Pharmaceutical Bulletin, 1982, vol. 30, # 9, p. 3160 - 3166
[3] Journal of Medicinal Chemistry, 1994, vol. 37, # 8, p. 1177 - 1188
[4] Patent: US6911450, 2005, B1. Location in patent: Page/Page column 15-16
[5] Journal of the American Chemical Society, 1954, vol. 76, p. 1137,1140
