tert-Butyl acetate → (2-Chloro-5-methyl-pyridin-4-yl)-acetic acid tert-butyl ester

Temperature

-78 °C

Hexamethyl disilazane (1.33 g, 8.23 mmol) is dissolved in dry toluene (15 ml) under an atmosphere of argon. After thoroughly purging the solvent with argon, the solution is cooled to −78° C., and n-BuLi (5.1 ml of a 1.6 M solution in hexanes, 8.23 mmol) is added. The mixture is stirred for 15 minutes at −78° C. and for 15 minutes at rt, whereupon a clear solution is obtained. Palladium dibenzylideneacetone (Pd2(dba)3, 151 mg, 0.16 mmol) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (136 mg, 0.35 mmol) are added. The mixture is stirred for 10 minutes at RT, then it is cooled to −10° C. Acetic acid tert-butyl ester (924 mg, 7.96 mmol) is slowly added heat. After 10 minutes at −10° C., 2,4-dichloro-5-methyl-pyridine (889 mg, 5.49 mmol) is added in one portion. The reaction mixture is allowed to warm to RT. After 1 h, TLC analysis indicated complete consumption of starting materials. The reaction mixture is diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. The organic layer is separated, washed with brine, dried over Na2SO4, and the solvent is evaporated. The residue is purified by FCC (hexanes/EtOAc, gradient from 100:0 to 90:10) to afford the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.45 (s, 9H), 2.26 (s, 3H), 3.52 (s, 2H), 7.18 (s, 1H), 8.18 (s, 1H). ES+−MS: 242.2, 244.2 (Cl) [M+H]+.

1. customAfter thoroughly purging the solvent with argon
2. additionn-BuLi (5.1 ml of a 1.6 M solution in hexanes, 8.23 mmol) is added
3. customis obtained
4. stirringThe mixture is stirred for 10 minutes at RT
5. temperatureit is cooled to −10° C
6. temperatureheat
7. waitAfter 10 minutes at −10° C.
8. temperatureto warm to RT
9. waitAfter 1 h
10. customconsumption of starting materials
11. additionThe reaction mixture is diluted with EtOAc
12. additionpoured into a saturated aqueous NH4Cl solution
13. customThe organic layer is separated
14. washwashed with brine
15. dry with materialdried over Na2SO4
16. customthe solvent is evaporated
17. customThe residue is purified by FCC (hexanes/EtOAc, gradient from 100:0 to 90:10)

ORD record

ord-8ddd20e455b54c3fa103aa47abc6a725

Source dataset

uspto-grants-2010_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07648989B2