反应详情

温度

-78 °C

The diastereomeric product 21 was obtained by a reaction of the lithium salt of the chiral auxiliary (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine with the bromo derivative 20 using a crucial modification of a procedure reported in the literature [U. Schollkopf, “Enantioselective Synthesis of Non-Proteinogenic Amino Acids via Metallated Bis-Lactim Ethers of 2,5-Diketopiperazines.” Tetrahedron, 39, pp 2085-2091 (1983)]. Briefly, (2R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (4.39 mL, 24.5 mmol) was dissolved in 4 mL of THF (freshly distilled from LiAlH4). The light yellow solution was cooled to −78° C. (dry ice/acetone bath) and stirred for 15 min under argon. A 2.5 M solution of n-butyl lithium (9.79 mL, 24.5 mmol) was added drop wise over a period of 10 min and the mixture was stirred for 20 min at −78° C. In a separate flask CuCN (1.096 g, 12.23 mmol) was stirred with 4 mL of freshly distilled THF at room temperature for 10 min. The white suspension was then cooled to 0° C. (ice bath) and stirred at that temperature for 20 min. The n-BuLi reaction mixture was then transferred to the white suspension of CuCN/THF under argon using a cannula. The resulting yellow suspension turned into a yellow solution within two minutes. The reaction mixture was then stirred at 0° C. for 15 min and cooled to −78° C. After 15 min of stirring at −78° C., a solution of bromomethyl anisole derivative 20 (4.00 g, 12.23 mmol) in 6 mL of freshly distilled THF was added drop wise. The color of the reaction mixture changed to greenish brown. After stirring for a further period of 2 hours at −78° C., the reaction mixture was warmed gradually to room temperature. The reaction mixture was then poured into a saturated solution of NH4Cl and extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to provide an oily compound which was purified by flash column chromatography to yield pure 2,5-Dihydro-3,6-dimethoxy-2-isopropyl-5-(2-iodo-4-methoxybenzyl)-(2R,5S)-pyrazine (21) as a yellow oil (3.95 g, 75%).

1. distillationfreshly distilled from LiAlH4)
2. stirringthe mixture was stirred for 20 min at −78° C
3. temperatureThe white suspension was then cooled to 0° C. (ice bath)
4. stirringstirred at that temperature for 20 min
5. waitThe resulting yellow suspension turned into a yellow solution within two minutes
6. stirringThe reaction mixture was then stirred at 0° C. for 15 min
7. temperaturecooled to −78° C
8. stirringAfter 15 min of stirring at −78° C.
9. stirringAfter stirring for a further period of 2 hours at −78° C.
10. temperaturethe reaction mixture was warmed gradually to room temperature
11. extractionextracted with EtOAc
12. dry with materialThe organic phase was dried over anhydrous Na2SO4
13. filtrationfiltered
14. customevaporated
15. customto provide an oily compound which
16. customwas purified by flash column chromatography