تفاعل #12052

معادلة التفاعل

(4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester

(4R,9aR)-6-(2-hydroxy-ethoxymethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester

intermediate b

(4R,9aR)-6-(2-hydroxy-ethoxymethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester

n-butyllithium

acetaldehyde

→

(4R,9aR)-6-(1-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester

المذيبات

THF

THF

ظروف التفاعل

المعالجة

1. 1
   workup.STIRRINGThe solution was stirred for a further 2 hours
2. 2
   درجة الحرارةto warm to room temperature slowly
3. 3
   workup.STIRRINGstirred for a further 4.5 hours
4. 4
   أخرىThe reaction was quenched with aqueous ammonium chloride (20 ml)
5. 5
   workup.ADDITIONdiluted with ethyl acetate
6. 6
   أخرىthe phases separated
7. 7
   غسيلThe organics were washed successively with water and brine
8. 8
   تجفيفdried (MgSO4)
9. 9
   تركيزconcentrated in vacuo
10. 10
    أخرىThe residue was purified by column chromatography [SiO2; isohexane-ethyl acetate (3:2)]

الإجراء التجريبي

To a stirred solution of (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) (2 g) in THF (24 ml) at −78° C. was added n-butyllithium (2.72 ml, 2.5 M in hexanes) dropwise. The solution was stirred at −78° C. for 45 mins and acetaldehyde (604 μl) in THF (2 ml) was added dropwise. The solution was stirred for a further 2 hours, allowed to warm to room temperature slowly and stirred for a further 4.5 hours. The reaction was quenched with aqueous ammonium chloride (20 ml), diluted with ethyl acetate and the phases separated. The organics were washed successively with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography [SiO2; isohexane-ethyl acetate (3:2)] to afford (4R,9aR)-6-(1-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (742 mg) as a yellow oil: 1H NMR (400 MHz, CDCl3) 7.16 (1H, d, J 7 Hz), 6.35 (1H, d, J 7 Hz), 4.37–4.31 (1H, br s), 4.31–4.19 (1H, br s), 4.09–3.95 (1H, m), 3.95–3.85 (1H, m), 3.13–2.94 (2H, m), 2.79–2.55 (1H, br s), 2.54 (1H, dd, J 6 and 16 Hz), 1.48 (9H, s), 1.44 (3H, d, J 6.5 Hz), 1.25 (1.5H, R epimer, d, J 6.5 Hz) and 1.24 (1.5H, S epimer, d, J 6.5 HZ); MS (ES) 334.3 (MH+).

المصدر