Isobutylene → Ethyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate

HRID 718337Notes

Reaction equation

HRID 718337 reaction equation
[Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][CH2:18]2)=[C:4]([C@H:10]([OH:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[CH3:25][C:26](=[CH2:28])[CH3:27]>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:17]2[CH2:18][CH2:19][C:20]([CH3:23])([CH3:24])[CH2:21][CH2:22]2)=[C:4]([C@H:10]([O:16][C:26]([CH3:28])([CH3:27])[CH3:25])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8]

Participants

4

Reactant 2

HCID 8255Isobutylene2×HCID 118314207Ethyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate

Product 1

HCID 118314215Ethyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetateYield 83%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A stirred ice-cold yellow mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (2.45 g, 6.14 mmol) and 70% HClO4 (1.054 ml, 12.27 mmol) in CH2Cl2 (100 mL) was saturated with isobutylene gas by bubbling through the reaction mixture (10 min). After 2 h, cold bath was removed and the turbid reaction mixture stirred for 22 h at rt. LCMS at this point showed 4:1 product to sm. So, saturated with isobutylene (5 min) at rt and stirred for additional 24 h. Then, neutralized with sat. Na2CO3 (30 mL), organic layer separated and aqueous layer extracted with CH2Cl2 (25 mL). The combined organic layers dried (MgSO4), filtered, concentrated and purified by flash chromatography using 5, 10, 15, 20 and 40% EtOAc/hex to afford (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (2.3074 g, 5.07 mmol, 83% yield) as yellow oil: 1H NMR (500 MHz, CDCl3) δ 6.19 (br. s., 1H), 4.17-4.24 (m, 1H), 4.08-4.14 (m, 1H), 4.04 (dt, J=2.5, 12.1 Hz, 1H), 3.51 (dt, J=2.5, 12.1 Hz, 1H), 2.85-2.91 (m, 1H), 2.64 (s, 3H), 2.57-2.62 (m, 1H), 2.55 (s, 3H), 1.55-1.66 (m, 2H), 1.41-1.46 (m, 1H), 1.32-1.37 (m, 1H), 1.21 (s, 9H), 1.20 (t, J=7.2 Hz, 2H), 1.08 (s, 3H), 1.03 (s, 3H). LCMS (M+H)=457.4. And (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (0.3 g, 0.751 mmol, 12.24% yield) as pale yellow paste: LCMS (M+H)=401.3.

Workup

  1. customby bubbling through the reaction mixture (10 min)
  2. customcold bath was removed
  3. customthe turbid reaction mixture
  4. customThen, neutralized with sat. Na2CO3 (30 mL), organic layer separated
  5. extractionaqueous layer extracted with CH2Cl2 (25 mL)
  6. dry with materialThe combined organic layers dried (MgSO4)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. custompurified by flash chromatography

Sources & evidence

ORD record
ord-d3aa40bca1f54733b311e45ebad002e4
Source dataset
uspto-grants-2015_11
Patent number
US09193720B2

Reaction notes

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