1-tert-butyl 2-methyl (2S)-4-methylidenepyrrolidine-1,2-dicarboxylate → 5-Azaspiro[2.4]heptane-5,6-dicarboxylic acid, 1,1-dibroMo-, 5-(1,1-diMethylethyl) 6-Methyl ester, (6S)-

HRID 1424669Notes

Reaction equation

HRID 1424669 reaction equation
[CH2:1]=[C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[Br:18][C:19](Br)([Br:23])C([O-])=O.[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCCl>[Br:18][C:19]1([Br:23])[C:2]2([CH2:3][C@@H:4]([C:14]([O:16][CH3:17])=[O:15])[N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])[CH2:6]2)[CH2:1]1

Participants

5

Reactant 2

HCID 157359851-tert-butyl 2-methyl (2S)-4-methylidenepyrrolidine-1,2-dicarboxylateHCID 23677969Sodium tribromoacetate2×

Product 1

HCID 710145515-Azaspiro[2.4]heptane-5,6-dicarboxylic acid, 1,1-dibroMo-, 5-(1,1-diMethylethyl) 6-Methyl ester, (6S)-Yield 88.4%

Reagents, catalysts & solvents 2

HCID 74236Tetrabutylammonium BromideCatalystHCID 111,2-DichloroethaneSolvent

Conditions

Temperature
70 °C

Procedure

To a mixture of (S)-1-tert-butyl 2-methyl 4-methylenepyrrolidine-1,2-dicarboxylate (6 g, 24.9 mmol) and tetrabutylammonium bromide (161 mg, 0.02 eq) in anhydrous 1,2-dichloroethane (60 mL, 10 volumes) was added sodium tribromoacetate (17.48 g, 2.2 eq). The mixture was degassed and filled with N2 gas. It was heated at 70° C. for 2.5 hrs before additional sodium tribromoacetate (2.4 g, 0.3 eq) was added. The mixture was heated at 70° C. for 40 min. After the completion of the reaction, it was allowed to cool to room temperature and evaporated. The residue was diluted with 30% hexanes in tert-butyl methyl ether (100 mL) and filtered through a pad of celite. The filtrate was washed with water and brine, dried (Na2SO4), filtered and evaporated to dryness. The residue was passed through a silica gel (5.5 wt. volumes) pad with 0-15% tert-butyl methyl ether in hexanes and concentrated to afford the title compound (9.09 g, 88%) as a yellow oil as a mixture of two regioisomers. 1H NMR (500 MHz, CDCl3): 4.63-4.44 (m, 1H), 3.92-3.86 (m, 1H), 3.79 and 3.74 (2 s, 3H), 3.53-3.42 (m, 1H), 2.83-2.35 (m, 1.5H), 1.91-1.70 (m, 2.5H), 1.48 and 1.43 (2 s, 9H). ESI MS m/z (M+H)+ 413.85.

Workup

  1. customThe mixture was degassed
  2. additionfilled with N2 gas
  3. additionwas added
  4. customAfter the completion of the reaction, it
  5. temperatureto cool to room temperature
  6. customevaporated
  7. additionThe residue was diluted with 30% hexanes in tert-butyl methyl ether (100 mL)
  8. filtrationfiltered through a pad of celite
  9. washThe filtrate was washed with water and brine
  10. dry with materialdried (Na2SO4)
  11. filtrationfiltered
  12. customevaporated to dryness
  13. concentrationconcentrated

Sources & evidence

ORD record
ord-6c69c92bcf1542d599f391c0d4c7cd3b
Source dataset
uspto-grants-2015_01
Patent number
US08927739B2

Reaction notes

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