Hexachloroethane → Tert-butyl 8-chloro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carboxylate

HRID 1405363Notes

Reaction equation

HRID 1405363 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:6]=12.[Li]CCCC.[Cl:33]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:33][C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:6]=12

Participants

5

Reactant 3

HCID 6214HexachloroethaneHCID 68153220Tert-butyl 8-bromo-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carboxylateHCID 178418339Butyllithium

Product 1

HCID 68153735Tert-butyl 8-chloro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carboxylateYield 53%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of tert-butyl 8-bromo-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (5.00 g, 11.1 mmol) in anhydrous THF (125 mL) at −78° C. was added nBuLi (8.84 mL of 2.5 M, 22.1 mmol) slowly. The reaction mixture was allowed to stir at −78 for 20 minutes before 1,1,1,2,2,2-hexachloroethane (5.36 g, 22.7 mmol) was added dropwise as a solution in THF (12 mL). The reaction mixture was allowed to slowly warm to room temperature and was stirred overnight. The reaction mixture was quenched with the addition of saturated aqueous ammonium chloride (100 mL). The volatiles were removed under reduced pressure to half volume. The remaining aqueous suspension was extracted with EtOAc (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a thick brown oil. The crude product was purified by silica gel column chromatography: 10-20% EtOAc/hexane gradient to provide tert-butyl 8-chloro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (2.40 g, 53%) as a yellow oil that crystallized upon standing. ESI-MS m/z calc. 407.2, found 407.9 (M+1)+; Retention time: 1.70 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 6.47 (s, 1H), 3.97 (t, J=5.5 Hz, 4H), 3.28 (s, 2H), 3.13 (s, 2H), 2.51-2.28 (m, 5H), 1.93 (d, J=13.7 Hz, 2H), 1.47 (d, J=9.5 Hz, 9H).

Workup

  1. customThe reaction mixture was quenched with the addition of saturated aqueous ammonium chloride (100 mL)
  2. customThe volatiles were removed under reduced pressure to half volume
  3. extractionThe remaining aqueous suspension was extracted with EtOAc (2×100 mL)
  4. dry with materialThe combined organic layers were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customto afford a thick brown oil
  8. customThe crude product was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-0150d5bbdae84d218fae54538232023c
Source dataset
uspto-grants-2014_12
Patent number
US08916565B2

Reaction notes

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