Nitrogen → Tert-butyl 6-acetyl-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carboxylate

HRID 1405351Notes

Reaction equation

HRID 1405351 reaction equation
Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([CH3:23])[C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.C1(N(C)C2CCCCC2)CCCCC1.N#N.[CH:40]([O:42]CCCC)=[CH2:41].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1>[C:40]([C:2]1[N:6]2[CH2:7][CH2:8][N:9]([CH3:23])[C:10]3([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]3)[C:5]2=[CH:4][CH:3]=1)(=[O:42])[CH3:41]

Participants

7

Reactant 5

HCID 947NitrogenHCID 8108Butyl vinyl etherHCID 24210N-Methyl dicyclohexylamineHCID 83681Tris(1,1-dimethylethyl)phosphineHCID 68153511Tert-butyl 6-bromo-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carboxylate

Product 1

HCID 68153308Tert-butyl 6-acetyl-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-carboxylateYield 37.1%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A solution of tert-butyl 6-bromo-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (2 g, 5.2 mmol) and N-cyclohexyl-N-methyl-cyclohexanamine (1.67 mL, 7.81 mmol) in 1,4-dioxane (8.0 mL) was purged with N2 for 5 minutes. 1-Vinyloxybutane (7.04 mL, 52.04 mmol), Pd(dba)3 (1.078 g, 1.04 mmol) and tri tert-butylphosphane (642.0 μL, 2.60 mmol) were added and the reaction was heated at 80° C. for 5 hours in a pressure vessel. The reaction was filtered through a plug of celite using ethyl acetate. The solvent was evaporated under reduced pressure. The crude product was purified by silica gel chromatography utilizing a gradient of 1-100% ethyl acetate in hexane to yield tert-butyl 6-acetyl-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (672.1 mg, 1.93 mmol, 37%) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 7.04 (d, J=4.1 Hz, 1H), 6.12 (d, J=4.2 Hz, 1H), 4.17 (t, J=6.0 Hz, 2H), 3.83-3.68 (m, 2H), 3.21 (t, J=6.0 Hz, 2H), 3.17-2.91 (m, 2H), 2.31 (s, 3H), 2.24 (s, 3H), 2.07-1.97 (m, 2H), 1.72-1.59 (m, 2H), 1.41 (s, 9H). ESI-MS m/z calc. 347.2, found 348.5 (M+1)+; Retention time: 0.95 minutes (3 minute run).

Workup

  1. filtrationThe reaction was filtered through a plug of celite
  2. customThe solvent was evaporated under reduced pressure
  3. customThe crude product was purified by silica gel chromatography

Sources & evidence

ORD record
ord-4826d69f87fd433f88a8a6cc5fc3fdf6
Source dataset
uspto-grants-2014_12
Patent number
US08916565B2

Reaction notes

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