Piperidine → Ethyl (9aS)-4-(4-bromo-2-thienyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizine-3-carboxylate

HRID 458474Notes

Reaction equation

HRID 458474 reaction equation
C(O[C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15]C(C)(C)C)=O)=O)C.[NH2:21]/[C:22](/[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[CH:23]\[C:24]([O:26][CH2:27][CH3:28])=[O:25].[Br:38][C:39]1[CH:40]=[C:41](C=O)[S:42][CH:43]=1.N1CCCCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].CCN(CC)CC>C1(C)C=CC=CC=1.C(Cl)Cl.O>[Br:38][C:39]1[CH:40]=[C:41]([C:4]2[C:5]3[C:13](=[O:15])[N:9]4[C@H:8]([C:6]=3[N:21]=[C:22]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[C:23]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:12][CH2:11][CH2:10]4)[S:42][CH:43]=1

Participants

10

Reactant 6

HCID 8082PiperidineHCID 8471TriethylamineHCID 877924-Bromothiophene-2-carbaldehydeHCID 180504Ceric ammonium nitrateHCID 18441995ethyl (2Z)-3-amino-5-(4-fluorophenyl)-2-pentenoateHCID 57407385(S)-1-Boc-2-(3-ethoxy-3-oxopropanoyl)pyrrolidine

Product 1

HCID 86598181Ethyl (9aS)-4-(4-bromo-2-thienyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizine-3-carboxylateYield 17%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1140TolueneSolventHCID 6344DichloromethaneSolvent

Procedure

tert-Butyl (2S)-2-(3-ethoxy-3-oxopropanoyl)-1-pyrrolidinecarboxylate (0.445 g, 1.00 mmol, 1 equiv), ethyl (2Z)-3-amino-5-(4-fluorophenyl)-2-pentenoate (0.237 g, 1.00 mmol, 1 equiv), 4-bromo-2-thiophenecarboxaldehyde (0.191 g, 1.00 mmol, 1 equiv), and piperidine (0.05 mL, 0.5 mmol, 0.5 equiv) were combined in toluene (2.0 mL). After 2 h at 90° C., the reaction was cooled to ambient temp. CAN (1.64 g, 3.00 mmol, 3 equiv) and H2O (2.0 mL) were added. After 0.5 h the layers were separated. The aqueous portion was extracted with EtOAc (2×4 mL) and the combined organic portions were concentrated to a brown oil. The crude oil was then treated with 4 N HCl in dioxane (2.0 mL). After 1 h, the mixture was concentrated to a brown oil. A CH2Cl2 solution (2.0 mL) of this crude oil was treated with Et3N (0.70 mL, 5.0 mmol, 5 equiv). After 8 h, the mixture was concentrated to a brown oil and radially chromatographed (SiO2, 2 mm plate, 50% hexanes-EtOAc) to provide the title compound as a pale yellow foam (0.088 g, 17%): 1H NMR (CDCl3, 400 MHz) δ 7.40 (d, J=1.5 Hz, 1H), 7.17–7.13 (m, 3H), 6.98–6.93 (m, 2H), 4.69 (dd, J=10.4, 6.2 Hz, 1H), 4.22–4.14 (m, 2H), 3.78–3.71 (m, 1H), 3.43–3.37 (m, 1H), 3.17–3.02 (m, 4H), 2.51–2.44 (m, 1H), 2.37–2.29 (m, 2H), 1.39–1.34 (m, 1H), 1.11 (t, J=7.1 Hz, 3H).

Workup

  1. customAfter 0.5 h the layers were separated
  2. extractionThe aqueous portion was extracted with EtOAc (2×4 mL)
  3. concentrationthe combined organic portions were concentrated to a brown oil
  4. additionThe crude oil was then treated with 4 N HCl in dioxane (2.0 mL)
  5. waitAfter 1 h
  6. concentrationthe mixture was concentrated to a brown oil
  7. waitAfter 8 h
  8. concentrationthe mixture was concentrated to a brown oil
  9. customradially chromatographed (SiO2, 2 mm plate, 50% hexanes-EtOAc)

Sources & evidence

ORD record
ord-4f17f2e8b10c48ddab9fbb02a2bc255d
Source dataset
uspto-grants-2007_03
Patent number
US07189851B2

Reaction notes

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