Cesium carbonate → Tert-butyl 4-(6-chloro-1,5-naphthyridin-3-yl)piperazine-1-carboxylate

HRID 2199897Notes

Reaction equation

HRID 2199897 reaction equation
[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6](I)=[CH:7][N:8]=2)[N:3]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N:16]1[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]1)=[CH:5]2

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 143452tert-Butyl piperazine-1-carboxylateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 866975562-Chloro-7-iodo-1,5-naphthyridine

Product 1

HCID 86697557Tert-butyl 4-(6-chloro-1,5-naphthyridin-3-yl)piperazine-1-carboxylateYield 29.7%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of 2-chloro-7-iodo-1,5-naphthyridine (D-17) (586 mg, 2.02 mmol, 1.0 eq) in 1,4-dioxane (20 mL), tert-butyl piperazine-1-carboxylate (372 mg, 2.00 mmol, 1.0 eq), cesium carbonate (922 mg, 2.83 mmol, 1.4 eq), tris(benzylideneacetone)dipalladium (37 mg, 0.04 mmol, 0.02 eq) and Xantphos (35 mg, 0.06 mmol, 0.03 eq) were added. The mixture was stirred at reflux for 16 h under an argon atmosphere. After the reaction mixture was cooled to RT, it was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (15% ethyl acetate/petroether) to afford the desired product, tert-butyl 4-(6-chloro-1,5-naphthyridin-3-yl)piperazine-1-carboxylate (D-18) (207 mg, 29.4% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3-d6) δ: 8.79 (d, J=2.7 Hz, 1H), 8.16 (d, J=8.7 Hz, 1H), 7.43 (d, J=2.7 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H), 3.64 (m, 4H), 3.34 (m, 4H), 1.49 (s, 9H); EST-MS m/z: 349.13[M+H]+.

Workup

  1. temperatureat reflux for 16 h under an argon atmosphere
  2. extractionextracted with ethyl acetate (3×50 mL)
  3. washThe combined organic layer was washed with brine (50 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationThe filtrate was concentrated in vacuo
  7. customThe resultant residue was purified by silica gel column chromatography (15% ethyl acetate/petroether)

Sources & evidence

ORD record
ord-764f8bf32ddf4b18aa17417e66598a6d
Source dataset
uspto-grants-2016_06
Patent number
US09359352B2

Reaction notes

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