Beta-Lapachone → 5-(acetyloxy)-2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromen-6-yl N-(tert-butoxycarbonyl)glycinate

HRID 1159434Notes

Reaction equation

HRID 1159434 reaction equation
[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]2[C:8](=[O:12])[C:7](=[O:13])[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[C:4]=2[O:3]1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]([OH:38])=O)=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N([CH2:44][CH3:45])CC)C.CN(C([O:53]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OC(=O)C)(=O)C.C(OCC)(=O)C.[Zn].CN(C=O)C>[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]([O:13][C:7]1[C:8]([O:12][C:44](=[O:53])[CH3:45])=[C:9]2[C:4](=[C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=13)[O:3][C:2]([CH3:18])([CH3:1])[CH2:11][CH2:10]2)=[O:38])=[O:33])([CH3:28])([CH3:29])[CH3:30]

Participants

10

Reactant 5

HCID 3885Beta-LapachoneHCID 8471Triethylamine2×HCID 24489Sodium DithioniteHCID 78288N-(tert-butoxycarbonyl)glycineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)

Product 1

HCID 595143795-(acetyloxy)-2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromen-6-yl N-(tert-butoxycarbonyl)glycinateYield 60%

Reagents, catalysts & solvents 4

HCID 23994ZincCatalyst2×HCID 6228DimethylformamideSolventHCID 7918Acetic AnhydrideSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

A mixture of zinc dust (6.0 g, 91.7 mmol), 2,2-dimethyl-3,4-dihydro-2H-benzo[h]chromene-5,6-dione (6.0 g, 24.8 mmol), Na2S2O4 (17.26 g, 99.1 mmol), N-(tert-butoxycarbonyl)glycine (8.77 g, 49.6 mmol), triethylamine (3.1 ml, 22.3 mmol), HBTU (18.79 g, 49.6 mmol), and DMF (100 ml) is stirred for 16 hours at room temperature. To the reaction mixture is then added ethyl acetate (300 ml). The reaction is filtered and the filtrate washed with H2O (4×200 ml). The organic extract is dried with Na2SO4, and concentrated under reduced pressure to yield a residue. The residue is dissolved in acetic anhydride (30 ml), zinc dust (3.0 g, 45.9 mmol) and triethylamine (3.35 ml, 24.0 mmol) are then added. The mixture is heated to 90° C. with vigorous stirring and held at 90° C. for 2 hours, after which it is allowed to cool and the solvent is removed under reduced pressure to yield a second residue. The second residue is dissolved in ethyl acetate (200 ml) and washed with water (2×100 ml). The organic extract is dried with Na2SO4 and concentrated under reduced pressure to yield unrefined product. The unrefined product is purified by flash column chromatography on silica, eluting with 2% ethyl acetate in dichloromethane, to afford product about 60% pure. The product is further purified by crystallization from ethyl acetate/hexane, which gives the desired product as pure white solid (3.2 g, 31%). M.p.=177° C.; 400 MHz 1H NMR (CDCl3) δ: 8.21 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.46 (m, 2H), 5.13 (br. s, 1H), 4.30 (d, J=5.6 Hz, 2H), 2.68 (t, J=6.6 Hz, 2H), 2.38 (s, 3H), 1.87 (t, J=6.6 Hz, 2H), 1.48 (s, 9H), 1.42 (s, 6H); LCMS: 444 [M+H]; Calc. for C24H29NO7: C, 64.94; H, 6.59; N, 3.16; Found C, 64.98; H, 6.51; N, 3.15.

Workup

  1. filtrationThe reaction is filtered
  2. washthe filtrate washed with H2O (4×200 ml)
  3. extractionThe organic extract
  4. dry with materialis dried with Na2SO4
  5. concentrationconcentrated under reduced pressure
  6. customto yield a residue
  7. temperatureThe mixture is heated to 90° C.
  8. stirringwith vigorous stirring
  9. waitheld at 90° C. for 2 hours
  10. temperatureto cool
  11. customthe solvent is removed under reduced pressure
  12. customto yield a second residue
  13. washwashed with water (2×100 ml)
  14. extractionThe organic extract
  15. dry with materialis dried with Na2SO4
  16. concentrationconcentrated under reduced pressure
  17. customto yield unrefined product
  18. customThe unrefined product is purified by flash column chromatography on silica
  19. washeluting with 2% ethyl acetate in dichloromethane

Sources & evidence

ORD record
ord-9aecab900cfe4548abe78451a75a5c23
Source dataset
uspto-grants-2010_10
Patent number
US07812051B2

Reaction notes

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