Piperidine → (E)-2-(2-(4-(4-aminobenzylamino)-3-methoxystyryl)-6-methyl-4H-pyran-4-ylidene)malononitrile

HRID 576454Notes

Reaction equation

HRID 576454 reaction equation
[CH3:1][C:2]1[O:3][C:4]([CH3:13])=[CH:5][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:7]=1.C(OC([N:21]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39]C(=O)OC(C)(C)C)=[CH:35][CH:34]=1)[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=O)=[CH:24][C:23]=1[O:30][CH3:31])=O)(C)(C)C.N1CCCCC1>CCO>[NH2:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][NH:21][C:22]2[CH:27]=[CH:26][C:25](/[CH:28]=[CH:13]/[C:4]3[O:3][C:2]([CH3:1])=[CH:7][C:6](=[C:8]([C:11]#[N:12])[C:9]#[N:10])[CH:5]=3)=[CH:24][C:23]=2[O:30][CH3:31])=[CH:34][CH:35]=1

Participants

5

Reactant 3

HCID 8082PiperidineHCID 1199154-(Dicyanomethylene)-2,6-dimethyl-4H-pyranHCID 86720231Tert-butyl 4-(((tert-butyloxycarbonyl)(4-formyl-2-methoxyphenyl)amino)methyl)phenylcarbamate

Product 1

HCID 76071877(E)-2-(2-(4-(4-aminobenzylamino)-3-methoxystyryl)-6-methyl-4H-pyran-4-ylidene)malononitrile

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 2-(2,6-dimethyl-4H-pyran-4-ylidene) malononitrile (1, 16.5 mg, 96 μmol) and aldehyde 2d (34.9 mg, 76.5 μmol) were dissolved in anhydrous EtOH (0.5 ml) at 65 C. Piperidine (1 μl) was added and the mixture was stirred at 80° C. for 6 hrs. The solvent was removed with a stream of N2 and the crude mixture was purified by reverse phase HPLC using water/acetonitrile 40-100% gradient. Yield: 8.1 mg (17.4%). LCMS: m/z 611 (M+H+), 623 (M+Na+). H-NMR (400 MHz, CD2Cl2): 7.45 (1H, d, J=16 Hz) 7.29 (2H, d, J=12 Hz) 7.17 (2H, d, J=8 Hz) 7.03-7.12 (2H, m) 6.69-6.79 (2H, m) 6.52-6.61 (2H, m) 4.76 (2H, brs) 3.89 (3H, s) 2.43 (3H, s) 1.52, (9H, s) 1.41 (9H, brs). C-NMR (400 MHz, CD2Cl2): 162.54, 159.01, 156.35, 152.56, 137.61, 137.21, 134.39, 133.06, 132.89, 128.82, 120.38, 118.39, 117.99, 115.03, 114.99, 107.37, 106.31, 80.21, 58.97, 55.49, 29.68, 28.00, 27.93, 19.75. The purified product (8.1 mg) was treated with a 4N HCl solution in dioxane (4 N, 0.65 ml) for 3 hrs. The mixture was diluted with hexanes, the precipitate centrifuged, re-suspended and washed with hexanes, then dried under vacuum. LCMS ESI+ m/z: 411 (M+H+). H-NMR (400 MHz, DMSO-D6) 7.22-7.28 (5H, m) 6.83-6.89 (2H, m) 6.65 (1H, d, J=16 Hz) 6.54 (1H, d, J=16 Hz) 5.54 91H, s) 5.32 (1H, s) 4.22-4.38 (2H, brs) 3.92 (3H, s) 2.39 (3H, s).

Workup

  1. customThe solvent was removed with a stream of N2
  2. customthe crude mixture was purified by reverse phase
  3. additionThe purified product (8.1 mg) was treated with a 4N HCl solution in dioxane (4 N, 0.65 ml) for 3 hrs
  4. additionThe mixture was diluted with hexanes
  5. washwashed with hexanes
  6. customdried under vacuum

Sources & evidence

ORD record
ord-ad0f5ca75362458b9f4a7a8cba96c5e6
Source dataset
uspto-grants-2015_05
Patent number
US09040019B2

Reaction notes

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