Trimethylphosphine → N-(6-Cyano-9-thiophen-3-ylmethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide

HRID 545539Notes

Reaction equation

HRID 545539 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH2:7][C:6]2=1)#[N:2].CP(C)C.[S:26]1[CH:30]=[CH:29][C:28]([CH2:31]O)=[CH:27]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:31][C:28]1[CH:29]=[CH:30][S:26][CH:27]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:7][C:6]2=1)#[N:2]

Participants

6

Reactant 4

HCID 68983TrimethylphosphineHCID 730421,1'-(Azodicarbonyl)dipiperidineHCID 123570Thiophene-3-methanolHCID 57431662N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide

Product 1

HCID 59161311N-(6-Cyano-9-thiophen-3-ylmethyl-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramideYield 11%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Add sequentially to a slurry of N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (Preparation 3) (100 mg, 0.36 mmol) in THF (2 mL) at 0° C.: trimethylphosphine (1.0 M in toluene, 530 μL, 0.53 mmol), 3-thiophenemethanol (61 mg, 50 μL, 0.53 mmol), and 1,1′-(azodicarbonyl)-dipiperidine (ADDP, 134 mg, 0.53 mmol). Warm up to room temperature and stir in a sealed vial for 18 h. Evaporate the reaction solvent and dissolve the residue in EtOAc (5 ML). Add water (2 mL) and load onto a Varian Chem Elut CE1005 solid-phase extraction cartridge (Varian part number 12198006). Elute with EtOAc, collect, and concentrate (about 50 mL). Purify the crude product on silica gel (12 g) eluting with 30-90% EtOAc/hexanes to give the title compound in 11% yield as a colorless oil. MS (ES): m/z 378 (M+1), 376 (M−1); 1H NMR (CDCl3): δ 7.81 (s, 1H), 7.40 (dd, 1H, J=8.4, 1.2 Hz), 7.33 (d, 1H, J=8.4 Hz), 7.30 (m, 1H), 6.86-6.81 (m, 2H), 5.60 (d, 1H, J=7.5 Hz), 5.29 (s, 2H), 4.41 (m, 1H), 3.16 (dd, 1H, J=15.2, 5.1 Hz), 2.90-2.72 (m, 2H), 2.63 (dd, 1H, J=15.4, 7.5 Hz), 2.36 (m, 1H), 2.16 (m, 1H), 2.02 (m, 1H), 1.18 (dd, 7H, J=6.8, 3.7 Hz), 1.18 (dd, 6H, J=6.8, 3.7 Hz).

Workup

  1. customEvaporate the reaction solvent
  2. dissolutiondissolve the residue in EtOAc (5 ML)
  3. extractionAdd water (2 mL) and load onto a Varian Chem Elut CE1005 solid-phase extraction cartridge (Varian part number 12198006)
  4. washElute with EtOAc
  5. customcollect
  6. concentrationconcentrate (about 50 mL)
  7. customPurify the crude product on silica gel (12 g)
  8. washeluting with 30-90% EtOAc/hexanes

Sources & evidence

ORD record
ord-c4f1626c66b44a009908e57443e2eb13
Source dataset
uspto-grants-2011_05
Patent number
US07935722B2

Reaction notes

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