Cesium carbonate → benzyl (1S,5S)-6-(5-cyano-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

HRID 2251452Notes

Reaction equation

HRID 2251452 reaction equation
[C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:25]1[CH:26]=[N:27][CH:28]=[C:29]([C:31]#[N:32])[CH:30]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:31]([C:29]1[CH:30]=[C:25]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]3)[CH:26]=[N:27][CH:28]=1)#[N:32]

Participants

8

Reactant 3

HCID 10796Cesium carbonateHCID 7367935-BromonicotinonitrileHCID 23635906benzyl (1S,5S)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylate

Product 1

HCID 23635910benzyl (1S,5S)-6-(5-cyano-3-pyridinyl)-3,6-diazabicyclo[3.2.0]heptane-3-carboxylateYield 64.3%

Reagents, catalysts & solvents 4

HCID 634876Binap, (A+-)-CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

The product of Example 52D (830 mg, 3.58 mmol) in toluene (20 mL) was treated with Pd2(dba)3 (71.0 mg, 0.072 mmol), BINAP (134 mg, 0.214 mmol), Cs2CO3 (2.32 g, 7.16 mmol) and 3-bromo-5-cyanopyridine (0.98 g, 5.37 mmol). The mixture was heated at 100° C. under N2 for 10 hours and then allowed to cool to room temperature and diluted with ethyl acetate (100 mL). The brown solution was washed with water (2×10 mL) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, EtOAc:hexane, 50:50, Rf 0.3) to provide the title compound (770 mg, 64% yield). 1H NMR (MeOH-d4, 300 MHz) δ 3.2(dd, J=12.9, 4 Hz, 1H), 3.30-3.4 (m, 2H), 3.6(dd, J=8.2, 3 Hz, 1H), 3.96-4.10 (m, 3H), 4.74 (dd, J=6.1, 4.0 Hz, 1H), 5.10 (m, 2H), 7.15 (dd, J=2.7, 1.7 Hz, 1H), 7.25 (m, 3H), 7.35 (m, 2H), 7.96 (d, J=2.7 Hz, 1H), 8.15 (d, J=1.7 Hz, 1H); MS (DCI/NH3) m/z 335 (M+H)+.

Workup

  1. temperatureto cool to room temperature
  2. washThe brown solution was washed with water (2×10 mL)
  3. concentrationconcentrated under reduced pressure
  4. customThe residue was purified by chromatography (SiO2, EtOAc:hexane, 50:50, Rf 0.3)

Sources & evidence

ORD record
ord-5bbc9c7511f24ff59f9114c2455d6015
Source dataset
uspto-grants-2008_01
Patent number
US07319106B2

Reaction notes

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