3,4-dihydro-2H-pyran → 4-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

HRID 334106Notes

Reaction equation

HRID 334106 reaction equation
[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1

Participants

5

Reactant 2

HCID 80803,4-dihydro-2H-pyranHCID 3930374-Chloro-1H-indazole

Product 1

HCID 666979414-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazoleYield 95%

Reagents, catalysts & solvents 2

HCID 466102Benzenesulfonic acid, 4-methyl-, compd. with pyridine (1:1)CatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
45 °C

Procedure

To a 1 L flask with mechanical stirrer was added 4-chloro-1H-indazole (75.0 g, 0.492 mol), pyridinium p-toluenesulfonate (1.24 g, 4.92 mmol), CH2Cl2 (500 ml) and 3,4-dihydro-2H-pyran (98.6 ml, 1.08 mol). With stirring, this mixture was heated to 45° C. for 16 hours. Analysis of reaction mixture shows production of both isomers of product. Cooled reaction to 25° C. and added CH2Cl2 (200 ml). Washed the solution with water (300 ml) and saturated NaHCO3 (250 ml). Dried the organics with MgSO4 and concentrated to dryness. Purified the crude product by dissolving in EtOAc/hexanes (4:6, 1 L) and adding SiO2 (1.2 L). The mixture was filtered and the cake was washed with EtOAc/Hexanes (4:6, 2 L). The organics were concentrated in vacuo to yield 4-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 110.2 g (95%) as an orange solid. Isomer 1: 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=1 Hz, 1H), 7.50 (dd, J=9 Hz, 1 Hz 1H), 7.29 (dd, J=9 Hz, 8 Hz 1H), 7.15 (dd, J=8 Hz, 1 Hz 1H) 5.71 (dd, J=9 Hz, 3 Hz 1H) 4.02 (m, 1H) 3.55 (m, 1H) 2.51 (m, 1H) 2.02 (m, 2H) 1.55 (m, 3H). LCMS (ESI pos) m/e 237 (M+1); Isomer 2: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=1 Hz, 1H), 7.62 (dd, J=9 Hz, 1 Hz 1H), 7.20 (dd, J=9 Hz, 8 Hz 1H), 7.06 (dd, J=8 Hz, 1 Hz 1H) 5.69 (dd, J=9 Hz, 3 Hz 1H) 4.15 (m, 1H) 3.80 (m, 1H) 2.22 (m, 2H) 2.05 (m, 1H) 1.75 (m, 3H). LCMS (ESI pos) m/e 237 (M+1).

Workup

  1. customAnalysis of reaction mixture
  2. temperatureCooled
  3. customreaction to 25° C.
  4. washWashed the solution with water (300 ml) and saturated NaHCO3 (250 ml)
  5. dry with materialDried the organics with MgSO4
  6. concentrationconcentrated to dryness
  7. customPurified the crude product
  8. dissolutionby dissolving in EtOAc/hexanes (4:6, 1 L)
  9. additionadding SiO2 (1.2 L)
  10. filtrationThe mixture was filtered
  11. washthe cake was washed with EtOAc/Hexanes (4:6, 2 L)
  12. concentrationThe organics were concentrated in vacuo

Sources & evidence

ORD record
ord-9cb25e391d9045d9bf101f5ebb5b87fa
Source dataset
uspto-grants-2014_11
Patent number
US08883799B2

Reaction notes

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