Ethyl 1-(4-bromo-2-iodobenzyl)-4-(trifluoromethyl)cyclohexanecarboxylate → 6'-Bromo-4-(trifluoromethyl)spiro[cyclohexane-1,2'-inden]-1'(3'H)-one

HRID 539308Notes

Reaction equation

HRID 539308 reaction equation
[Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2([C:17](OCC)=[O:18])[CH2:12][CH2:11][CH:10]([C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:8]2)=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.[Cl-].[Li+]>C1COCC1>[Br:1][C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([CH2:12][CH2:11][CH:10]([C:13]([F:15])([F:14])[F:16])[CH2:9][CH2:8]3)[C:17]2=[O:18])=[CH:4][CH:3]=1

Participants

4

Reactant 2

HCID 67979570Ethyl 1-(4-bromo-2-iodobenzyl)-4-(trifluoromethyl)cyclohexanecarboxylate2×HCID 178461733HCID 178461733, compound

Product 1

HCID 679795566'-Bromo-4-(trifluoromethyl)spiro[cyclohexane-1,2'-inden]-1'(3'H)-oneYield 52.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

Ethyl 1-(4-bromo-2-iodobenzyl)-4-(trifluoromethyl)cyclohexanecarboxylate (Intermediate 77, 2.41 g, 4.64 mmol) was dissolved in THF (40 mL). The atmosphere was exchanged to argon, and the solution was cooled to −78° C. Isopropylmagnesium chloride—lithium chloride (1.3 M in THF) (2.86 mL, 3.71 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for min. The reaction mixture left to warm up to r.t., while stirred for 30 min. The reaction mixture was quenched with sat. NH4Cl. Brine was added, and the phases were separated. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative chromatography (XBridge C18 (10 μm, 50×250 mm) column with a gradient of 50-100% MeCN) in (95% 0.05M NH4OAc in MilliQ water and 5% MeCN) over 15 min at a flow rate of 100 mL/min). The purification provided the title compound (0.849 g, 52% yield): 1H NMR (400 MHz, CDCl3) δ ppm 1.51-1.61 (m, 3 H) 1.75-1.84 (m, 2 H) 1.97 (m, 2 H) 2.18 (m, 2 H) 2.90 (s, 2 H) 7.29 (dd, 1 H) 7.69 (dd, 1 H) 7.84 (d, 1 H); MS (ES+) 346 [M+H]+.

Workup

  1. waitThe reaction mixture left
  2. temperatureto warm up to r.t.
  3. stirringwhile stirred for 30 min
  4. customThe reaction mixture was quenched with sat. NH4Cl
  5. additionBrine was added
  6. customthe phases were separated
  7. washThe organic layer was washed with brine
  8. dry with materialdried over MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe residue was purified by preparative chromatography (XBridge C18 (10 μm, 50×250 mm) column with a gradient of 50-100% MeCN) in (95% 0.05M NH4OAc in MilliQ water and 5% MeCN) over 15 min at a flow rate of 100 mL/min)
  12. customThe purification

Sources & evidence

ORD record
ord-020657a28c4d4f0880d5b33c03654270
Source dataset
uspto-grants-2014_10
Patent number
US08865911B2

Reaction notes

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