Dichloromethane → HCID 70913338, compound

HRID 2208810Notes

Reaction equation

HRID 2208810 reaction equation
[Si](Cl)(C)(C)C.BrCCBr.[C:10]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].Br[C:23]1[CH:24]=[C:25]([N:34]([CH2:41][CH3:42])[CH:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:26]([CH3:33])=[C:27]([CH:32]=1)[C:28]([O:30][CH3:31])=[O:29].C(Cl)Cl.[NH4+].[Cl-]>CC(N(C)C)=O.[Zn].[Cu]I>[CH2:41]([N:34]([CH:35]1[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1)[C:25]1[CH:24]=[C:23]([CH:19]2[CH2:20][N:17]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:18]2)[CH:32]=[C:27]([C:28]([O:30][CH3:31])=[O:29])[C:26]=1[CH3:33])[CH3:42]

Participants

10

Reactant 6

HCID 6344DichloromethaneHCID 6397ChlorotrimethylsilaneHCID 78391,2-DibromoethaneHCID 25517Ammonium ChlorideHCID 11000522Tert-butyl 3-iodoazetidine-1-carboxylateHCID 70872485methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate

Product 1

HCID 70913338HCID 70913338, compoundYield 63.6%

Reagents, catalysts & solvents 3

HCID 23994ZincCatalystHCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 31374DimethylacetamideSolvent3×

Conditions

Temperature
65 °C

Procedure

To a dry flask was added zinc dust (40 mg, 0.61 mmol) followed by anhydrous DMA (2 ml) and the vessel was flushed with nitrogen whilst stirring vigorously and heating to 65° C. TMS-Cl (9 μl, 0.07 mmol) and 1,2-dibromoethane (6 μl, 0.07 mmol) were added and the reaction was stirred at 65° C. for 30 mins, followed by the dropwise addition of N-Boc-3-iodoazetidine (133 mg, 0.47 mmol) as a solution in anhydrous DMA (1 ml). The reaction was then cooled to room temperature and methyl 5-bromo-3-[ethyl(oxan-4-yl)amino]-2-methylbenzoate (100 mg, 0.28 mmol) was added as a solution in anhydrous DMA (2 ml). The resulting solution was degassed with nitrogen for 5 mins after which Pd(dppf)Cl2.DCM (7 mg, 0.01 mmol) and copper (I) iodide (3 mg, 0.02 mmol) were added as solids. The reaction was heated to 80° C. for 16 h and then cooled to room temperature followed by the addition of saturated NH4Cl solution (50 ml). The aqueous phase was extracted with EtOAc (3×100 ml), and then the combined organic phases were washed with brine (2×50 ml), dried with Na2SO4, filtered and evaporated. The residue was purified over a 5 g Isolute column using 10-30% EtOAc in heptane as the eluent to afford the title compound as a colourless oil (77 mg, 62%). LC-MS 98%, 2.19 min (3.5 minute LC-MS method), m/z=433.2, 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J=1.6 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 4.31 (t, J=8.7 Hz, 2H), 3.94 (dd, J=14.4, 5.5 Hz, 4H), 3.89 (s, 3H), 3.77-3.64 (m, 1H), 3.31 (td, J=11.4, 2.7 Hz, 2H), 3.06 (q, J=7.0 Hz, 2H), 2.99-2.87 (m, 1H), 2.46 (s, 3H), 1.65 (ddd, J=11.1, 8.6, 6.0 Hz, 4H), 1.46 (s, 9H), 0.85 (dd, J=13.1, 6.1 Hz, 3H).

Workup

  1. customthe vessel was flushed with nitrogen
  2. stirringthe reaction was stirred at 65° C. for 30 mins
  3. temperatureThe reaction was then cooled to room temperature
  4. customThe resulting solution was degassed with nitrogen for 5 mins after which Pd(dppf)Cl2
  5. temperatureThe reaction was heated to 80° C. for 16 h
  6. temperaturecooled to room temperature
  7. extractionThe aqueous phase was extracted with EtOAc (3×100 ml)
  8. washthe combined organic phases were washed with brine (2×50 ml)
  9. dry with materialdried with Na2SO4
  10. filtrationfiltered
  11. customevaporated
  12. customThe residue was purified over a 5 g Isolute column

Sources & evidence

ORD record
ord-94159c12749841f39317b41059175e88
Source dataset
uspto-grants-2016_06
Patent number
US09376422B2

Reaction notes

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