Chlorotrimethylsilane → tert-Butyl 3-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)azetidine-1-carboxylate

HRID 1499860Notes

Reaction equation

HRID 1499860 reaction equation
BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.[C:22]([C:25]1[CH:32]=[C:31]([Cl:33])[C:28]([C:29]#[N:30])=[C:27](I)[C:26]=1[O:35][CH2:36][CH3:37])(=[O:24])[CH3:23].[Cl-].[NH4+]>CN(C)C(=O)C.[Zn].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].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[C:22]([C:25]1[C:26]([O:35][CH2:36][CH3:37])=[C:27]([CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)[C:28]([C:29]#[N:30])=[C:31]([Cl:33])[CH:32]=1)(=[O:24])[CH3:23]

Participants

10

Reactant 5

HCID 6397ChlorotrimethylsilaneHCID 78391,2-DibromoethaneHCID 25517Ammonium ChlorideHCID 11000522Tert-butyl 3-iodoazetidine-1-carboxylateHCID 866669594-Acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile

Product 1

HCID 86677783tert-Butyl 3-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)azetidine-1-carboxylateYield 90.1%

Reagents, catalysts & solvents 4

HCID 23994ZincCatalystHCID 521585Tris(furan-2-yl)phosphaneCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 31374DimethylacetamideSolvent3×

Conditions

Temperature
70 °C

Procedure

Zinc (4.60 g, 70.3 mmol) and oven dried Celite (870 mg) was added to a flask and the flask was heated with a heat gun while under high-vac for 5 min and then back-filled with nitrogen. N,N-Dimethylacetamide (57 mL) was added, followed by 1,2-dibromoethane (430 μL, 5.0 mmol) and the mixture was heated at 70° C. for 10 min and then cooled to room temperature. The reaction mixture was treated with chlorotrimethylsilane (630 μL, 5.0 mmol) dropwise and stirred at room temperature for 1 h. The reaction mixture was treated with a solution of tert-butyl 3-iodoazetidine-1-carboxylate (18 g, 62 mmol) in N,N-dimethylacetamide (28 mL) dropwise (internal temperature was kept below 40° C. with a water bath) and heated at 40° C. for 2 h. The zinc-iodo reagent (transferred via canula) was filtered through a plastic filter (that was appropriately sealed to avoid atmospheric exposure) directly into a clean, dry flask that was flushed with nitrogen. The reaction mixture was treated with tris(dibenzylideneacetone)dipalladium(0) (720 mg, 0.79 mmol) and tri-(2-furyl)phosphine (370 mg, 1.6 mmol) and degassed with nitrogen for a few minutes. The reaction mixture was treated with a solution of 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile (14 g, 41 mmol) in N,N-dimethylacetamide (130 mL) (degassed with nitrogen) quickly and heated at 70° C. for 2 h. The reaction mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with water (4×500 mL) and brine (1×500 mL), dried with magnesium sulfate, filtered, and concentrated to a crude dark oil. The crude material was purified by flash column chromatography using ethyl acetate in hexanes (5%-45%) to give the desired product (14 g, 88%). 1H NMR (300 MHz, CDCl3) δ 7.46 (s, 1H), 4.42-4.20 (m, 5H), 3.80 (q, J=7.0 Hz, 2H), 2.59 (s, 3H), 1.44 (s, 9H), 1.37 (t, J=7.0 Hz, 3H). LCMS for C15H16ClN2O4 ([M-(t-Bu)+H]+H)+: m/z=323.1; Found: 323.0.

Workup

  1. additionwas added to a flask
  2. temperaturethe flask was heated with a heat gun while under high-vac for 5 min
  3. additionback-filled with nitrogen
  4. temperaturecooled to room temperature
  5. temperatureheated at 40° C. for 2 h
  6. filtrationThe zinc-iodo reagent (transferred via canula) was filtered through a plastic
  7. filtrationfilter (that
  8. customwas appropriately sealed
  9. customdry flask that
  10. customwas flushed with nitrogen
  11. customdegassed with nitrogen for a few minutes
  12. temperatureheated at 70° C. for 2 h
  13. extractionextracted with ethyl acetate (3×300 mL)
  14. washThe combined organic extracts were washed with water (4×500 mL) and brine (1×500 mL)
  15. dry with materialdried with magnesium sulfate
  16. filtrationfiltered
  17. concentrationconcentrated to a crude dark oil
  18. customThe crude material was purified by flash column chromatography

Sources & evidence

ORD record
ord-bc0ad38ada38454fbc752f54a2906574
Source dataset
uspto-grants-2015_12
Patent number
US09199982B2

Reaction notes

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