Nitrogen → HCID 56595565, compound

HRID 2095358Notes

Reaction equation

HRID 2095358 reaction equation
Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:7]=1.C(N(CC)CC)C.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30].N#N>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O.CCCCCC>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][C@H:10]1[CH2:9][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:7]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]

Participants

9

Reactant 4

HCID 947NitrogenHCID 8471TriethylamineHCID 66111TrimethylsilylacetyleneHCID 10688713(S)-Tert-butyl 2-(((5-bromopyridin-3-YL)oxy)methyl)azetidine-1-carboxylate

Product 1

HCID 56595565HCID 56595565, compoundYield 99.3%

Reagents, catalysts & solvents 4

HCID 11776TriphenylphosphineCatalystHCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 21226206Ethyl acetate hexaneSolvent

Procedure

A 50 mL round-bottom flask with stir bar was charged with 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]pyridine (564 mg, 1.64 mmol), copper(I) iodide (25 mg, 0.13 mmol, 0.08 equiv.), bis(triphenylphosphine)palladium(II) chloride (49 mg, 66 μmol, 0.04 equiv.), and triphenylphosphine (34 mg, 0.13 mmol, 0.08 equiv.). Anhydrous triethylamine (5 mL) and trimethylsilylacetylene (0.63 mL, 4.45 mmol, 2.7 equiv.) were added. The flask was equipped with a reflux condenser topped by a N2 balloon, and the reaction mixture was heated to gentle reflux (heating mantle) for 16 h. A black color appeared soon after heating. After cooling, the mixture consisted of an amber solution and a black precipitate. TLC (silica gel, EtOAc/hexane 55:45) demonstrated complete conversion (Rf 0.6; starting material: Rf 0.55). The reaction mixture was evaporated and the residue was taken up in DMPU (0.8 mL+0.4 mL rinse) and was chromatographed on silica gel (25×2.5 cm, EtOAc/hexane 35:65 switching to 45:55 after appearance of the product). After evaporation of the product-containing fractions, the residue was twice evaporated with CH3CN and the solution before the final evaporation was filtered over a cotton plug to remove a small amount of solid. Drying (50° C./14 torr) afforded 587 mg (99%) of the product as a light-amber glass of sufficient purity to be used in the subsequent step. 1H NMR (CDCl3, TMS, 250 MHz) δ 8.30 (d, 1H, J=1.4 Hz), 8.27 (d, 1H, J=2.8 Hz), 7.30 (dd, 1H, 1.6, 2.7 Hz), 4.51 (m, 1H), 4.32 (m, 1H), 4.12 (dd, 1H, J=2.8, 10.1 Hz), 3.88 (t, 2H, J=7.6 Hz), 2.43-2.20 (m, 2H), 1.43 (s, 9H), 0.26 (s, 9H); 13C NMR (CDCl3, 62.5 MHz) δ 156.1, 154.3, 145.0, 138.1, 133.9, 123.2, 120.3, 101.2, 98.0, 79.6, 68.6, 59.9, 46.9 (br), 28.3, 18.9, 0.1.

Workup

  1. customThe flask was equipped with a reflux condenser
  2. temperaturethe reaction mixture was heated
  3. temperatureto gentle reflux
  4. temperature(heating mantle) for 16 h
  5. temperatureafter heating
  6. temperatureAfter cooling
  7. customThe reaction mixture was evaporated
  8. customwas chromatographed on silica gel (25×2.5 cm, EtOAc/hexane 35:65 switching to 45:55 after appearance of the product)
  9. customAfter evaporation of the product-containing fractions
  10. customthe residue was twice evaporated with CH3CN
  11. customthe solution before the final evaporation
  12. filtrationwas filtered over a cotton plug
  13. customto remove a small amount of solid
  14. customDrying (50° C./14 torr)

Sources & evidence

ORD record
ord-763a72d9371142d99b99a089bc0065d1
Source dataset
uspto-grants-2013_05
Patent number
US08445684B2

Reaction notes

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