Iodine → HCID 86669691, compound

HRID 1623953Notes

Reaction equation

HRID 1623953 reaction equation
II.Br[CH2:4][CH:5]1[CH2:7][CH2:6]1.[OH:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:17]2[CH2:18][C@H:19]3[CH2:31][C@H:20]3[C:21]=2[N:22]([C:24]2[CH:29]=[N:28][C:27](Br)=[CH:26][N:25]=2)[N:23]=1)=[O:15])([CH3:12])[CH3:11]>CC(N(C)C)=O.C1COCC1.[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:17]2[CH2:18][C@H:19]3[CH2:31][C@H:20]3[C:21]=2[N:22]([C:24]2[CH:29]=[N:28][C:27]([CH2:4][CH:5]3[CH2:7][CH2:6]3)=[CH:26][N:25]=2)[N:23]=1)=[O:15])([CH3:12])[CH3:11]

Participants

8

Reactant 3

HCID 807IodineHCID 81503BromomethylcyclopropaneHCID 86669649HCID 86669649, compound

Product 1

HCID 86669691HCID 86669691, compoundYield 7.6%

Reagents, catalysts & solvents 4

HCID 23994ZincCatalystHCID 178418851HCID 178418851, compoundCatalystHCID 8028TetrahydrofuranSolventHCID 31374DimethylacetamideSolvent

Conditions

Temperature
70 °C

Procedure

Under nitrogen protection, zinc suspension (1.76 mL, 1.338 mmol) was added to a solution of diiodine (4.5 mg, 0.018 mmol) in DMA at room temperature. After several minutes, (bromomethyl)cyclopropane (120 mg, 0.892 mmol) was added. The reaction mixture was heated at 70° C. for 3 h, cooled down to room temperature, then transferred to a flask containing (1aR,5aR)-2-(5-bromo-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (70 mg, 0.178 mmol) and bis(tri-t-butylphosphine)palladium (0) (9.1 mg, 0.018 mmol) in THF (1 mL). The whole reaction mixture was heated at reflux overnight, cooled down and quenched with saturated sodium bicarbonate. The solid was filtered, and the filtrate was extracted with ethyl acetate. The combined organics were dried and concentrated. The residue was purified by silica gel column chromatography to give the title compound (5 mg) as white solid. LCMS m/z=368.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.46 (td, J=4.7 and 3.3 Hz, 1H), 1.22-1.28 (m, 1H), 1.40 (s, 3H), 1.41 (s, 3H), 1.95-2.04 (m, 1H), 2.09-2.16 (m 1H), 2.26-2.32 (m, 1H), 2.37-2.41 (m, 4H), 2.68-2.74 (m, 1H), 2.91 (d, J=16.8 Hz, 1H), 3.00 (dd, J=16.5 and 6.2 Hz, 1H), 3.69 (d, J=6.3 Hz, 2H), 3.72-3.77 (m, 1H), 4.78 (br, 1H), 6.97 (s, 1H), 8.26 (d, J=1.3 Hz, 1H), 9.15 (d, J=1.3 Hz, 1H).

Workup

  1. waitAfter several minutes
  2. temperaturecooled down to room temperature
  3. customtransferred to a flask
  4. customThe whole reaction mixture
  5. temperaturewas heated
  6. temperatureat reflux overnight
  7. temperaturecooled down
  8. customquenched with saturated sodium bicarbonate
  9. filtrationThe solid was filtered
  10. extractionthe filtrate was extracted with ethyl acetate
  11. customThe combined organics were dried
  12. concentrationconcentrated
  13. customThe residue was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-255e9058a8f240e3a4f8bb1093ebc472
Source dataset
uspto-grants-2014_07
Patent number
US08778950B2

Reaction notes

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