Cyclopropanecarbohydrazide → Methyl 10-bromo-3-(2-(cyclopropanecarbonyl)hydrazinecarbonyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate

HRID 575423Notes

Reaction equation

HRID 575423 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13](I)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1.[CH:22]1([C:25]([NH:27][NH2:28])=[O:26])[CH2:24][CH2:23]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:50][C:32]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>CN(C)C=O.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([C:32]([NH:28][NH:27][C:25]([CH:22]4[CH2:24][CH2:23]4)=[O:26])=[O:50])=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1

Participants

7

Reactant 3

HCID 81396CyclopropanecarbohydrazideHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86693477Methyl 10-bromo-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate

Product 1

HCID 86693476Methyl 10-bromo-3-(2-(cyclopropanecarbonyl)hydrazinecarbonyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylateYield 519.8%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
80 °C

Procedure

Methyl 10-bromo-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (100 mg, 0.2178 mmol) and cyclopropanecarbohydrazide (1.5 equiv., 34.43 mg, 0.3267 mmol) were dissolved in dry N,N-dimethylformamide (0.87 mL) and triethylamine (0.13 mL). The solution was sparged with nitrogen. Palladium(II) acetate (0.05 equiv., 2.5 mg, 0.01089 mmol) and xantphos (0.05000, 6.430 mg, 0.01089 mmol) were added and the solution was purged and fixed with a CO balloon. The reaction was heated to 80° C. for 2 h. The reaction was monitored by LC/MS for consumption of starting material. The reaction was cooled to room temperature and diluted with methylene chloride. Saturated aqueous sodium bicarbonate was added and the mixture was extracted twice with methylene chloride. The organic layers were combined, dried with sodium sulfate and concentrated. Purified by flash chromatography (10-100% EtOAc in heptanes) to afford 26 mg (26% yield) of a white solid.

Workup

  1. customThe solution was sparged with nitrogen
  2. customthe solution was purged
  3. customThe reaction was monitored by LC/MS for consumption of starting material
  4. temperatureThe reaction was cooled to room temperature
  5. additiondiluted with methylene chloride
  6. additionSaturated aqueous sodium bicarbonate was added
  7. extractionthe mixture was extracted twice with methylene chloride
  8. dry with materialdried with sodium sulfate
  9. concentrationconcentrated
  10. customPurified by flash chromatography (10-100% EtOAc in heptanes)

Sources & evidence

ORD record
ord-ff67a407f97c4b9894a3c8f725759176
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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