Methyl 10-bromo-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate → methyl 10-bromo-3-((3-methyloxetan-3-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate

HRID 575468Notes

Reaction equation

HRID 575468 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.[I-].[CH3:23][C:24]1([CH2:28][Zn+])[CH2:27][O:26][CH2:25]1>CC(N(C)C)=O>[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]([CH2:23][C:24]4([CH3:28])[CH2:27][O:26][CH2:25]4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:21]=1

Participants

4

Reactant 2

HCID 86693477Methyl 10-bromo-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylateHCID 178429773HCID 178429773, compound

Product 1

HCID 86693533methyl 10-bromo-3-((3-methyloxetan-3-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylateYield 40.4%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
90 °C

Procedure

A solution of methyl 10-bromo-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (75 mg, 0.16 mmol) in 1 mL DMA was sparged with nitrogen and treated with ((3-methyloxetan-3-yl)methyl)zinc(II) iodide (1.11 mL, 0.59 M, 0.65 mmol) reagent while nitrogen was sparging. After 1 min, solid Pd(PPh3)4 (ca. 10 mol %) was added and the mixture stirred at 90° C. overnight. The mixture was diluted with ammonium chloride and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated by rotoevaporation. Purification by flash column chromatography (12 g isco, 10-100% EtOAc) gave 27 mg of methyl 10-bromo-3-((3-methyloxetan-3-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. This product was taken up in 1 mL of DMF and treated with 0.2 mL formamide then 0.2 mL of 25% wt NaOMe in MeOH. After 1 hour at room temp, the mixture was diluted with ammonium chloride and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated by rotoevaporation. This material was used in subsequent operations without further purification.

Workup

  1. customwas sparging
  2. additionsolid Pd(PPh3)4 (ca. 10 mol %) was added
  3. additionThe mixture was diluted with ammonium chloride
  4. extractionextracted with ethyl acetate
  5. washThe combined organics were washed with brine
  6. dry with materialdried over sodium sulfate
  7. concentrationconcentrated by rotoevaporation
  8. customPurification by flash column chromatography (12 g isco, 10-100% EtOAc)

Sources & evidence

ORD record
ord-3e8bef9b9f0345c7bd61ec68c94e2616
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

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