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(R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol → (R)-9-(3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl)-3-methyl-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide

HRID 575446
Notes
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Reaction equation

HRID 575446 reaction equation
I[C:2]1[CH:3]=[CH:4][C:5]2[CH:18]3[CH2:19][CH:16]([CH2:17]3)[C:8]3[N:9]([CH3:15])[C:10]([C:12]([NH2:14])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:20]=1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C@:27]([OH:31])([C:29]#[CH:30])[CH3:28])[N:23]=1>N1CCCCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:31][C@:27]([C:24]1[N:23]=[C:22]([CH3:21])[O:26][N:25]=1)([CH3:28])[C:29]#[C:30][C:2]1[CH:3]=[CH:4][C:5]2[CH:18]3[CH2:19][CH:16]([CH2:17]3)[C:8]3[N:9]([CH3:15])[C:10]([C:12]([NH2:14])=[O:13])=[N:11][C:7]=3[C:6]=2[CH:20]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 2

HCID 86669593(R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-olHCID 866935079-Iodo-3-methyl-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide

Product 1

HCID 86693508(R)-9-(3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl)-3-methyl-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamideYield 77%

Reagents, catalysts & solvents 3

HCID 24350
Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)
Catalyst
HCID 178418397HCID 178418397, compoundCatalyst
HCID 8082PiperidineSolvent

Conditions

Temperature
40 °C

Procedure

To a solution 9-iodo-3-methyl-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxamide (100 mg, 0.26 mmol) in piperidine (2 mL) was introduced (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (160 mg, 1.05 mmol) and copper(I) iodide (2.5 mg, 0.01 mmol). The solution was de-oxygenated by nitrogen bubbling for five minutes, then tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.01 mmol) added and bubbling continued for a further two minutes. The pressure tube was closed under an atmosphere of nitrogen and the reaction mixture warmed to 40° C. for 2.5 hr. After evaporation of the reaction mixture in vacuo, the residue was suspended in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate (6 mL), water (2×10 mL) and brine (5 mL). The organic extract was dried over sodium sulfate, filtered, and the filtrate adsorbed onto silica gel in vacuo. Purification of the dry-loaded material by silica gel flash column chromatography (eluent: heptane/ethyl acetate gradient) was followed by suspension of the product in acetonitrile (0.8 mL). The solid was collected by filtration to furnish the title compound (80 mg, 0.20 mmol, 77%) as a colorless solid: 1H NMR (500 MHz, CDCl3) δ 1.61-1.73 (m, 2H), 2.05 (s, 3H), 2.65 (s, 3H), 2.94 (q, J=8.62 Hz, 2H), 3.47 (td, J=7.25, 3.47 Hz, 1H), 3.57-3.70 (m, 2H), 4.01 (s, 3H), 5.57 (br. s., 1H), 7.02 (d, J=7.88 Hz, 1H), 7.17 (d, J=7.88 Hz, 1H), 7.70 (br. s., 1H), 8.51 (s, 1H); M+H=404.

Workup

  1. custombubbling
  2. waitcontinued for a further two minutes
  3. customThe pressure tube was closed under an atmosphere of nitrogen
  4. customAfter evaporation of the reaction mixture in vacuo
  5. washwashed with saturated aqueous sodium bicarbonate (6 mL), water (2×10 mL) and brine (5 mL)
  6. extractionThe organic extract
  7. dry with materialwas dried over sodium sulfate
  8. filtrationfiltered
  9. customPurification of the dry-loaded material by silica gel flash column chromatography (eluent: heptane/ethyl acetate gradient)
  10. additionwas followed by suspension of the product in acetonitrile (0.8 mL)
  11. filtrationThe solid was collected by filtration

Sources & evidence

ORD record
ord-26b5a762e27c4046b8e6f3e27addfd36
Source dataset
uspto-grants-2015_05
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09034866B2

Reaction notes

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