1,1-Dimethylethyl (2S)-2-[(methoxymethylamino)carbonyl]-1-pyrrolidinecarboxylate → (s)-Tert-butyl 2-(3-(4-iodophenyl)propioloyl)pyrrolidine-1-carboxylate

HRID 18350Notes

Reaction equation

HRID 18350 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][CH:4]=1)#[CH:2].C([Mg]Br)C.[CH3:14][C:15]([O:18][C:19]([N:21]1[C@H:25]([C:26](N(OC)C)=[O:27])[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])[CH3:16]>C1COCC1>[I:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:26]([C@@H:25]2[CH2:24][CH2:23][CH2:22][N:21]2[C:19]([O:18][C:15]([CH3:17])([CH3:16])[CH3:14])=[O:20])=[O:27])=[CH:4][CH:5]=1

Participants

5

Reactant 3

HCID 6882981,1-Dimethylethyl (2S)-2-[(methoxymethylamino)carbonyl]-1-pyrrolidinecarboxylateHCID 121608331-Ethynyl-4-iodobenzeneHCID 178418443HCID 178418443, compound

Product 1

HCID 59345144(s)-Tert-butyl 2-(3-(4-iodophenyl)propioloyl)pyrrolidine-1-carboxylateYield 71%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of 1-ethynyl-4-iodobenzene 6 (0.908 g, 3.98 mmol) in THF (20 mL) at −78° C. was added ethylmagnesium bromide (3M in ether, 1.39 mL, 4.18 mmol). After 10 minutes the cooling bath was removed and the solution was allowed to stir at room temperature for 1 hour. The reaction mixture was then re-cooled to 0° C. and added to a solution of N-(tert-butoxycarbonyl)-L-proline N′-methoxy-N′-methylamide 2 (0.970 g, 3.76 mmol) in THF (10 mL). The reaction mixture was warmed to room temperature and stirring was continued for 12 hours before the mixture was quenched with saturated NH4Cl. The mixture was diluted with ethyl acetate/H2O, the layers separated and the aqueous phase was re-extracted with ethyl acetate (2×). The combined organic layers were washed (H2O, brine), dried (Na2SO4), and filtered, and the solvent was removed in vacuo. The resulting residue was purified by flash chromatography (hexane:ethyl acetate, 4:1) to give (S)-tert-butyl 2-(3-(4-iodophenyl)propioloyl)pyrrolidine-1-carboxylate 7 (0.908 g, 71%) as a yellow oil which solidified on standing. 1H NMR (400 MHz, CDCl3) δ 7.72-7.76 (m, 2H), 7.26-7.30 (m, 2H), 4.49 (dd, J=8.8, 4.3 Hz, 0.3H), 4.29 (dd, J=8.5, 5.5 Hz, 0.7H), 3.59 (app t, J=6.7 Hz, 2H), 2.20-2.33 (m, 1H), 1.85-2.10 (m, 3H), 1.45, 1.40 (s, 9H, rotamers in 2:3 ratio). LCMS: Anal. Calcd. for C18H20INO3: 425. found: 326 (M+H-Boc)+.

Workup

  1. customAfter 10 minutes the cooling bath was removed
  2. temperatureThe reaction mixture was then re-cooled to 0° C.
  3. temperatureThe reaction mixture was warmed to room temperature
  4. stirringstirring
  5. waitwas continued for 12 hours before the mixture
  6. customwas quenched with saturated NH4Cl
  7. additionThe mixture was diluted with ethyl acetate/H2O
  8. customthe layers separated
  9. extractionthe aqueous phase was re-extracted with ethyl acetate (2×)
  10. washThe combined organic layers were washed (H2O, brine)
  11. dry with materialdried (Na2SO4)
  12. filtrationfiltered
  13. customthe solvent was removed in vacuo
  14. customThe resulting residue was purified by flash chromatography (hexane:ethyl acetate, 4:1)

Sources & evidence

ORD record
ord-2442c5f9e02e4732bcf8c49e84769110
Source dataset
uspto-grants-2010_06
Patent number
US07741347B2

Reaction notes

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