Chloroiodomethane → tert-butyl (3S)-3-[[(tert-butyldiphenylsilyl)oxy]methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylate

HRID 625564Notes

Reaction equation

HRID 625564 reaction equation
[CH2:1]([Zn]CC)C.[Si:6]([O:23][CH2:24][C@@H:25]1[CH2:29][CH:28]=[CH:27][N:26]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:19]([CH3:22])([CH3:21])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.ClCI>C1(C)C=CC=CC=1>[Si:6]([O:23][CH2:24][C@@H:25]1[CH2:29][CH:28]2[CH:27]([CH2:1]2)[N:26]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:19]([CH3:21])([CH3:22])[CH3:20])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1

Participants

5

Reactant 3

HCID 11644ChloroiodomethaneHCID 13008516(S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-2,3-dihydro-1H-pyrrole-1-carboxylateHCID 178418750HCID 178418750, compound

Product 1

HCID 59236982tert-butyl (3S)-3-[[(tert-butyldiphenylsilyl)oxy]methyl]-2-azabicyclo[3.1.0]hexane-2-carboxylateYield 90.8%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
-25 °C

Procedure

Diethylzinc (19 mL of ˜1.1 M in toluene, 21 mmol) was added dropwise over 15 min to a cooled (−30° C.) toluene (27 mL) solution of (S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-2,3-dihydro-1H-pyrrole-1-carboxylate (3.94 g, 9.0 mmol). Chloroiodomethane (stabilized over copper; 3.0 mL, 41 mmol) was added dropwise over 10 min and stirred while maintaining the bath temperature at −25° C. for 1 h and between −25° C. and −21° C. for 18.5 h. The reaction mixture was opened to the air and quenched by the slow addition of 50% saturated NaHCO3 solution (40 mL) and then removed from the cooling bath and stirred at ambient temperature for 20 min. The reaction mixture was filtered through a filter paper and the white cake was washed with 50 mL of toluene. The organic phase of the filtrate was separated and washed with water (40 mL, 2×), dried (MgSO4) and concentrated in vacuo. The crude material was purified using by silica gel chromatography (350 g silica gel; sample was loaded with 7% EtOAc/hexanes; eluted with 7-20% EtOAc/hexanes) to afford (3S)-tert-butyl 3-((tert-butyldiphenylsilyloxy)methyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (3.69 g, 90.7%) as a mixture of cis/trans-isomers. [Note: the exact cis/trans-isomer ratio was not determined at this stage]. LC-MS: [M+Na]+=474.14. Rt=2.39 min under the following HPLC conditions: Solvent gradient from 100% A: 0% B to 0% A: 100% B (A=0.1% TFA in 1:9 MeOH/water; B=0.1% TFA in 9:1 MeOH/water) over 2 min and hold for 1 min; detection at 220 nm; PHENOMENEX® Luna 3.0×50 mm S10 column. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.62-7.60 (m, 4H), 7.49-7.40 (m, 6H), 3.77/3.67 (overlapping br s, 3H), 3.11-3.07 (m, 1H), 2.23 (app br s, 1H), 2.05-2.00 (m, 1H), 1.56-1.50 (m, 1H), 1.33 (very broad s, 9H), 1.00 (s, 9H), 0.80 (m, 1H), 0.30 (m, 1H).

Workup

  1. customquenched by the slow addition of 50% saturated NaHCO3 solution (40 mL)
  2. customremoved from the cooling bath
  3. stirringstirred at ambient temperature for 20 min
  4. filtrationThe reaction mixture was filtered through a filter paper
  5. washthe white cake was washed with 50 mL of toluene
  6. customThe organic phase of the filtrate was separated
  7. washwashed with water (40 mL, 2×)
  8. dry with materialdried (MgSO4)
  9. concentrationconcentrated in vacuo
  10. customThe crude material was purified
  11. washusing by silica gel chromatography (350 g silica gel; sample was loaded with 7% EtOAc/hexanes; eluted with 7-20% EtOAc/hexanes)

Sources & evidence

ORD record
ord-83af62b378a1434ca26c9353beedce04
Source dataset
uspto-grants-2016_04
Patent number
US09303007B2

Reaction notes

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