Methyl iodide → (2S,4S)-1-tert-butyl 2-methyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate

HRID 590661Notes

Reaction equation

HRID 590661 reaction equation
[OH:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.[C:19](C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.CI>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[CH3:19][O:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1

Participants

6

Reactant 3

HCID 6328Methyl iodideHCID 685102,6-Di-tert-butylpyridineHCID 696750381-(1,1-Dimethylethyl) 2-methyl (2S,4S)-4-(hydroxymethyl)-1,2-pyrrolidinedicarboxylate

Product 1

HCID 69675330(2S,4S)-1-tert-butyl 2-methyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylateYield 78%

Reagents, catalysts & solvents 2

HCID 76223Silver(I) trifluoromethanesulfonateCatalystHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (2.57 g, 9.9 mmol) in CH2Cl2 (50 mL) was added AgOTf (4.07 g, 15.8 mmol) and 2,6-di-tert-butylpyridine (4.4 mL, 19.8 mmol). The reaction mixture was cooled to 0° C. (external temperature, ice bath) and MeI (0.98 mL, 15.8 mmol) was slowly added. The resulting slurry was stirred at 0° C. for 1.5 h and at room temperature for 1.5 h. The slurry was diluted with CH2Cl2 and filtered through celite. The filtrate was concentrated to dryness, dissolved in Et2O, and washed with HCl (1N) and brine. The aqueous layers were backextracted with Et2O and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by silica gel chromatography (10% to 75% to 100% EtOAc/Hexanes) to provide (2S,4S)-1-tert-butyl 2-methyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (2.11 g, 78%). 1H-NMR: 400 MHz, (CDCl3) δ: (mixture of rotomers, major reported) 4.20 (t, 1H), 3.71 (s, 3H), 3.67 (m, 1H), 3.34 (m, 2H), 3.30 (s, 3H), 3.16 (t, 1H), 2.43 (m, 2H), 1.74 (m, 1H), 1.38 (s, 9H).

Workup

  1. additionwas slowly added
  2. filtrationfiltered through celite
  3. concentrationThe filtrate was concentrated to dryness
  4. dissolutiondissolved in Et2O
  5. washwashed with HCl (1N) and brine
  6. dry with materialthe combined organic layers were dried over Na2SO4
  7. concentrationconcentrated
  8. customThe crude oil was purified by silica gel chromatography (10% to 75% to 100% EtOAc/Hexanes)

Sources & evidence

ORD record
ord-a1d276a3e2ee4f51ae07d376d06dfbc0
Source dataset
uspto-grants-2016_01
Patent number
US09233974B2

Reaction notes

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