Ammonia → tert-butyl (2S)-2-cyanopyrrolidine-1-carboxylate

HRID 1484080Notes

Reaction equation

HRID 1484080 reaction equation
[C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10](O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([N:18](CC)CC)C.C(OC(Cl)=O)C(C)C.N.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CO.C1COCC1.CCOC(C)=O.ClCCl>[C:10]([C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])#[N:18]

Participants

10

Reactant 5

HCID 222AmmoniaHCID 8471Triethylamine2×HCID 9845Trifluoroacetic anhydrideHCID 62365Isobutyl chloroformateHCID 850831,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (2S)-

Product 1

HCID 6951263tert-butyl (2S)-2-cyanopyrrolidine-1-carboxylateYield 50%

Reagents, catalysts & solvents 4

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-25 °C

Procedure

To a flame dried flask was added 2 grams (9.3 mmols) of N-Boc proline followed by 93 ml, of dichloromethane and 4.24 grams (41.85 mmols) of triethylamine. The reaction mixture was then cooled to −25° C. and 2.5 grams (18.6 mmols) of iso-butylchloroformate was added dropwise. After stirring for 45 minutes at this low temperature, 0.83 grams (49 mmol) of ammonia was added to the reaction mixture as a 7N solution in methanol. The flask was allowed to warm to ambient temperature and stir for an additional 16 hours. After this time, the reaction mixture was evaporated to dryness and reconstituted in 200 mL of EtOAc. The organic layer was washed four 15 mL portions of 1N HCl, dried with MgSO4 and evaporated to dryness. The crude material was then immediately dehydrated to the nitrile according to general procedure E using 1.9 grams (18.88 mmols) of triethylamine and 2.34 grams (11.16 mmols) of trifluoroacetic anhydride in 93 mL of THF. After standard work-up and purification techniques (column chromatography, 25% EtOAc in hexanes), 0.91 grams (4.65 mmols, 50%) of the title product was recovered as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 4.53 (d, J=5.5 Hz, 0.5H), 4.48-4.38 (m, 0.5H), 3.57-3.41 (m, 1H), 3.41-3.22 (m, 1H), 2.31-1.92 (m, 4H), 1.47 (d, J=9.4 Hz, 9H). 13C NMR (75 MHz, CDCl3) δ 153.25, 119.38, 81.64, 47.39, 45.93, 31.86, 31.01, 28.52, 24.88, 24.04.

Workup

  1. customTo a flame dried flask
  2. temperatureto warm to ambient temperature
  3. customAfter this time, the reaction mixture was evaporated to dryness
  4. washThe organic layer was washed four 15 mL portions of 1N HCl
  5. dry with materialdried with MgSO4
  6. customevaporated to dryness

Sources & evidence

ORD record
ord-1dc5ae61c68c4ab9bb3065d65d79f107
Source dataset
uspto-grants-2016_08
Patent number
US09421177B2

Reaction notes

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