Reaction #46653

Reaction equation

(S)-benzyl 2-(tert-butoxycarbonylamino)pent-4-ynoate

sodium ascorbate

NaN3

NaN3

BnBr

→

desired product

(S)-benzyl 3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(tert-butoxycarbonylamino)propanoate

Solvents

DMF H2O

H2O

EtOAc

Conditions

Workup

1. 1
   Temperatureheating
2. 2
   workup.WAITwas continued for 12 h
3. 3
   OtherThe layers were separated
4. 4
   Extractionthe aqueous layer extracted 3× with EtOAc
5. 5
   Washthe combined organic phases washed (H2O×3, brine)
6. 6
   Dryingdried (Na2SO4)
7. 7
   Filtrationfiltered
8. 8
   Concentrationconcentrated
9. 9
   OtherThe residue was purified by flash (Biotage, 40+M 0-5% MeOH in CH2Cl2; TLC 3% MeOH in CH2Cl2)
10. 10
    Otherto afford a light yellow oil which

Procedure

To a mixture of (S)-benzyl 2-(tert-butoxycarbonylamino)pent-4-ynoate (0.50 g, 1.65 mmol), sodium ascorbate (0.036 g, 0.18 mmol), CuSO4-5H2O (0.022 g, 0.09 mmol) and NaN3 (0.13 g, 2.1 mmol) in DMF-H2O (5 mL, 4:1) at rt was added BnBr (0.24 mL, 2.02 mmol) and the mixture was warmed to 65° C. After 5 h LCMS indicated low conversion. A further portion of NaN3 (100 mg) was added and heating was continued for 12 h. The reaction was poured into EtOAc and H2O and shaken. The layers were separated and the aqueous layer extracted 3× with EtOAc and the combined organic phases washed (H2O×3, brine), dried (Na2SO4), filtered, and concentrated. The residue was purified by flash (Biotage, 40+M 0-5% MeOH in CH2Cl2; TLC 3% MeOH in CH2Cl2) to afford a light yellow oil which solidified on standing (748.3 mg, 104%). The NMR was consistent with the desired product but suggests the presence of DMF. The material was used as is without further purification. 1HNMR (400 MHz, DMSO-d6) δ 7.84 (s, 1H), 7.27-7.32 (m, 10H), 5.54 (s, 2H), 5.07 (s, 2H), 4.25 (m, 1H), 3.16 (dd, J=1.0, 5.3 Hz, 1H), 3.06 (dd, J=5.3, 14.7 Hz), 2.96 (dd, J=9.1, 14.7 Hz, 1H), 1.31 (s, 9H). LCMS: Anal. Calcd. for C24H28N4O4: 436. found: 437 (M+H)+.

Source