Mild and Efficient Synthesis of Fmoc-Protected Amino Azides from Fmoc-Protected Amino Alcohols

 

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Abstract

Fmoc-protected amino azides - key intermediates for monomers of oligomeric urea and guanidine - can be efficiently prepared from the corresponding amino alcohol through iodination followed by substitution with sodium azide. This synthetic route avoids the preparation, storage, and handling of the highly toxic azidic acid that is used in an alternative method.

References and Notes

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All compounds gave satisfactory analytical data. Described below are a representative procedure and spectral data for Fmoc-protected glutamate azide 2h. Fmoc-protected glutamate alcohol 1h (50 mg, 0.12 mmol) in dry CH₂Cl₂ was added to a pre-mixed (5 min) solution of PPh₃ (94 mg, 0.36 mmol, 3 equiv), iodine (91 mg, 0.36 mmol, 3 equiv) and imidazole (41 mg, 0.6 mmol, 5 equiv) in 1.2 mL dry CH₂Cl₂. The reaction mixture was stirred at r.t. for 1.5 h. After completion of the reaction the solvent was evaporated at reduced pressure and the corresponding iodide was purified by silica gel column chromatography (10% EtOAc in hexane). The iodide was then dissolved in 0.5 mL DMF, mixed with NaN₃ (39 mg, 0.6 mmol, 5 equiv with respect to alcohol 1h) and stirred at r.t. for 3.5 h. After solvent removal and silica gel column chromatography (10% EtOAc in hexane), azide 2h was obtained as a white solid in high yield. Yield 50 mg (94% overall from alcohol 1h); mp 65-66 °C. ¹H NMR (CDCl₃): δ = 1.47 (s, 9 H), 1.82-1.86 (m, 2 H), 2.29-2.36 (m, 2 H), 3.42-3.48 (m, 2 H), 3.75-3.87 (br m, 1 H), 4.23 (t, 1 H, J = 6.9 Hz), 4.38-4.50 (m, 2 H), 5.03 (d, 1 H, J = 7.7 Hz), 7.31-7.45 (m, 4 H), 7.61 (d, 2 H, J = 7.2 Hz), 7.79 (d, 2 H, J = 7.2 Hz). ESI-MS: m/z = 437.0 [M + H]⁺.
Additional list of ¹H NMR of new compounds:
Compound 2g: ¹H NMR (CDCl₃): δ = 1.76-1.83 (m, 2 H), 2.29-2.31 (m, 2 H), 3.31-3.37 (m, 2 H), 3.72 (br m, 1 H), 4.20 (t, 1 H, J = 6.5 Hz), 4.37-4.50 (m, 2 H), 5.01 (d, 1 H, J = 7.9 Hz), 6.75 (s, 1 H), 7.18-7.29 (m, 17 H), 7.35-7.41 (m, 2 H), 7.57 (d, 2 H, J = 7.4 Hz), 7.74 (d, 2 H, J = 7.4 Hz).
Compound 2i: ¹H NMR (CDCl₃): δ = 1.42 (s, 6 H), 1.41-1.58 (m, 4 H), 2.06 (s, 3 H), 2.49 (s, 3 H), 2.56 (s, 3 H), 2.90 (s, 2 H), 3.16-3.31 (m, 4 H), 3.72 (br m, 1 H), 4.14 (t, 1 H, J = 6.5 Hz), 4.32-4.41 (m, 2 H), 5.30 (d, 1 H, J = 8.4 Hz), 6.34 (br s, 2 H), 7.24-7.27 (m, 2 H), 7.34-7.38 (m, 2 H), 7.54-7.55 (m, 2 H), 7.73 (d, 2 H, J = 7.4 Hz).
Compound 2j: ¹H NMR (CDCl₃): δ = 1.65 (s, 9 H), 2.93-2.99 (m, 2 H), 3.45-3.49 (m, 2 H), 4.17-4.22 (m, 2 H), 4.41-4.43 (m, 2 H) 4.98 (d, 1 H, J = 7.8 Hz), 7.27-7.41 (m, 6 H), 7.46-7.63 (m, 4 Hz), 7.76 (d, 2 H, J = 7.4 Hz), 8.14 (br s, 1 H).