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Mitsunobu reaction: benzyl alcohol + phthalimide → N-benzyl phthalimide
R–OH + Nu–H + PPh3 + DIAD → R–Nu + PPh3=O + reduced DIAD
PPh3/DIAD-mediated dehydrative coupling of an alcohol with an acidic pronucleophile (pKa ≲ 13). Phthalimide as the nucleophile gives an N-alkyl phthalimide that hydrolyses to the free primary amine — the classic Gabriel-like sequence. SN2 mechanism with clean inversion of configuration at the alcohol carbon. PPh3 is oxidised to PPh3=O; DIAD is reduced to the corresponding hydrazine. Both byproducts complicate purification — chromatography is usually required.
Conditions: PPh3 (1.1 equiv) and DIAD (1.1 equiv) in dry THF (1.0 M based on alcohol). Add DIAD slowly to a stirred mixture at 0 °C, then warm to room temperature and stir for 4–12 h (overnight is safest). Argon atmosphere; DIAD reduces explosively at >100 °C. Workup: concentrate, redissolve in EtOAc, wash with sat. NaHCO3 + brine, dry MgSO4, evaporate. Column chromatography (hexane/EtOAc, gradient) removes PPh3=O and the spent hydrazine.
- Expected yield
- 70–90 %
- Expected duration
- 4–12 h (commonly overnight) at 0 °C → room temperature