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TCI Practical Example: The Mitsunobu Type S_N2 Reaction Using BEHT Triflate Salt, an Intermediate of the Mitsunobu Reaction

We are proud to present the Mitsunobu type S_N2 reaction of benzyl (S)-(-)-lactate and indoline using BEHT triflate, a bench-stable intermediate salt. BEHT triflate can be used in the Mitsunobu reaction with lower acidic amines.

Used Chemicals

• Benzyl (S)-(-)-Lactate [L0161]
• Indoline [I0033]
• BEHT Triflate [B7082]
• N,N-Diisopropylethylamine (= DIEA) [D1599]
• 1,2-Dichloroethane (= DCE)

Procedure

DIEA (0.17 mL, 1.00 mmol) was added to a suspension of benzyl (S)-(-)-lactate (180 mg, 1.00 mmol), indoline (119 mg, 1.20 mmol) and BEHT triflate (704 mg, 1.20 mmol, 1.2 eq.) in DCE (1 mL) at room temperature. The mixture was stirred at room temperature for one day. The reaction mixture was quenched with sat. NaHCO₃ aq. (5 mL) and the aqueous layer was extracted with dichloromethane (3 × 5 mL). The combined organic layer was washed with brine, dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate:hexane = 0:100 – 5:95 on silica gel) to give benzyl (R)-2-(indolin-1-yl)propanoate as a pale red oil (154 mg, 54% yield).

Experimenter's Comments

The reaction mixture was monitored by UPLC.

Analytical Data

Benzyl (R)-2-(Indolin-1-yl)propanoate

¹H NMR (400 MHz, CDCl₃); δ 7.30–7.26 (m, 3H), 7.18 (dd, J = 3.2, 7.2 Hz, 2H), 7.05 (d, J = 7.3 Hz, 1H), 7.00 (t, J = 7.3 Hz, 1H), 6.64 (t, J = 7.3 Hz, 1H), 6.39 (d, J = 7.3 Hz, 1H), 5.11 (d, J = 12.8 Hz, 1H), 5.07 (d, J = 12.8 Hz, 1H), 4.32 (q, J = 7.0 Hz, 1H), 3.53 (t, J = 8.4 Hz, 2H), 2.95 (t, J = 8.4 Hz, 2H), 1.49 (d, J = 7.0 Hz, 3H).

Lead Reference

• Universal Reagent for Mild and Stereospecific Nucleophilic Substitution of Alcohols with Amines
  • W. S. Bechara, I. K. Sagamanova, L. Thai-Savard, M. Dauphinais, S. Régnier, C. Noël, S. B. D. Jarvis, A. B. Charette, Angew. Chem. Int. Ed. 2025, 64, e202420312.