Regio- and Diastereoselective Vinylogous Mannich Addition of 3-Alkenyl-2-oxindoles to α-Fluoroalkyl Aldimines

Abstract

An efficient asymmetric vinylogous Mannich (AVM) addition reaction of 3-alkenyl-2-oxindoles to α-fluoroalkyl aldimines has been developed. This reaction provided various optical active α-alkylidene-δ-amino-δ-fluoroalkyl oxindoles in excellent yields, complete γ-site ­regioselectivity, and excellent diastereoselectivities.

Key words

fluoroalkylated compounds - oxindole - asymmetric - Mannich addition

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• 15 General Procedure for the Synthesis of α-Alkylidene-δ-amino-δ-fluoroalkyl OxindolesA solution of KHMDS (0.36 mL, 1 M solution in THF) was slowly added to a dried Scheck flask containing 3-alkenyl-2-oxindoles 2 (0.36 mmol) in THF (2.0 mL) at –78 °C under N₂ atmosphere. After stirring at –78 °C for 1 h, the mixture of 1 (0.3 mmol) and Ti(Oi-Pr)₄ (0.33 mmol) in THF (1.0 mL) was added dropwise, and the mixture was stirred for 12 h at –78 °C. Then sat. aq NH₄Cl solution and H₂O was added at –78 °C. The mixture was brought to r.t. After 5 min, the mixture was filtered through Celite, and the filtrate was extracted with EtOAc. The combined organic solution was dried over MgSO₄. After the removal of volatile solvents under vacuum, the crude product was purified by silica gel column chromatography to give the required product.
• 16 Analytical Data for Compound 3aMp 60–61 °C. [α]_D ^17.0 +187.7 (c 0.41, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.88 (d, J = 8.2 Hz, 1 H), 7.60 (d, J = 7.8 Hz, 1 H), 7.35 (t, J = 7.9 Hz, 1 H), 7.20 (t, J = 7.7 Hz, 1 H), 4.35 (dd, J = 24.4, 11.2 Hz, 2 H), 4.19–3.96 (m, 1 H), 2.62 (dd, J = 12.7, 3.8 Hz, 1 H), 2.43 (s, 3 H), 1.67 (s, 9 H), 1.06 (s, 9 H). ¹⁹F NMR (377 MHz, CDCl₃): δ = –74.87 (d, J = 6.5 Hz, 3 F). ¹³C NMR (101 MHz, CDCl₃): δ = 166.5, 152.0, 149.1, 138.3, 128.9, 125.6, 125.2 (q, J = 284.8 Hz), 124.1, 123.9, 123.2, 114.6, 84.6, 57.2, 56.4 (q, J = 30.2 Hz), 35.3, 28.1, 24.2, 22.2. IR (KBr): ν_max = 3261, 3060, 2975, 1731, 1613, 1462, 1535, 1300, 1258, 1157, 1090, 841, 748 cm^–1. MS (EI): m/z = 497.2 [M + Na]⁺. ESI-HRMS: m/z [M + Na]⁺ calcd for C₂₂H₂₉F₃N₂O₄SNa: 497.1692; found: 497.1712.
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