Catalytic Enantioselective Synthesis of Chiral 3-Amino-2-oxindoles by a Mannich Approach

Abstract

A catalytic enantioselective Mannich-type reaction of a cyclohexanone-derived alkenyl trichloroacetate with isatin imines was achieved using an (S)-BINOL-derived chiral tin dibromide possessing a 4-tert-butylphenyl group at 3- and 3′-positions as the chiral precatalyst in the presence of sodium methoxide, sodium iodide, and methanol. Optically active 3-alkylated 3-amino-2-oxindoles having up to 90% enantiomeric excess were diastereoselectively obtained in high yields under the influence of the in situ generated chiral tin iodide methoxide.

Key words

alkenyl ester - asymmetric catalysis - imine - Mannich-type reaction - tin

• References and Notes

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• 9 We adopted NaOMe in MeOH in place of NaOEt in EtOH because the first combination gave a higher enantioselectivity in the chiral-tin-catalyzed asymmetric aldol reaction of isatin derivatives.⁶ Relatively small bases and alcohols are considered to be favorable for enantioface differentiation of bulky prochiral substrates such as isatin imines.
• 10 To generate a chiral tin iodide methoxide with high purity, it is necessary to transform the corresponding chiral tin dibromide to chiral tin diiodide followed by the treatment with 1 equiv of NaOMe. Indeed, the addition of 5 mol% of NaI to chiral tin dibromide 4a (5 mol%) resulted in lower enantioselectivity.
• 11 Typical Experimental Procedure for the Asymmetric Mannich-Type Reaction: Synthesis of 1-Benzyl-3-[(4-bromophenyl)amino]-3-(2-oxocyclohexyl)indolin-2-one (3a, Table 2, Entry 8, Table 3, Entry 1, Table 4, Entry 1). A mixture of chiral tin dibromide 4a ⁸ (20.6 mg, 0.025 mmol) and NaI (7.5 mg, 0.05 mmol) in dry THF (3 mL) was stirred for 10 min. Then, NaOMe in MeOH (25 μL, 0.025 mmol) and MeOH (0.175 mL) were added, and the resulting mixture was stirred for 30 min. Subsequently, isatin imine 2a (195.6 mg, 0.5 mmol) and alkenyl trichloroacetate 1 (243.5 mg, 1.0 mmol) were added to the mixture at 60 °C. After being stirred for 15 min at this temperature, the reaction mixture was treated with MeOH (1 mL), brine (2 mL), and solid KF (1.0 g) at ambient temperature for 5 min. The resulting precipitate was filtered off, and the filtrate was dried over Na₂SO₄ and then concentrated in vacuo. The residual crude product was purified by column chromatography on silica gel to give Mannich product 3a (244.1 mg, >99% yield). The dr was determined to be 90:10 by ¹H NMR analysis. The enantioselectivity of the major diastereomer was determined to be 90% ee by HPLC analysis using a chiral column (Daicel Chiralpak AD-3, hexane–i-PrOH (9:1), flow rate = 1.0 mL/min): t _R1 = 38.8 min (minor), t _R2 = 49.9 min (major). Spectral Data of the Product TLC: R_f = 0.34 (EtOAc–hexane, 1:2). ¹H NMR (400 MHz, CDCl₃): δ = 7.41 (d, J = 7.2 Hz, 1 H, ArH), 7.34–7.15 (m, 4 H, ArH), 7.05–6.99 (m, 3 H, ArH), 6.98–6.94 (m, 2 H, ArH), 6.66 (d, J = 7.8 Hz, 1 H, ArH), 6.28–6.23 (m, 2 H, ArH), 5.12 (d, J = 15.7 Hz, 1 H, one proton of CH₂), 4.73 (br, 1 H, NH), 4.56 (d, J = 15.9 Hz, 1 H, one proton of CH₂), 3.09 (dd, J = 5.6, 13.2 Hz, 1 H, CH), 2.53–2.30 (m, 3 H, CH₂ and one proton of CH₂), 2.07–1.94 (m, 2 H, CH₂), 1.93–1.77 (m, 1 H, one proton of CH₂), 1.73–1.55 (m, 2 H, CH₂). ¹³C NMR (100 MHz, CDCl₃): δ = 209.5, 176.7, 144.1, 143.9, 135.4, 131.6 (2 C), 129.5, 128.6 (2 C), 127.5, 127.2 (2 C), 124.9, 122.6, 121.5 (2 C), 120.0, 114.0, 109.7, 66.3, 57.6, 44.1, 42.4, 27.5, 26.6, 24.8. IR (neat): 3341, 2940, 1705, 1608, 1486, 1463, 1348, 1304, 1177, 1007, 752 cm^–1. HRMS (ESI⁺): m/z (%) calcd for C₂₇H₂₆O₂N₂Br [M + H]⁺: 489.1172; found: 489.1168. [α]_D ^26.1 +130.9 (c 0.1, CHCl₃, 90% ee); mp 121–125 °C
• 12 To obtain more evidence for the hypothesis, we performed the reaction by the chiral tin iodide methoxide (X = I) derived from 4a (100% ee) under diluted conditions using twofold volume of dry THF and as a result, the ee of product 3a was slightly increased by 6%. This result suggested that the position of equilibrium moved so that the concentration of a homochiral dimer decreased under diluted conditions.