Modification of Pseudo-C ₃-Symmetric Trisoxazoline and Its Application to the Friedel-Crafts Alkylation of Indoles and Pyrrole with Alkylidene Malonates

Abstract

New pseudo-C ₃-symmetric hetero-trisoxazoline can be easily prepared on a gram scale in good yield. Its combination with copper(II) triflate exhibits high enantiomeric induction in the asymmetric Friedel-Crafts alkylation between indoles and alkylidene malonates, with up to 97% ee and good to excellent yields. The catalyst loading can be lowered to 0.5 mol% without loss of the enantiomeric excess.

asymmetric catalysis - alkylation - copper - enantioselectivity - indoles

References and Notes

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12

Procedure for the preparation of i -Pr-bisoxazoline:
2-(3,5-Di-tert-butylbenzyl)malononitrile (5.36 g, 20 mmol) and Zn(OTf)₂ (7.27 g, 20 mmol) in anhydrous toluene (150 mL) was stirred for 5 min under a nitrogen atmosphere. To the mixture was added a solution of (S)-2-amino-3-methyl-butan-1-ol (4.16 g, 40 mmol) in anhydrous toluene (50 mL) and the resulting reaction mixture was heated at reflux for 72 h. After cooling to r.t., the mixture was washed with brine (3 × 100 mL) and NaHCO₃ (3 × 100 mL), dried over Na₂SO₄, and concentrated. The residue was purified by flash chromatography to give pure i-Pr-BOX as a buff-colored oil. Yield: 6.07 g (69%). [α]_D ^²0 -34.1 (c 0.50, CHCl₃); IR (neat): 2959, 2872, 1665, 1599, 1468, 1362, 1249, 1201, 991, 713 cm^-¹; ^¹H NMR (300 MHz, CDCl₃): δ = 7.24 (t, J = 1.8 Hz, 1 H), 7.08 (d, J = 1.8 Hz, 2 H), 4.17-4.26 (m, 2 H), 4.00 (t, J = 7.8 Hz, 1 H), 3.80-3.97 (m, 4 H), 3.15-3.31 (m, 2 H), 1.69-1.80 (m, 1 H), 1.52-1.62 (m, 1 H), 1.30 (s, 18 H), 0.72-0.90 (m, 12 H); ^¹³C NMR (75 MHz, CDCl₃): δ = 163.63, 163.60, 149.9, 136.7, 122.78, 120.0, 71.4, 71.4, 69.7, 69.6, 41.0, 35.9, 34.3, 31.9, 31.1, 18.1, 18.0, 17.4; MS (EI): m/z = 440 [M⁺]; HRMS (EI): m/z [M]⁺ calcd for C₂₈H₄₄O₂N₂ 440.3403. Found: 440.3402.
Typical procedure for the synthesis of chiral hetero-trisoxazoline 2: To a solution of bisoxazoline 5 (2.97 g, 7.0 mmol) in dried THF (90 mL) was added dropwise t-BuLi (5.0 mL, 1.6 M in hexanes, 8.0 mmol) within 15-20 min at -78 ˚C. The resulting yellow solution was stirred for 1 h at the same temperature, then a solution of 2-chloromethyl oxazoline 6a (1.99 g, 9.8 mmol) in THF (50 mL) was added dropwise at -78 ˚C over 20 min. The mixture was slowly warmed to room temperature and kept stirring for a further 36 h. The solvent was removed and the residue was diluted with CH₂Cl₂ (100 mL), then washed with H₂O (20 mL). The aqueous layer was extracted with CH₂Cl₂ (2 × 20 mL), and the combined organic phases were dried over Na₂SO₄, filtered, and concentrated. Petroleum ether was added to precipitate 2-chloromethyl oxazoline, the filtrate was collected, and the solvent was removed in vacuo. The residue was purified by flash chromatography (PE-EtOAc, 10:1→1:2) to give pure product as a white solid. Yield: 2.64 g (64%); [α]_D ^²0 -8.2 (c 1.00, CHCl₃); IR (KBr): 2958, 2926, 2870, 1659, 1599, 1478, 1459, 1362, 1247, 1177, 1001, 752 cm^-¹; ^¹H NMR (400 MHz, CDCl₃): δ = 7.80 (d, J = 6.0 Hz, 1 H), 7.22-7.26 (m, 4 H), 7.08 (s, 2 H), 5.54 (d, J = 8.0 Hz, 1 H), 5.37 (t, J = 6.8 Hz, 1 H), 4.28 (t, J = 8.8 Hz, 1 H), 3.98 (t, J = 7.6 Hz, 1 H), 3.70-3.83 (m, 3 H), 3.35-3.55 (m, 4 H), 3.06-3.13 (m, 2 H), 2.68 (d, J = 14.8 Hz, 1 H), 1.67-1.76 (m, 1 H), 1.54-1.62 (m, 1 H), 1.26 (s, 18 H), 0.70-0.87 (m, 12 H); ^¹³C NMR (100 MHz, CDCl₃): δ = 165.5, 165.3, 164.7, 150.0, 142.4, 140.1, 135.3, 128.2, 127.2, 125.4, 125.4, 124.9, 120.5, 82.9, 76.4, 71.7, 71.0, 70.0, 69.4, 46.0, 40.1, 38.3, 34.6, 32.4, 31.8, 31.5, 30.4, 18.8, 18.4, 17.6, 17.0; MS (EI): m/z = 611 [M⁺]; HRMS (EI): m/z [M]⁺ calcd for C₃₉H₅₃O₃N₃: 611.4087. Found: 611.4088.
Typical procedure for 2/Cu(OTf) ₂ -catalyzed asymmetric Friedel-Crafts reaction (9b as an example): To a Schlenk tube was added 2 (18.4 mg, 0.030 mmol), Cu(OTf)₂ (9.1 mg, 0.025 mmol), and s-BuOH (1.25 mL) under an N₂ atmos-phere, and the resulting blue-green solution was stirred at room temperature for 2-3 h. The solution of catalyst was transferred to 8b (62.5 mg, 0.25 mmol) under an air atmos-phere and the mixture was allowed to stir at -25 ˚C for 15 min, then indole (36.0 mg, 0.30 mmol) was added. The reaction was held at -25 ˚C until complete (reaction monitored by TLC), then the mixture was concentrated under reduced pressure, and the residue was submitted to flash column chromatography on silica gel (CH₂Cl₂-PE, 1:1 then pure CH₂Cl₂) to afford the desired product 9b as a white solid. Yield: 91.6 mg (99%); 94% ee [Chiralcel OD-H,
i-PrOH-hexane, 10:90, 0.90 mL/min, 254 nm: t _R (minor) = 20.35 min, t _R (major) = 24.73 min.]; ^¹H NMR (300 MHz, CDCl₃): δ = 8.01 (br s, 1 H), 7.55 (d, J = 8.1 Hz, 1 H), 7.19-7.38 (m, 6 H), 7.11-7.16 (m, 2 H), 7.01-7.06 (m, 1 H), 5.08 (d, J = 12 Hz, 1 H), 4.29 (d, J = 12 Hz, 1 H), 3.99 (m, 4 H), 1.00 (m, 6 H).