Enantioselective Brønsted Acid Catalysis in the Friedel-Crafts Reaction of Indoles with Secondary ortho-Hydroxybenzylic Alcohols

Abstract

The reaction of indole and various methyl-substituted indoles with the title compounds was studied in the presence of chiral phosphoric acids, which act as Brønsted acid catalysts. While yields were generally high (>90%), significant enantioselectivities (up to 77% ee) were only achieved for certain substrate-catalyst combinations. In addition, a kinetic resolution of the starting material was observed, which led to an enrichment of one chiral alcohol to up to 68% ee after 76% conversion. The Friedel-Crafts reaction is not stereospecific (no direct S_N2-type substitution), but rather is likely to proceed via a cation, which is bound to the chiral Brønsted acid or its anion in a close contact ion pair.

Key words

carbocations - stereoselective synthesis - electrophilic aromatic substitutions - alkylations - enantioselectivity - organocatalysis

References and Notes

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Representative Procedure (8)
A Schlenk flask containing 250 mg of 4 Å MS was charged with benzylic alcohol 3 (21.0 mg, 100 µmol) and indole (46.9 mg, 400 µmol) in dry trifluorotoluene (1.5 mL). Catalyst 7g (7.53 mg, 10 µmol) was added, and the resulting mixture was stirred at r.t. until the starting material was completely consumed (monitored by TLC). The crude reaction mixture was purified directly by flash column chromatography on silica gel (eluent: pentane-Et₂O = 4:1 to 2:1) yielding compound 8 (30.9 mg, 100 µmol, quant., 50% ee) as a light-brown solid. ^¹H NMR (360 MHz, CDCl₃): δ = 1.15 (s, 9 H), 3.71 (s, 3 H), 4.51 (s, 1 H), 5.30 (s, 1 H), 6.28 (d, ⁴ J = 2.3 Hz, 1 H), 6.44 (dd, ^³ J = 8.5 Hz, ⁴ J = 2.3 Hz, 1 H), 7.04 (virt. t, ^³ J = ca. 7.5 Hz, 1 H), 7.15 (virt. t, ^³ J = ca. 7.6 Hz, 1 H), 7.26 (d, ^³ J = 8.5 Hz, 1 H), 7.29 (d, ^³ J = 8.1 Hz, 1 H), 7.36 (d, ^³ J = 1.9 Hz, 1 H), 7.52 (d, ^³ J = 8.0 Hz, 1 H), 8.02 (br s, 1 H) ppm. ^¹³C NMR (90.6 MHz, CDCl₃): δ = 28.9, 35.8, 45.4, 55.1, 101.6, 105.8, 110.8, 117.3, 119.4, 119.5, 121.2, 121.5, 122.2, 128.7, 132.1, 135.5, 154.9, 158.6 ppm. HRMS: m/z calcd for C₂₀H₂₃NO₂: 309.1723; found: 309.1724.

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An analysis of the absolute structure based on Bayesian statistics and Friedel pairs with a coverage of 99% resulted in a probability of 1.00.
Crystal Data
Formula: C₂₀H₂₃NO₂˙C₄H₁₀O; M _r = 383.51; crystal color and shape: colorless fragment, crystal dimensions: 0.13 × 0.23 × 0.69 mm; crystal system: monoclinic; space group: P2₁ (no. 4); a = 10.2950 (4), b = 7.7382 (3), c = 15.1602 (5) Å, β = 104.737 (2)˚; V = 1168.00(8) Å^³; Z = 2; µ _{MoK α} = 0.071 mm^-¹; ρ _calcd = 1.090 g cm^-³; θ range = 1.39-25.33˚; data collected: 27134; independent data [I _o > 2σ (I _o)/all data/R _int]: 3857/4255/0.027; data/restraints/parameters: 4255/1/267; R1 [I _o > 2σ (I _o)/all data]: 0.0376/0.0419; wR2
[I _o > 2σ (I _o)/all data]: 0.1086/0.1119; GOF = 1.089; Δρ _max/min: 0.11/-0.13 e Å^-³; Flack parameter; x = -0.6 (13); ‘Flack Equivalent’ Hooft parameter y = -0.3 (3). For detailed information see Supporting Information. CCDC 808871
[(-)-8] contains the supplementary crystallographic data for this compound. This data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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Crystal Data
Formula: C₁₂H₁₈O₃; M _r = 210.26; crystal color and shape: colorless fragment, crystal dimensions: 0.46 × 0.51 × 0.61 mm; crystal system: orthorhombic; space group: P2₁2₁2₁ (no. 19); a = 6.6950 (1), b = 9.1455 (2), c = 19.2531 (4) Å; V = 1178.85 (4) Å^³; Z = 4; µ _{CuK α} = 0.680 mm^-¹; ρ _calcd = 1.185 g cm^-³; θ range = 4.59-66.30˚; data collected: 27197; independent data [I _o > 2σ (I _o)/all data/R _int]: 1984/1995/0.027; data/restraints/parameters: 1995/0/209; R1 [I _o > 2σ (I _o)/all data]: 0.0215/0.0216; wR2 [I _o > 2σ (I _o)/all data]: 0.0582/0.0582; GOF = 1.111; Δρ _max/min: 0.13/-0.12 e Å^-³; Flack parameter; x = 0.03 (15); ‘Flack Equivalent’ Hooft parameter y = 0.05 (3). For detailed information see Supporting Information. CCDC 808870 [(+)-3)] contains the supplementary crystallographic data for this compound. This data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.