Synthesis of Chiral Calixarene-Like Salen Ligand and Application in Catalytic Asymmetric Friedel-Crafts Reaction of Aromatic Amines with Glyoxylate

Abstract

A new calixarene-like salen ligand is efficiently prepared from 2,6-bishydroxymethyl-4-tert-butyl phenol as starting material by a five-step synthesis. The enantioselective Friedel-Crafts reactions of aromatic amine with glyoxylate are examined employing a titanium derivative of this new ligand as the chiral catalyst, and ­provide modest to excellent enantioselectivities up to 98% ee.

salen ligand - macrocycle - asymmetric catalysis - Friedel-Crafts reaction - titanium complex

References and Notes

1

For reviews, see: Chem. Rev. 2003, 103, 2761-3400 (thematic issue of enantioselective catalysis).

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9

Procedure for the Synthesis of Compound 6.
To a solution of 1.5 g (2.80 mmol) diformyl triphenol (5) in 100 mL of dry CH₂Cl₂ was added 0.34 g (3 mmol) (1R,2R)-1,2-diaminocyclohexane and 2 g anhyd Na₂SO₄. The mixture was stirred for 24 h at r.t. After the solids were filtered, the solution was reduced to about 10 mL in vacuo. Addition of 30 mL of MeOH gave a yellow solid, which was then recrystallized with CH₂Cl₂-MeOH (1:1) to give 1.1 g of compound 6 (yield: 65%), yellow solid, mp 130-132 °C, [α]_D ²⁵ -25.8 (c 0.6, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 14.05 (s, 3 H), 8.22 (s, 2 H), 7.07 (s, 2 H), 7.04 (s, 2 H), 6.97 (s, 2 H), 4.09 (d, J = 14.2 Hz, 2 H), 3.84 (d, J = 14.2 Hz, 2 H), 3.32 (s, 4 H), 1.91-1.40 (m, 8 H), 1.21 (s, 18 H), 1.19 (s, 9 H) ppm. ¹³C NMR (300 MHz, CDCl₃): δ = 165.7, 158.5, 141.0, 131.7, 129.1, 127.4, 126.4, 125.9, 117.2, 72.0, 34.2, 33.6, 31.9, 31.7, 31.2, 24.5 ppm. IR (KBr): ν = 3421, 3252, 2935, 2890, 1628, 1532, 1485, 1410, 1360 cm^-1. MS (ES): m/z (%) = 609.5 (100). Anal. Calcd (%) for C₄₀H₅₂N₂O₃: C, 78.95; H, 8.55; N, 4.62. Found: C, 78.92; H, 8.60; N, 4.50.

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13

Typical Procedure for the Asymmetric Friedel-Crafts Reaction of Aromatic Amine with Glyoxylate.
In a 15-mL Schlenk tube, salen compound 6 (32 mg, 0.05 mmol) was dissolved in 2 mL of Et₂O under argon atmosphere, followed by the addition of titanium tetraisopropoxide (0.5 M in Et₂O, 100 µL, 0.05 mmol) and the mixture was stirred for 2 h at r.t. The resulting solution was cooled to 0 °C, and then N,N-dimethylaniline (125 µL, 1 mmol) and freshly distilled ethyl glyoxylate (160 µL, 2 mmol) were introduced into the reaction system, and stirred at 0 °C for about 24 h. The reaction process was monitored by TLC. After completion of the reaction, the solvent was removed under reduced pressure, the product was separated by preparative TLC (PE-EtOAc, 4:1) to give 180 mg (85% yield) 2-(4-dimethylaminophenyl)-2-hydroxyacetic acid ethyl ester. [α]_D ²⁵ +103.2 (c 0.5, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.29-7.25 (m, 2 H), 6.73-6.65 (m, 2 H), 5.08 (d, J = 6.0 Hz, 1 H), 4.27-4.15 (m, 2 H), 3.33 (d, J = 6.0 Hz, 1 H), 2.96 (s, 6 H), 1.23 (t, 3 H). The ee was determined by HPLC on a Chiralcel OD-H column, hexane-2-PrOH = 95:5, flow rate = 1.0 mL/min; t _R = 18.64 (minor), t _R = 24.94 (major).

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