Multivalent polyglycerol supported imidazolidin-4-one organocatalysts for enantioselective Friedel-Crafts alkylations

Abstract

The first immobilization of a MacMillan's first generation organocatalyst onto dendritic support is described. A modified tyrosine-based imidazolidin-4-one was grafted to a soluble high-loading hyperbranched polyglycerol via a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction and readily purified by dialysis. The efficiency of differently functionalized multivalent organocatalysts 4a-c was tested in the asymmetric Friedel-Crafts alkylation of N-methylpyrrole with α,β-unsaturated aldehydes. A variety of substituted enals was investigated to explore the activity of the catalytic system which was also compared with monovalent analogues. The catalyst 4b showed excellent turnover rates and no loss of activity due to immobilization, albeit moderate enantioselectivities were observed. Moreover, easy recovery by selective precipitation allowed the reuse of the catalyst for three cycles.

Keywords: Friedel–Crafts; homogeneous catalysis; hyperbranched polyglycerol; imidazolidin-4-one; multivalency.

Scheme 1

Synthesis of hyperbranched polyglycerol-supported and G1 dendronized imidazolidin-4-ones 4a–c and 8 using a CuAAC reaction. Reaction conditions: (a) 1 (1.0 equiv), MsCl (1.2 equiv, with respect to degrees of functionalization), pyridine, 25 °C, 16 h, 76% 2a, 82% 2b and 87% 2c. (b) 2a–c (1.0 equiv), NaN₃ (3.0 equiv), DMF, 65 °C, 72 h, 72% 3a, 81% 3b and 86% 3c. (c) 3a–c (1.0 equiv), 5 (2.0 equiv), CuSO₄·5H₂O (0.2 equiv), sodium ascorbate (2.0 equiv), THF/H₂O 3:1 (v/v), 25 °C, 48 h, 71% 4a, 40% 4b and 35% 4c. (d) 6 (1.1 equiv), 5 (1.0 equiv), CuSO₄·5H₂O (0.1 equiv), sodium ascorbate (0.2 equiv), DIPEA (0.1 equiv), THF/H₂O 3:1 (v/v), 25 °C, 12 h, 70%. (e) 7, Dowex 50, MeOH, reflux, 12 h, 95%.

Scheme 2

Synthesis of tyrosine-based imidazolidin-4-one 5. Reaction conditions: (a) 9 (1.0 equiv), MeNH₂ (5.0 equiv), EtOH, 25 °C, 20 h. (b) PTSA (0.01 equiv), acetone, MeOH, reflux, 18 h, 79% (2 steps). (c) 10 (1.0 equiv), NaH (1.1 equiv), 6-chloro-1-hexyne (1.3 equiv), TBAI (0.01 equiv), DMF, 25 °C, 16 h, 88%.