Design of Novel Hydrogen-Bonding Donor Organocatalysts and Their Application to Asymmetric Direct Aldol Reaction

Abstract

Asymmetric catalytic activities of various organocatalysts bearing double hydrogen-bonding donor units showing different pK _a values were examined for direct aldol reactions of cyclohexanone with aromatic aldehydes. Organocatalyst with motif exhibiting the highest acidity resulted in the corresponding aldol products with the highest enantioselectivity. A good correlation has been observed between the asymmetric catalytic activity for direct aldol reactions and acidities of double hydrogen-bonding donating units.

Key words

organocatalyst - direct aldol reaction - hydrogen-bonding donor - asymmetric reaction

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• 11 Organocatalyst 8 Colorless powder; mp 225–227 °C; [α]_D ²⁰ +79.2 (c 1.00, MeOH). ¹H NMR (400 MHz, CD₃OD): δ = 1.97 (m, 2 H), 2.13–2.15 (m, 2 H), 3.25–3.33 (m, 2 H), 3.5 (dd, J = 5.7, 14.8 Hz, 1 H), 3.78 (m, 1 H), 3.93 (m, 1 H), 7.55 (s, 1 H), 7.60 (s, 2 H). ¹³C NMR (100 MHz, CD₃OD): δ = 25.6, 28.0, 45.0, 46.5, 62.4, 68.9, 116.7, 120.4, 125.0 (q, ¹ J _C–F = 271.7 Hz), 125.2, 132.5 (q, ² J _C–F = 32.7 Hz), 151.7, 154.2. Anal. Calcd for C₁₇H₁₅F₁₂N₃O₄S₂: C, 33.07; H, 2.45; N, 6.81. Found: C, 32.98; H, 2.59; N, 6.68. Organocatalyst 9 Colorless powder; mp 243–245 °C; [α]_D ²⁰ +85.7 (c 1.00, MeOH). ¹H NMR (400 MHz, CD₃OD): δ = 1.90–2.03 (m, 2 H), 2.11–2.19 (m, 2 H), 3.30–3.33 (m, 2 H), 3.55 (dd, J = 6.2, 15.0 Hz, 1 H), 3.84 (dd, J = 2.8, 15.0 Hz, 1 H), 3.87–3.97 (m, 1 H), 7.34 (S, 2 H), 7.51 (s, 1 H); ¹³C NMR (100 MHz, CD₃OD): δ = 25.6, 28.1, 45.0, 46.6, 62.6, 68.8, 116.8, 125.0 (q, ¹ J _C-F = 272.0 Hz), 125.6, 132.7 (q, ² J _C–F = 33.0 Hz), 152.8, 154.4. Anal. Calcd for C₁₈H₁₅F₁₂N₃O₄S₂: C, 34.35; H, 2.40; N, 6.68. Found: C, 34.51; H, 2.68; N, 6.65.
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• 14 Typical Procedure of the Aldol Reaction Using Organocatalyst 9 To a mixture of p-nitrobenzaldehyde (10a, 30.2 mg, 0.200 mmol) and cyclohexanone (209 μL, 2.00 mmol) was added organocatalyst 9 (12.6 mg, 0.0200 mmol) at r.t. After stirring at r.t. for 72 h, the reaction mixture was directly purified by flash column chromatography on silica gel with a 2:1 mixture of hexane and EtOAc to afford 12a (44.9 mg, 90%) as a white powder.