Planar Chiral PHANOLs as Organocatalysts for the Diels-Alder Reaction via Double Hydrogen-Bonding to a Carbonyl Group

Abstract

Planar chiral PHANOLs have been shown to catalyze Diels-Alder reactions of a,b-unsaturated aldehydes and ketones with various dienes. Rate accelerations of up to ca. 30-fold were obtained using the electron deficient 4,12-dihydroxy-7,15-dinitro[2.2]paracyclophane as a catalyst. It is proposed that the carbonyl group of the dienophile is activated via a double hydrogen-bonding mode. Although the PHANOLs are inherently chiral, little or no asymmetric induction was observed when using enantiopure (R)-PHANOL.

Key words

organocatalysis - planar chiral bisphenols - double hydrogen bonding - Diels-Alder reactions - carbonyl activation

References

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10

Inspection of X-ray crystal structures of biphenylenediol shows a phenolic O-O separation of 4.0 Å. Molecular modelling of PHANOL 1 reveals an expected phenolic O-O separation of ca. 4.1 Å.

13

Procedures and Data for Compounds 3-5: 4,12-Dibromo-7,15-dinitro[2.2]paracyclophane ( 3). A heterogeneous mixture of nitronium tetrafluoroborate (2.7 g, 20 mmol) in sulfolane (30 mL) in a sealed flask was immersed in an ultrasound bath until the mixture had homogenized. The resultant solution was added dropwise to a solution of 4,12-dibromo[2.2]paracyclophane 2 (2.5 g, 6.7 mmol) in CH₂Cl₂ (30 mL) at -78 °C under nitrogen. After 15 min the reaction mixture was allowed to warm to r.t., and was heated to 50 °C for 1 h. The reaction was quenched with H₂O (20 mL), the organic layer was separated from the aqueous layer, and the volatiles removed under reduced pressure. The residue was added to the aqueous layer, forming a precipitate, which was isolated by filtration. The aqueous layer was extracted with Et₂O (3 ¥ 30 mL), and the combined organic layers added to the precipitate. The resultant solution was washed with H₂O (2 ¥ 50 mL) and brine (1 ¥ 50 mL), dried over MgSO₄, and chromatographed (1:1 CH₂Cl₂:petroleum ether) to yield 3 (2.36 g, 77%) as a yellow solid: Mp 185-190 °C. R_f = 0.35 (1:1 CH₂Cl₂:petroleum ether). IR (DRIFTS): 3100, 2950, 2850, 1570, 1500, 1470, 1330 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 3.04-3.24 (4 H, m), 3.45-3.52 (2 H, m), 3.83-3.90 (2 H, m), 7.37 (2 H, s), 7.38 (2 H, s). ¹³C NMR (75 MHz, CDCl₃): δ = 32.0, 34.5, 127.9, 132.5, 136.5, 136.7, 141.6, 148.5. MS (EI): m/z = 458 (M⁺), 456 (M⁺), 454 (M⁺), 229, 227. HRMS (EI) calcd for C₁₆H₁₂O₄N₂ ^81,81Br₂: 457.9123, C₁₆H₁₂O₄N₂ ^79,81Br₂: 455.9143, C₁₆H₁₂O₄N₂ ^79,79Br₂: 453.9164. Found: 457.9132, 455.9147, 453.9176. 4,12-Dimethoxy-7,15-dinitro[2.2]paracyclophane ( 4). DMF (50 mL) was added to a flask charged with 4,12-dibromo-7,15-dinitro[2.2]paracyclophane (3) (1.11 g, 2.4 mmol), Cu(CH₃CN)₄BF₄ (80 mg, 0.24 mmol) and sodium methoxide (7.9 g, 146 mmol) under nitrogen, and the heterogeneous mixture was stirred for 30 min. The mixture was poured into an aqueous solution of HOAc (2 M, 100 mL), and extracted with EtOAc (2 ¥ 50 mL). The combined organic layers were washed with water (4 ¥ 100 mL) and brine (50 mL), dried over anhyd MgSO₄ and chromatographed (2:1 CH₂Cl₂:petroleum ether) to yield 4 (576 mg, 66%) as a yellow solid: Mp 178-180 °C. R_f = 0.30 (2:1 CH₂Cl₂:petroleum ether). IR (DRIFTS): 3067, 2966, 2942, 2857, 1594, 1561, 1505, 1455, 1438 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 2.90 (4 H, m), 3.31 (2 H, m), 3.80 (6 H, s), 3.95 (2 H, m), 6.18 (2 H, s), 7.39 (2 H, s). ¹³C NMR (75 MHz, CDCl₃): δ = 29.7, 34.2, 56.0, 116.0, 128.5, 129.5, 140.8, 142.9, 162.5. MS (EI): m/z = 358 (M⁺), 328, 179. Anal. Calcd for C₁₈H₁₈N₂O₆: H, 5.06; C, 60.33; N, 7.82. Found: H, 4.96; C, 60.25; N, 7.79. 4,12-Dihydroxy-7,15-dinitro[2.2]paracyclophane ( 5). 4,12-Dimethoxy-7,15-dinitro[2.2]paracyclophane (4) (500 mg, 1.4 mmol) was added to an aqueous solution of hydrobromic acid (50 mL, 48% w/w) and HOAc (5 mL). The solution was heated to 135 °C for 16 h, allowed to cool, diluted with H₂O (150 mL), neutralized to pH = 7 with sat. aq NaHCO₃ solution (ca. 200 mL) and extracted with EtOAc (3 ¥ 100 mL). The combined organic layers were washed with brine, dried over MgSO₄ and evaporated to give 5 (371 mg, 80%) as a dark solid: Mp 280 °C (dec.). R_f = 0.22 (2:98 MeOH:CH₂Cl₂). IR (DRIFTS): 3600-3000 cm^-1. ¹H NMR (300 MHz, CD₃SOCD₃): δ = 2.67 (4 H, m), 3.24 (2 H, m), 3.72 (2 H, m), 6.31 (2 H, s), 7.24 (2 H, s), 10.83 (2 H, s, broad). ¹³C NMR (68 MHz, CD₃SOCD₃): δ = 29.9, 33.7, 121.2, 126.7, 130.3, 140.5, 141.4, 162.6. MS (EI): m/z = 330, 314, 300, 282, 165, 149, 136, 120, 106, 79, 65. HRMS (EI): calcd for C₁₆H₁₄O₆N₂: 330.0852. Found: 330.0845. Anal. Calcd for C₁₆H₁₄N₂O₆: H, 4.27; C, 55.18; N, 8.48. Found: H, 3.99; C, 54.97; N, 8.36.

15

Both PHANOLs were fully soluble in EtOAc, DMSO and DMF, where presumably they are able to form strong hydrogen bonds to the solvent. Their lack of solubility in non-hydrogen bonding solvents precluded the direct examination (without solvent interference) of dienophile-PHANOL interactions by ¹H NMR.

16

1,1′-Binaphthyl-2,2′-diol.

20

The PHANOL system is clearly related to the Kelly biphenylene diol [8] (Figure [1] ) in so much as it employs two phenolic groups held with the correct orientation to doubly hydrogen bond to the two sp² lone pairs of a carbonyl group. It would be instructive to compare their relative reactivity. In the Kelly system, using 40-50 mol% of catalyst the reactions are typically run in CD₂Cl₂, with a 10-fold excess of diene at 55 °C, whereas for PHANOL (10 mol%) a 1:1 stoichiometry of diene:dienophile was employed with no solvent at ambient temperature: the conditions are not directly comparable. However, for the two entries that were run at ambient temperature in Kelly’s work (1. 10 equiv CpH, 1 equiv MVK, 40 mol% catalyst, 10 min, 90% conversion; 2. 10 equiv CpH, 1 equiv acrolein, 40 mol% catalyst, 30 min, 76%), comparable conversions were obtained using just 10 mol% PHANOL (Table [1] , entries 2, 7).