Brønsted Acid Catalyzed Asymmetric Reduction of 2- and 2,9-Substituted 1,10-Phenanthrolines

Abstract

Several 2- and 2,9-substituted 1,10-phenanthrolines are reduced asymmetrically for the first time using a Hantzsch dihydropyridine in the presence of BINOL-derived phosphoric acid catalysts. The best results are obtained with phenanthrolines bearing unbranched or nitrogen-containing alkyl groups in the 2- or 2,9-positions, which afford chiral octahydrophenanthrolines in a range of yields (40-88%) and good to excellent levels of enantiomeric purity (78-99% ee).

Key words

reduction - phenanthroline - Brønsted acid - enantioselective - organocatalysis

References and Notes

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13

Reduction of 6a with Catalyst 4b and Enantiomeric AssayA flame-dried screw-cap vial with a stir bar was charged with 6a (50 mg, 0.26 mmol), dihydropyridine 3 (390 mg, 1.54 mmol, 6 equiv), catalyst 4b (3.6 mg, 0.005 mmol, 2 mol%) and dry benzene (5 mL). The vial was flushed with argon, capped, and the mixture was heated with stirring at 60 °C for 24 h. The reaction mixture was transferred to a round-bottomed flask and the solvent was removed under reduced pressure. Absolute EtOH (5 mL) and KOH (2 pellets, ca. 200 mg) were added, and the mixture was heated to reflux for 45 min. Then, H₂O (5 mL) was added and EtOH was removed under reduced pressure. The remaining aqueous mixture was extracted with CH₂Cl₂ (3 × 5 mL) and the combined organic extract was dried over anhyd Na₂SO₄, filtered, and concentrated in vacuo. Column chromatog-raphy (silica gel, 83:15:2 hexanes-EtOAc-Et₃N; R _f = 0.28) gave (+)-(R)-7a (29 mg, 54%).Compound (+)-(R)-7a: viscous colorless oil; [α]_D ²⁰ +53.5 (c 1.27, acetone); lit.¹⁴ [α]_D ²⁰ -41.4 (c 1.70, acetone) at 68% ee. ¹H NMR (300 MHz, acetone-d ₆): δ = 6.23 (ABq, 2 H), 3.62 (b, 2 H), 3.30-3.22 (m, 3 H), 2.79-2.54 (m, 4 H), 1.89-1.74 (m, 3 H), 1.50-1.40 (m, 1 H), 1.20 (d, 3 H, J = 6.3 Hz). ¹³C NMR (75.5 MHz, acetone-d ₆): δ = 132.7, 132.1, 119.0, 118.5, 118.2, 117.9, 47.5, 42.2, 30.4, 27.0, 26.7, 22.4, 22.0.A solution of 7a (24 mg, 0.12 mmol), triphosgene (39 mg, 0.13 mmol), and Et₃N (33 µL, 0.24 mmol) in dry THF (2 mL) was stirred at r.t. for 16 h. Then, H₂O (4 mL) was added and the THF was removed under reduced pressure. The remaining aqueous mixture was extracted with CH₂Cl₂ (3 × 4 mL), washed with H₂O (5 mL) and brine (5 mL), dried over anhyd Na₂SO₄, filtered, and concentrated in vacuo. Column chromatography (silica gel, 3:1 CH₂Cl₂-Et₂O, R _f = 0.35) gave (-)-(R)-8a (23 mg, 85%).Compound (-)-(R)-8a: colorless solid; [α]_D ²⁰ -26.9 (c 1.08, CHCl₃); lit.¹⁴ [α]_D ²⁰ +21.0 (c 4.37, CHCl₃) at 68% ee. CSP HPLC analysis [Chiralpak AS-H; eluent: hexanes-i-PrOH (80:20), 1.0 mL/min] determined 90.5:9.5 er, 81% ee [t _R(minor) = 10.63 min, t _R(major) = 11.73 min]. ¹H NMR (300 MHz, CDCl₃): δ = 6.76 (s, 2 H), 4.45-4.37 (m, 1 H), 3.89-3.78 (m, 2 H), 2.92-2.72 (m, 4 H), 2.12 (quin, 2 H, J = 5.7 Hz), 2.07-1.98 (m, 2 H), 1.40 (d, 3 H, J = 6.3 Hz). ¹³C NMR (75.5 MHz, CDCl₃): δ = 152.7, 125.2, 124.7, 118.3 (2 C), 116.8, 116.7, 45.3, 38.9, 29.3, 23.4, 22.8, 20.2, 19.2.

16

Reduction of 6g with Catalyst 4b and Enantiomeric AssayA flame-dried screw-cap vial with a stir bar was charged with 6g (58 mg, 0.20 mmol), dihydropyridine 3 (304 mg, 1.20 mmol, 6 equiv), catalyst 4b (7 mg, 0.01 mmol, 5 mol%) and dry benzene (4 mL). The vial was flushed with argon, capped, and the mixture was heated with stirring at 60 °C for 24 h. The reaction mixture was transferred to a round-bottomed flask and the solvent was removed under reduced pressure. Column chromatography [silica gel, hexanes-EtOAc (97:3)] gave, sequentially, 2,9-dibutyl-1,2,3,4-tetrahydro-1,10-phenanthroline (9g, 5 mg, 8%, R _f = 0.39) and octahydrophenanthroline 7g (53 mg, 88%, R _f = 0.19) as a 3:2 mixture of ent and meso isomers.Compound 9g: pale yellow oil. ¹H NMR (300 MHz, acetone-d ₆): δ = 7.98 (d, 1 H, J = 8.4 Hz), 7.26 (d, 1 H, J = 8.4 Hz), 7.06 (d, 1 H, J = 8.1 Hz), 6.93 (d, 1 H, J = 8.1 Hz), 6.10 (b, 1 H), 3.49-3.39 (m, 1 H), 2.93-2.82 (m, 5 H), 1.82-1.75 (m, 2 H), 1.68-1.43 (m, 9 H), 0.95 (t, 6 H, J = 7.5 Hz).Compound ent/meso-7g:¹⁰ pale yellow oil. ¹H NMR (300 MHz, acetone-d ₆): δ = 6.26 (s, 1 H), 6.25 (s, 1 H), 3.59 (b, 1 H), 3.50 (b, 1 H), 3.20-3.05 (m, 2 H), 2.71-2.60 (m, 4 H), 1.93-1.88 (m, 2 H), 1.56-1.32 (m, 14 H), 0.92 (t, 6 H, J = 6.9 Hz). ¹³C NMR (75.5 MHz, acetone-d ₆): δ = 133.2, 133.1, 119.9, 119.8 118.9, 118.7, 52.8, 52.7, 37.1, 37.0, 28.9, 28.8, 28.6, 27.2, 23.5, 14.3.A solution of ent/meso-7g (51 mg, 0.17 mmol), triphosgene (55 mg, 0.19 mmol), and Et₃N (47 µL, 0.34 mmoL) in dry THF (4 mL) was stirred at r.t. for 16 h. Then, H₂O (4 mL) was added and the THF was removed under reduced pressure. The remaining aqueous mixture was extracted with CH₂Cl₂ (3 × 4 mL), washed with H₂O (5 mL) and brine (5 mL), dried over anhyd Na₂SO₄, filtered, and concentrated in vacuo. Column chromatography [silica gel, hexane-EtOAc (90:10)] gave, sequentially, (-)-(R,R)-8g (30 mg, 55%, R _f = 0.16), and meso-8g (20 mg, 36%, R _f = 0.08). Compound (-)-(R,R)-8g: clear colorless oil; [α]_D ²⁰ -102 (c 1.50, CHCl₃). CSP HPLC analysis [Chiralcel OD-H; eluent: hexanes-i-PrOH (98:2), 0.5 mL/min] determined 99.5:0.5 er, 99% ee [t _R(minor) = 11.09 min, t _R(major) = 11.81 min]. IR (KBr, neat): 2954, 2931, 2858, 1703 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 6.72 (s, 2 H), 4.31-4.28 (m, 2 H), 2.83-2.75 (m, 4 H), 2.19-2.13 (m, 2 H), 2.00-1.95 (m, 2 H), 1.83-1.78 (m, 4 H), 1.53-1.32 (m, 10 H), 0.91 (t, 6 H, J = 6.9 Hz). ¹³C NMR (75.5 MHz, CDCl₃): δ = 152.8, 124.8, 118.0, 116.5, 49.5, 33.0, 28.1, 26.2, 22.6, 20.0, 14.0. MS (EI): m/z (%) = 326 (71) [M⁺], 269 (100). HRMS (EI): m/z calcd for C₂₁H₃₀N₂O: 326.2358; found: 326.2356.