Chiral Sodium Phosphate Catalyzed Enantioselective 1,4-Addition of TMSCN to Aromatic Enones

Abstract

A facile enantioselective 1,4-addition of TMSCN to aromatic enones has been developed using chiral sodium phosphate. Thus, in the presence of 20 mol% of sodium salt generated in situ from (R)-3,3′-di(1-adamantyl)-1,1′-binaphthyl-2,2′-diylphosphoric acid and NaOH, β-cyano ketones were obtained in high yield (86-96%) and up to 72% ee within three hours at 80 ˚C in toluene.

Key words

asymmetric catalysis - enones - 1,4-addition - nitriles - phosphates

References and Notes

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Preparation of 6h
To a stirred solution of (R)-BINOL (6a; 1.431 g, 5.0 mmol) and 1-adamantanol (1.522 g, 10.0 mmol) in CH₂Cl₂ (25 mL), concd H₂SO₄ (0.8 mL) was added dropwise at 0 ˚C over 5 min. After stirring at 0 ˚C for 30 min the ice bath was removed. The suspension was stirred at r.t. for an additional 6 h before aq NaOH (5%) was added to neutralize H₂SO₄ thus to quench the reaction. The resulting mixture was extracted by CH₂Cl₂ twice. The combined organic phase was washed with brine, dried over Na₂SO₄, and concentrated. The crude solid was purified by silica gel chromatography using PE-EtOAc (10:1, v/v) as the eluent to yield (R)-3,3′-di(1-adamantyl)-1,1′-binaphthyl-2,2′-diol (6h) as a white solid (1.670 g, 3.01 mmol); 60% yield, mp 207-209 ˚C; [α]_D ^¹7 -82.5 (c 0.114, CHCl₃). ^¹H NMR (500 MHz, CDCl₃): δ = 1.79-1.85 (dd, J = 21.0, 12.0 Hz, 12 H, CHCH ₂CH), 2.00 (s, 12 H, CCH ₂CH), 2.15 [s, 6 H, CH(CH₂)₃], 7.17 (d, J = 9.0 Hz, 2 H, ArH), 7.37-7.43 (m, 4 H, ArH), 7.80 (s, 2 H, ArH), 7.97 (d, J = 9.0 Hz, 2 H, ArH) ppm. ^¹³C NMR (125 MHz, CDCl₃): δ = 29.0, 36.1, 36.8, 43.1, 110.7, 117.5, 123.5, 124.0, 125.7, 129.5, 131.4, 131.6, 147.0, 152.3 ppm.
Preparation of 7h
(R)-3,3′-Di(1-adamantyl)-1,1′-binaphthyl-2,2′-diol (6h; 555 mg, 1 mmol) was dissolved in pyridine (3 mL) in a 50 mL Schlenk tube. Phosphorous oxychloride (185 µL, 2 mmol) was added dropwise at r.t. After stirring for 10 h at r.t., H₂O (3 mL) was added. The resulting mixture was stirred for additional 6 h at r.t. followed by addition of CH₂Cl₂. All pyridine was removed by reverse extraction with 1 M HCl. The organic phase was washed with brine, dried over Na₂SO₄, and concentrated. The crude solid was purified by flash silica gel chromatography CH₂Cl₂-MeOH (5:1, v/v) as the eluent to yield (R)-3,3′-di(1-adamantyl)-1,1′-binaphthyl-2,2′-diylphosphoric acid (7h) as a white solid (555 mg, 0.9 mmol); 90% yield; mp >300 ˚C; [α]_D ^²¹ -283.3 (c 0.240, CHCl₃). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.75 (s, 12 H, CHCH ₂CH), 1.95 (s, 12 H, CCH ₂CH), 2.07 [s, 6 H, CH(CH₂)₃], 7.21-7.23 (m, 2 H, ArH), 7.41-7.42 (m, 4 H, ArH), 7.87 (s, 2 H, ArH), 8.01 (d, J = 8.8 Hz, 2 H, ArH) ppm. ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 28.5, 35.9, 36.4, 42.7, 121.6, 122.4, 123.4, 124.3, 126.0, 130.0, 130.3, 130.8, 147.1, 149.3 ppm. ^³¹P NMR (162 MHz, DMSO-d ₆): δ = 3.5 (s) ppm.

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Typical Procedure for the Asymmetric 1,4-Addition of TMSCN to Enones After (R)-3,3′-di(1-adamantyl)-1,1′-binaphthyl-2,2′-diyl phosphoric acid (7h, 18.5 mg, 0.03 mmol, 20 mol%) and NaOH (1.2 mg, 0.03 mmol, 20 mol%) were placed in a dry Schlenk tube under argon. Toluene (0.5 mL) was added, and the mixture was stirred at 30 ˚C for 1 h. Then, chalcone (1a, 31.2 mg, 0.15 mmol), 2-t-BuPhOH (0.03 mmol, 20 mol%), additional toluene (0.5 mL), and TMSCN (0.33 mmol, 2.2 equiv) were added at r.t. Equipped with cold finger, the reaction mixture was stirred at 80 ˚C until the reaction was completed (monitored by TLC). The reaction was quenched with 1 M HCl (0.3 mL) followed by diluting with dioxane (2 mL) and stirring for additional 30 min at r.t. To work it up, H₂O (2 mL) was added, and the resulting mixture was extracted with EtOAc (5 mL) (Caution! HCN possibly generated in the reaction mixture is highly toxic. Those operations should be conducted in a well-ventilated hood). The extract was washed with H₂O (2 mL), brine (3 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (PE-EtOAc, 20:1, v/v) to afford pure product 2a as a white solid in 94% yield and 71% ee.
4-Oxo-2,4-diphenylbutanenitrile (2a)
^¹H NMR (400 MHz, CDCl₃): δ = 3.52 (dd, J = 18.0, 6.0 Hz, 1 H, NCCHCH _A H_BCO), 3.74 (dd, J = 18.0, 8.0 Hz, 1 H, NCCHCH_A H _B CO), 4.57 (dd, J = 8.0, 6.0 Hz, 1 H, NCCHCH_AH_BCO), 7.34-7.49 (m, 7 H, ArH), 7.58-7.62 (m, 1 H, ArH), 7.92-7.94 (m, 2 H, ArH) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 31.9, 44.5, 120.6, 127.5, 128.1, 128.4, 128.8, 129.3, 133.9, 135.3, 135.8, 194.6 ppm. IR (KBr): ν = 1681, 2236 cm^-¹. HPLC [Chiralpak AS-H, 254 nm, n-hexane-2-PrOH (70:30), 1.0 mL/min]: t _R(major) = 13.3 min, t _R(minor) = 21.4 min; [α]_D ^¹7 -20.0 (c 0.100, CH₂Cl₂, 71% ee).

15

CCDC-787260 contains the supplementary crystallographic data of 2f for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.