Organocatalyzed Enantioselective Synthesis of Nitroalkanes Bearing All-Carbon Quaternary Stereogenic Centers through Conjugate Addition of Acetone Cyanohydrin

Abstract

The first organocatalyzed phase-transfer enantioselective conjugate addition of cyanide ion derived from acetone cyanohydrin to β,β′-disubstituted nitroolefins is reported. The reaction leads to the efficient formation of nitroalkanes bearing an all-carbon quaternary stereogenic center in up to 72% ee.

Key words

asymmetric synthesis - conjugate addition - cyanohydrins - organocatalysis - quaternary stereogenic center

References and Notes

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• 18a

  See ref. 3.

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19

N , O -Di[3,5-bis(trifluoromethyl)benzyl]cinchoninium bromide (2c): 3,5-Bis(trifluoromethyl)benzyl bromide (0.48 mL, 2.6 mmol) was added to a suspension of cinchonine (0.59 g, 2.0 mmol) in toluene (6 mL). The mixture was vigorously stirred at 90 ˚C for 18 h and then cooled to r.t. and filtered. The white solid obtained (0.82 g, 68%) was washed with toluene (2 × 25 mL), dried under reduced pressure and used without further purification. 3,5-Bis(trifluoromethyl)benzyl bromide (0.37 mL, 2.0 mmol) and 50% aq NaOH (53 mg, 1.33 mmol) were added to a solution of N-3,5-bis(trifluoromethyl)benzylcinchoninium bromide (0.4 g, 0.66 mmol) in CH₂Cl₂ (7 mL). The reaction mixture was stirred for 6 h at r.t. and then quenched by addition of H₂O. The aqueous layer was extracted with CH₂Cl₂ (2 × 5 mL) and the combined organic layers were dried (MgSO₄), filtered and evaporated in vacuo. The crude product was purified by chromatography on silica gel column with hexane-EtOAc-MeOH-CH₂Cl₂ (5:4:2:1) as eluent to give the title product as a pale yellow solid (0.32 g, 58%); mp 162-165 ˚C; [α]_D ^²0 +48.3 (c = 0.94, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 8.93 (br s, 1 H), 8.74 (d, J = 7.4 Hz, 1 H), 8.37 (s, 2 H), 8.06 (s, 2 H), 7.90 (s, 2 H), 7.81 (s, 1 H), 7.54 (t, J = 7.05 Hz, 2 H), 7.43 (m, 1 H), 6.76 (br s, 1 H), 6.60 (d, J = 12.3 Hz, 1 H), 5.80 (m, 1 H), 5.53 (d, J = 12.4 Hz, 1 H), 5.23 (d, J = 10.5 Hz, 2 H), 5.04 (d, J = 17.0 Hz, 2 H), 4.82 (d, J = 12.4 Hz, 1 H), 4.65 (br s, 1 H), 4.15 (t, J = 10.0 Hz, 1 H), 3.29 (t, J = 11.0 Hz, 1 H), 2.65 (m, 1 H), 2.49 (m, 3 H), 1.84 (m, 2 H), 1.49 (m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 149.2, 148.5, 139.4, 139.3, 139.0, 134.5, 134.05, 132.4 (q, J = 34 Hz), 130.0, 129.9, 128.8, 127.8, 127.5, 123.05 (q, J = 273 Hz, CF₃), 124.9, 124.4, 122.5 (q, J  = 273 Hz, CF₃), 122.4, 118.4, 75.1, 69.9, 66.8, 60.9, 56.0, 55.0, 37.3, 26.8, 23.4, 22.1. ^¹9F NMR (376 MHz, CDCl₃): δ = 62.9 (s, 6 F), -63.0 (s, 6 F). IR (CHCl₃): 3367, 3030, 2960, 1371, 1278, 1176, 1142, 903 cm^-¹. ESI-MS (+): m/z = 779 [M⁺]. ESI-MS (-): m/z = 81, 79 [M^-]. Anal. Calcd for C₃₇H₃₁BrF₁₂N₂O: C, 53.70; H, 3.78; N, 3.39. Found: C, 53.74; H, 3.72; N, 3.44.

20

General Procedure for the Hydrocyanation of β,β′-Disubstituted Nitroolefins: Catalyst (8.3 mg, 0.01 mmol) was added to a screw-tapped test tube that contained a mixture of nitroolefin (0.1 mmol), acetone cyanohydrin (0.018 mL, 0.2 mmol) and toluene (1 mL). After the resulting mixture had been cooled to -30 ˚C finely powdered K₂CO₃ (28 mg, 0.2 mmol) was added in one portion. The reaction mixture was then vigorously stirred at the same temperature without any precaution to exclude moisture or air. After 72 h, the reaction product was directly isolated by column chromatography on silica gel with hexane-EtOAc (5:1) as eluent.
2-Methyl-3-nitro-2-phenylpropanenitrile: HPLC on an AD-H column with hexane-i-PrOH (80:20) as eluent, flow rate: 0.75 mL min^-¹, t _R = 9.37 min (major), t _R = 10.40 min (minor), λ = 220 nm; [α]_D ^²0 +12.4 (c = 0.45, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 7.38-7.53 (m, 5 H), 4.78 (d, J = 13.0 Hz, 1 H), 4.72 (d, J = 13.0 Hz, 1 H), 1.90 (s, 3 H). ^¹³C NMR (150 MHz, CDCl₃): δ = 135.0, 129.6, 129.3, 125.5, 119.95, 81.6, 41.3, 24.8. IR (CHCl₃): 3021, 2928, 2855, 2248, 1562, 1449, 1374, 780, 700 cm^-¹. ESI-MS
(+): m/z = 213 [M⁺ + Na].
2-Methyl-2-(naphthalen-2-yl)-3-nitropropanenitrile: HPLC on an AD-H column with hexane-i-PrOH (95:5) as eluent, flow rate: 0.50 mL min^-¹, t _R = 52.59 min (minor),
t _R = 54.75 min (major), λ = 254 nm; [α]_D ^²0 +11.6 (c = 0.59, CHCl₃); mp 133-135 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 8.03 (d, J = 2.2 Hz, 1 H), 7.94 (d, J = 8.7 Hz, 1 H), 7.87 (m, 2 H), 7.57 (m, 2 H), 7.51 (dd, J ₁ = 8.7 Hz, J ₂ = 2.2 Hz, 1 H), 4.89 (d, J = 13.0 Hz, 1 H), 4.81 (d, J = 13.0 Hz, 1 H), 1.99 (s, 3 H). ^¹³C NMR (150 MHz, CDCl₃): δ = 133.13, 133.07, 132.1, 129.75, 128.3, 127.7, 127.4, 127.3, 125.6, 122.0, 120.0, 81.45, 41.5, 24.8. IR (CHCl₃): 3036, 2927, 2248, 1563, 1373 cm^-¹. ESI-MS (+): m/z = 263 [M⁺ + Na].
2-(4-Chlorophenyl)-2-methyl-3-nitropropanenitrile: HPLC on an AD-H column with hexane-i-PrOH (80:20) as eluent, flow rate: 0.75 mL min^-¹, t _R = 10.63 min (minor), t _R = 11.85 min (major), λ = 220 nm; [α]_D ^²0 -16.7 (c = 0.65, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 7.44 (s, 4 H), 4.74 (s, 2 H), 1.88 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 135.4, 133.5, 129.7, 126.9, 119.5, 81.2, 40.9, 24.9. IR (CHCl₃): 3054, 2927, 2248, 1564, 1495, 1374, 1103, 1014, 815 cm^-¹. ESI-MS (+): m/z = 247 [M⁺ + Na].