Chiral Allylic Cyanohydrins as Versatile Substrates for Diastereoselective Copper(I)-mediated S_N2′ Allylic Substitutions

Abstract

2,6-Difluorobenzoated derivatives bearing a protected cyanohydrin function undergo highly stereoselective copper(I)-mediated S_N2′ allylic substitution reactions with diorganozinc reagents leading to chiral unsaturated nitriles.

asymmetric synthesis - allylic substitution - cyano­hydrins - copper - zinc - unsaturated nitriles

References and Notes

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10

The stereochemistry of the double bond was confirmed by 2D ¹H NMR spectroscopy.

11

Typical Procedure for the S _N 2′ Substitution: Preparation of (2 S , E )-2-(2-Methyl-2-pentylcyclopentylidene)aceto-nitrile (2d)
A flame-dried flask equipped with a magnetic stirring bar, an argon inlet, and a septum was charged with CuCN·2LiCl solution (2.6 mL, 1.0 M in THF, 2.64 mmol, 1.2 equiv), anhyd NMP (2.6 mL, overall ratio of solvents THF-NMP = 2:1). The mixture was cooled at -30 °C. To this solution was added dropwise dipentylzinc solution (1.1 mL, 4.8 M in THF, 5.28 mmol, 2.4 equiv). The resulting mixture was stirred at -30 °C for 45 min, and then (2S)-cyano(2-methylcyclopent-1-enyl)methyl 2,6-difluorobenzoate (1b, 610 mg, 2.2 mmol, 90% ee) was added dropwise as a solution in THF (1.5 mL). The reaction mixture was stirred at -30 °C to 0 °C for 2 h and sat. aq NH₄Cl solution (5 mL) was added. The quenched reaction mixture was poured into 25% aq NH₃ (2 mL), aq sat. NH₄Cl (100 mL) and Et₂O (100 mL) and stirred at 25 °C until the copper salts had dissolved then extracted with Et₂O (3 × 100 mL). The combined extracts were washed with H₂O, brine and dried over Mg₂SO₄. Evaporation of the solvents and purification by column chromatography (silica gel, pentane-Et₂O, 9:1) afforded the unsaturated nitrile 2d (382 mg, 2.0 mmol, 91%, 90% ee) as a pale yellow oil.
¹H NMR (300 MHz, CDCl₃): δ = 5.02 (t, ³ J = 2.55 Hz, 1 H), 2.81-2.56 (m, 2 H), 1.78-1.66 (m, 2 H), 1.66-1.53 (m, 2 H), 1.34-1.16 (m, 8 H), 1.04 (s, 3 H), 0.87 (t, ³ J = 6.75 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 181.9, 117.9, 89.9, 47.6, 40.4, 38.9, 34.0, 32.6, 26.1, 24.4, 22.7, 22.1, 14.3. MS (EI, 70 eV): m/z (%) = 191 (8) [M⁺], 176 (11), 162 (8), 148 (12), 121 (89), 120 (100), 106 (12), 93 (23), 79 (25). HRMS: m/z calcd: 191.1674; found: 191.1651. [α]_D ²⁰ -15.9 (c 1.49, CHCl₃). GC (Chirasil-Dex CB), 100 °C (5 min), ramp of 2 °C/min to 140 °C; t _R(min) = 23.45 (R), 23.93 (S).
(2 R , E )-(-2-Methyl-2-phenethylcyclopentylidene)aceto-nitrile (2h)
¹H NMR (400 MHz, CDCl₃): δ = 7.31-7.14 (m, 5 H), 5.09 (t, ³ J = 2.55 Hz, 1 H), 2.91-2.46 (m, 4 H), 1.88-1.58 (m, 6 H), 1.14 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 181.4, 142.2, 128.7, 128.4, 126.2, 117.8, 90.3, 47.7, 42.5, 38.9, 34.0, 31.3, 26.1, 22.2. MS (EI, 70 eV): m/z (%) = 225, 121 (16), 134 (9), 105 (100), 104 (63), 91 (64), 79 (18), 77 (18), 65 (15). HRMS: m/z calculated: 225.1517; found: 225.1487. [α]_D ²⁰ -5.8 (c 0.69, CHCl₃). GC (Chirasil-Dex CB), 100 °C (5 min), ramp of 2 °C/min to 160 °C; t _{R (}min) = 49.21 (R), 50.24 (S).
{4a-Methyl-hexahydro-cyclopenta[ b ]pyran-7a-yl}aceto-nitrile (8b)
¹H NMR (300 MHz, CDCl₃): δ = 3.81-3.74 (m, 1 H), 3.53-3.43 (m, 1 H), 2.85 (d, ² J = 16.8 Hz, 1 H), 2.35 (d, ² J = 16.8 Hz, 1 H), 2.19-2.00 (m, 2 H), 1.94-1.58 (m, 5 H), 1.45-1.17 (m, 3 H), 0.85 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 117.8, 82.8, 61.8, 42.5, 36.5, 34.8, 30.2, 25.5, 21.3, 20.8, 18.9. MS (EI, 70 eV): m/z (%) = 180, 162 (2), 150 (2), 139 (100), 111 (15), 93 (15), 81 (12), 68 (36). HRMS: m/z calcd: 180.1388; found: 180.1390.