l-Proline-Promoted Rosenmund-von Braun Reaction

Abstract

l-Proline was identified as an effective additive to promote the Rosenmund-von Braun reaction at a lower temperature (80-120 °C). This modified Rosenmund-von Braun cyanation of aryl bromides exhibits excellent functional-group compatibility, and provide an efficient and convenient approach for the synthesis of aryl nitriles.

Key words

l-proline - Rosenmund-von Braun reaction - copper - aryl halides - aryl nitriles

References and Notes

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10

General Procedure for the l-Proline-Promoted Rosenmund-von Braun ReactionTo a mixture of CuCN (2 mmol), l-proline (1 mmol), and anhyd DMF (3 mL) under argon, aryl bromide (1 mmol) was added at r.t. The mixture was stirred at 120 °C for 45 h. After the resulting suspension was cooled to r.t., diluted with EtOAc (15 mL), and washed with H₂O (3 × 4 mL). The organic phase was dried over Na₂SO₄, concentrated, and the residue was purified by flash chromatography on silica with EtOAc-hexane to yield the product.Analytical Data of Compounds 2a-o4-Methoxybenzonitrile (2a): ESI-MS: m/z = 134 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃): δ = 3.84 (3 H, s), 6.94 (2 H, d, J = 8.8 Hz), 7.56 (2 H, d, J = 8.4 Hz).4-Nitrobenzonitrile (2b): ¹H NMR (400 MHz, CDCl₃): δ = 7.88 (2 H, d, J = 8.8 Hz), 7.37 (2 H, d, J = 8.8 Hz).Benzonitrile (2c): ESI-MS: m/z = 104 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃): δ = 7.46-7.67 (5 H, m). 2-Amino-4-chloro-5-fluorobenzonitrile (2d): ¹H NMR (400 MHz, DMSO-d): δ = 6.18 (2 H, br), 6.94 (1 H, d, J = 6.8 Hz), 7.58 (1 H, d, J = 9.2 Hz).2,4-Dimethoxy-6-methylbenzonitrile (2e): ¹H NMR (400 MHz, CDCl₃): δ = 2.45 (3 H, s), 3.81 (3 H, s), 3.86 (3 H, s), 6.27 (1 H, d, J = 2.0 Hz), 6.36 (1 H, d, J = 1.6 Hz).3-Bromo-4,6-dimethoxy-2-methylbenzonitrile (2f-1): ESI-MS: m/z = 255 [M]⁺, 257 [M + 2]⁺. HRMS (EI): m/z calcd for C₁₀H₁₀BrNO₂ [M]⁺: 254.9895; found: 254.9868. ¹H NMR (400 MHz, CDCl₃): δ = 2.59 (3 H, s), 3.94 (3 H, s), 3.96 (3 H, s), 6.34 (1 H, s)4,6-Dimethoxy-2-methylisophthalonitrile (2f-2): ESI-MS: m/z = 202 [M]⁺. HRMS (EI): m/z calcd for C₁₁H₁₀N₂O₂ [M]⁺: 202.0742; found: 202.0747. ¹H NMR (400 MHz, CDCl₃):δ = 2.66 (3 H, s), 4.00 (6 H, s), 6.34 (1 H, s).3,4,5-Trimethoxybenzonitrile (2g): ¹H NMR (400 MHz, CDCl₃): δ = 3.88 (6 H, s), 3.90 (3 H, s), 6.86 (2 H, s).N-(4-Cyanophenyl)acetamide (2h): ¹H NMR (400 MHz, CDCl₃): δ = 2.15 (3 H, s), 7.46 (1 H, s), 7.53 (2 H, d, J = 8.8 Hz), 7.58 (2 H, d, J = 8.8 Hz).4-Hydroxybenzonitrile (2i): ESI-MS: 118 [M - H]⁺. ¹H NMR (400 MHz, CDCl₃): δ = 6.01 (1 H, s), 6.90 (2 H, d, J = 9.6 Hz), 7.55 (2 H, d, J = 8.8 Hz).3-Aminobenzonitrile (2j): ESI-MS: 117 [M - H]⁺. ¹H NMR (400 MHz, CDCl₃): δ = 3.86 (1 H, s), 6.85 (1 H, d, J = 8.0 Hz), 6.90 (1 H, s), 7.01 (1 H, d, J = 7.2 Hz), 7.22 (1 H, t, J = 8.0 Hz).1-Naphthonitrile (2k): ¹H NMR (400 MHz, CDCl₃): δ = 8.14 (1 H, d, J = 8.8 Hz), 7.98 (1 H, d, J = 8.4 Hz), 7.80-7.84 (2 H, m), 7.58-7.62 (1 H, t, J = 8.4 Hz), 7.50-7.54 (1 H, t, J = 8.0 Hz), 7.40-7.44 (1 H, t, J = 8.0 Hz).3-Methoxy-2-naphthonitrile (2l): ¹H NMR (400 MHz, CDCl₃): δ = 3.95 (3 H, s), 7.12 (1 H, s), 7.37 (1 H, t, J = 8.0 Hz), 7.49-7.52 (1 H, t, J = 8.4 Hz), 7.68 (1 H, d, J = 8.0 Hz), 7.71 (1 H, d, J = 8.0 Hz), 8.08 (1 H, s).Methyl 4-cyanobenzoate (2m): ¹H NMR (400 MHz, CDCl₃): δ = 3.96 (3 H, s), 7.74 (2 H, d, J = 6.4 Hz), 8.13 (2 H, d, J = 6.4 Hz).4-(4-Bromobenzoyl)benzonitrile (2n): ESI-MS: m/z 285 [M - H]⁺, 286 [M - 2]⁺. ¹H NMR (400 MHz, CDCl₃): δ = 7.66 (4 H, s), 7.79 (2 H, d, J = 8.0 Hz), 7.86 (2 H, d, J = 8.4 Hz).6-Methoxypyridine-3-carbonitrile (2o): ESI-MS: m/z = 135 [M + H]⁺. ¹H NMR (400 MHz, CDCl₃): δ = 3.99 (3 H, s), 6.80 (1 H, d, J = 8.4 Hz), 7.76 (1 H, dd, J = 2.0, 8.4 Hz), 8.48 (1 H, s).