One-Pot Conversion of Aromatic
Bromides and Aromatics into Aromatic Nitriles

Sousuke Ushijima; Hideo Togo

doi:10.1055/s-0029-1219935

LETTER

One-Pot Conversion of Aromatic Bromides and Aromatics into Aromatic Nitriles

Sousuke Ushijima, Hideo Togo*
Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
Fax: +81(43)2902792; e-Mail: togo@faculty.chiba-u.jp;

Abstract

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Abstract

Various aromatic bromides and iodides were smoothly converted into the corresponding aromatic nitriles in good to moderate yields by the treatment with butyllithium and subsequently DMF, followed by treatment with molecular iodine in aqueous ammonia. The same treatment of typical aromatics and heteroaromatics with butyllithium and subsequently DMF, followed by treatment with molecular iodine in aqueous ammonia also provided the corresponding aromatic nitriles in good yields. The present reactions are novel one-pot methods for the preparation of aromatic nitriles from aromatic bromides and aromatics, respectively, through the formation of aryllithiums and their DMF adducts.

Key words

aromatics - butyllithium - aryllithium - aromatic nitrile - molecular iodine - aqueous ammonia - aromatic bromide - aromatics

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References and Notes

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Typical Experimental Procedure for the Conversion of Aromatic Bromides into Aromatic Nitriles
Butyllithium (1.67 M solution in hexane, 3.3 mL, 5.5 mmol) was added dropwise to a solution of 4-bromotoluene (855 mg, 5 mmol) in THF (5 mL) at -70 ˚C. After 30 min, the resulting mixture was warmed and stirred for 5 min at 0 ˚C. Then, DMF (0.43 mL, 5.5 mmol) was added to the mixture, and the obtained mixture was stirred at 0 ˚C. After 1 h at the same temperature, aq NH₃ (10 mL, 150 mmol) and I₂ (1396 mg, 5.5 mmol) were added, and the obtained mixture was stirred for 2 h at r.t. The reaction mixture was quenched with sat. aq Na₂SO₃ (15 mL) and was extracted with Et₂O (3 × 20 mL). The organic layer was washed with brine and dried over Na₂SO₄ to provide 4-methylbenzonitrile in 80% yield. If necessary, the product was purified by a short column chromatography on silica gel (hexane-EtOAc = 9:1) to give pure 4-methylbenzonitrile as a colorless solid.
Most aromatic nitriles mentioned in this work are commer-cially available and were identified by comparison with the authentic samples.
4-Methylbenzonitrile
Mp 26-28 ˚C (commercial, mp 26-28 ˚C). IR: 2227 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.41 (s, 3 H), 7.26 (d, J = 8.1 Hz, 2 H), 7.52 (d, J = 8.1 Hz, 2 H).
3-Methylbenzonitrile Oil (commercial). IR: 2229 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.38 (s, 3 H), 7.32-7.47 (m, 4 H).
2-Methylbenzonitrile
Oil (commercial). IR: 2225 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.54 (s, 3 H), 7.26 (t, J = 7.6 Hz, 1 H), 7.31 (d, J = 7.6 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.58 (d, J = 7.6 Hz, 1 H).
2,4-Dimethylbenzonitrile
Mp 23-24 ˚C (commercial, mp 23-25 ˚C). IR: 2221 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.36 (s, 3 H), 2.47 (s, 3 H), 7.05 (d, J = 8.0 Hz, 1 H), 7.10 (s, 1 H) 7.43 (d, J = 8.0 Hz, 1 H).
3,4-Dimethylbenzonitrile
Mp 63-64 ˚C (commercial, mp 64-67 ˚C). IR: 2224 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.29 (s, 3 H), 2.32 (s, 3 H), 7.21 (d, J = 7.8 Hz, 1 H), 7.39 (d, J = 7.8 Hz, 1 H), 7.41 (s, 1 H).
2,5-Dimethylbenzonitrile
Oil (commercial). IR: 2227 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.33 (s, 3 H), 2.48 (s, 3 H), 7.18 (d, J = 7.9 Hz, 1 H), 7.27 (d, J = 7.9 Hz, 1 H), 7.36 (s, 1 H).

2,4,6-Trimethylbenzonitrile
Mp 50-51 ˚C (lit.⁹ⁱ mp 54-55 ˚C). IR: 2218 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.32 (s, 3 H), 2.47 (s, 6 H), 6.92 (s, 2 H).
4-Methoxybenzonitrile
Mp 54-55 ˚C (commercial, mp 57-59 ˚C). IR: 2216 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.86 (s, 3 H), 6.95 (d, J = 8.9 Hz, 2 H), 7.59 (d, J = 8.9 Hz, 2 H).
2,4-Dimethoxybenzonitrile
Mp 93-94 ˚C (commercial, mp 93-94 ˚C). IR: 2219 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.86 (s, 3 H), 3.90 (s, 3 H), 6.46 (s, 1 H), 6.51 (d, J = 8.5 Hz, 1 H), 7.48 (d, J = 8.5 Hz, 1 H).
2,4,6-Trimethoxybenzonitrile
Mp 139-140 ˚C (commercial, mp 143-145 ˚C. IR: 2212 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.86 (s, 3 H), 3.89 (s, 6 H), 6.07 (s, 2 H).
4-( N , N -Dimethyamino)benzonitrile
Mp 75 ˚C (commercial, mp 75 ˚C). IR: 2210 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.04 (s, 6 H), 6.64 (d, J = 9.1 Hz, 2 H), 7.47 (d, J = 9.1 Hz, 2 H).
1-Naphthonitrile
Mp 35-36 ˚C (commercial, mp 36-38 ˚C). IR: 2219 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.49 (t, J = 7.9 Hz, 1 H), 7.59 (t, J = 8.2 Hz, 1 H), 7.67 (t, J = 8.2 Hz, 1 H), 7.89 (d, J = 7.9 Hz, 1 H), 7.91 (d, J = 7.9 Hz, 1 H), 8.05 (d, J = 8.2 Hz, 1 H), 8.22 (d, J = 8.2 Hz, 1 H).
2-Naphthonitrile
Mp 68-70 ˚C (commercial, mp 66-70 ˚C). IR: 2225 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.58-7.68 (m, 3 H), 7.88-7.93 (m, 3 H), 8.24 (s, 1 H).
4-Cyanobiphenyl
Mp 85-88 ˚C (commercial, mp 85-87 ˚C). IR: 2225 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.44 (t, J = 7.3 Hz, 1 H), 7.49 (t, J = 7.3 Hz, 2 H), 7.59 (d, J = 7.3 Hz, 2 H), 7.69 (d, J = 8.8 Hz, 2 H), 7.73 (d, J = 8.8 Hz, 2 H).
2-Cyanopyridine
Mp 24-25 ˚C (commercial, mp 24-27 ˚C). IR: 2236 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.56 (dd, J = 7.8, 4.6 Hz, 1 H), 7.73 (d, J = 7.8 Hz, 1 H), 7.88 (t, J = 7.8 Hz, 1 H), 8.74 (d, J = 4.6 Hz, 1 H).
Typical Experimental Procedure for the Conversion of Aromatics into Aromatic Nitriles
Butyllithium (1.67 M solution in hexane, 2.9 mL, 4.8 mmol) was added dropwise into a solution of 1,3-dimethoxyben-zene (552 mg, 4 mmol) in THF (5 mL) at 0 ˚C, and the mixture was stirred for 2 h at the same temperature. Then, DMF (0.34 mL, 4.4 mmol) was added to the mixture, and the obtained mixture was stirred at 0 ˚C. After 2 h at the same temperature, aq NH₃ (8 mL, 120 mmol) and I₂ (1117 mg, 4.4 mmol) were added and stirred for 2 h at r.t. The reaction mixture was quenched with sat. aq Na₂SO₃ (15 mL) and was extracted with Et₂O (3 × 20 mL). The organic layer was washed with brine and dried over Na₂SO₄ to provide 2,6-dimethoxybenzonitrile in 91% yield. If necessary, the product was purified by a short column chromatography on silica gel (hexane-EtOAc = 3:1) to give pure 2,6-dimeth-oxybenzonitrile as a colorless solid.
2,6-Dimethoxybenzonitrile
Mp 117-119 ˚C (commercial, mp 119-123 ˚C). IR: 2220 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.90 (s, 6 H), 6.56 (d, J = 8.5 Hz, 2 H), 7.44 (t, J = 8.5 Hz, 1 H).
2-Methoxybenzonitrile
Oil (commercial). IR: 2230 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.91 (s, 3 H), 7.02-6.97 (m, 2 H), 7.59-7.52 (m, 2 H).
2,5-Dimethoxybenzonitrile
Mp 79-82 ˚C (commercial, mp 81-85 ˚C). IR: 2224 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.78 (s, 3 H), 3.89 (s, 3 H), 6.91 (d, J = 9.0 Hz, 1 H), 7.05-7.11 (m, 2 H).
2,3-Dimethoxybenzonitrile
Mp 41-42 ˚C (commercial, mp 43-46 ˚C). IR: 2228 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.89 (s, 3 H), 4.03 (s, 3 H), 7.07-7.16 (m, 3 H).
2-Cyano- N -methylindole
Mp 70-75 ˚C. IR: 2223 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.91 (s, 3 H), 7.16 (s, 1 H), 7.21 (t, J = 6.8, 1 H), 7.34-7.44 (m, 2 H), 7.66 (d, J = 8.2 Hz, 1 H).
N -Tosylindole-2-carbonitrile
Mp 160-161 ˚C (lit.^¹³ mp 160-162 ˚C). IR: 2227 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.37 (s, 3 H), 7.27 (d, J = 8.2 Hz, 1 H), 7.32 (d, J = 7.2 Hz, 1 H) 7.36 (s, 1 H), 7.52 (t, J = 7.2 Hz, 1 H), 7.58 (d, J = 8.2 Hz, 1 H), 7.90 (d, J = 8.4 Hz, 2 H), 8.21 (d, J = 8.4 Hz, 1 H).
2,4,6-Trimethoxybenzonitrile
Mp 139-140 ˚C (commercial, mp 143-145 ˚C). IR: 2212 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 3.86 (s, 3 H), 3.89 (s, 6 H), 6.07 (s, 2 H).
Benzofuran-2-carbonitrile
Oil (lit.^¹4). IR: 2227 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.36 (t, J = 7.5 Hz, 1 H), 7.46 (s, 1 H), 7.49-7.58 (m, 2 H), 7.68 (d, J = 7.9 Hz, 1 H).
Benzothiophene-2-carbonitrile
Oil (commercial, mp 24-28 ˚C). IR: 2217 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.43 (t, J = 7.6 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.77-7.85 (m, 3 H).
5-Decylfuran-2-carbonitrile
Oil. IR: 2229 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 0.88 (t, J = 7.0 Hz, 3 H), 1.21-1.38 (m, 14 H), 1.65 (quint, J = 7.1 Hz, 2 H), 2.66 (t, J = 7.1 Hz, 2 H), 6.11 (d, J = 3.4 Hz, 1 H), 6.99 (d, J = 3.4 Hz, 1 H). HRMS-FAB: m/z calcd for C₁₅H₂₄NO [M + H]⁺: 234.1858; found: 234.1861.

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