Versatile and Fluoride-Free Cyanation of Alkyl Halides and Sulfonates with Trimethylsilyl Cyanide

Abstract

Cyanation of biphenyl-4-ylmethyl methanesulfonate with trimethylsilyl cyanide using fluoride-free inorganic salts, such as Cs₂CO₃, K₂CO₃, and LiOH˙H₂O, as additives in MeCN quantitatively gave biphenyl-4-ylacetonitrile. This methodology was applied to various alkyl halides to give the corresponding nitrile compounds in good to excellent yields. Of note, 4-(hydroxymethyl)benzyliodide O-protected by the silyl group was converted into phenylacetonitrile derivative in 99% yield without desilylation.

cyanation - trimethylsilyl cyanide - fluoride-free inorganic salt

References and Notes

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General Procedure To a mixture of alkyl halide or methanesulfonate (5.40 mmol) and K₂CO₃ (6.49 mmol) in MeCN (10 mL) was added TMSCN (6.49 mmol). The reaction mixture was stirred at the required temperature until the reaction was completed. At the end of the reaction, 1 N NaOH (25 mL) was added to the reaction mixture, which was extracted with toluene (30 mL). The organic layer was washed with 1 N NaOH (25 mL) and then brine (25 mL), dried over MgSO₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give pure nitrile compounds.
Biphenyl-4-ylacetonitrile (2) [²7]
White solid; mp 94-96 ˚C. IR (ATR): ν = 3033, 2360, 2249, 1485, 1406, 1005, 907, 812, 750, 684, 461 cm^-¹. ^¹H NMR (300 MHz, CDCl₃, TMS): δ = 3.78 (2 H, s), 7.33-7.47 (5 H, m), 7.56-7.61 (4 H, m). MS: m/z = 193 [M⁺]. Anal. Calcd for C₁₄H₁₁N: C, 87.01; H, 5.74; N, 7.25. Found: C, 86.80; H, 5.70; N, 7.05.
{1-[(4-Methylphenyl)sulfonyl]-1 H -indole-3-yl}aceto-nitrile (4g) White solid; mp 161-163 ˚C. IR (KBr): ν = 3117, 2929, 2258, 1595, 1450, 1364, 1175, 1135, 1095, 979, 814, 670, 532 cm^-¹. ^¹H NMR (300 MHz, CDCl₃, TMS): δ = 2.34 (3 H, s), 3.74 (2 H, s), 7.23 (2 H, d, J = 8.2 Hz), 7.25-7.31 (1 H, m), 7.35-7.40 (1 H, m), 7.49 (1 H, d, J = 7.8 Hz), 7.60 (1 H, s), 7.77 (2 H, d, J = 8.4 Hz), 8.01 (1 H, d, J = 8.3 Hz). MS: m/z = 310 [M⁺]. Anal. Calcd for C₁₇H₁₄N₂O₂S: C, 65.79; H, 4.55; N, 9.03; S, 10.33. Found: C, 65.69; H, 4.58; N, 8.94; S, 10.37.
(4-{[ tert -Butyl(diphenyl)silyl]oxy}phenyl)acetonitrile (4h) Colorless oil. IR (neat): ν = 3071, 2930, 2891, 2857, 2250, 1736, 1609, 1509, 1427, 1256, 1113, 914, 821, 699, 611 cm^-¹. ^¹H NMR (300 MHz, CDCl₃, TMS): δ = 1.10 (9 H, s), 3.57 (2 H, s), 6.74 (2 H, d, J = 8.6 Hz), 7.02 (2 H, d, J = 8.7 Hz), 7.34-7.43 (6 H, m), 7.68-7.71 (4 H, m). MS: m/z = 371 [M⁺]. Anal. Calcd for C₂₄H₂₅NOSi: C, 77.58; H, 6.78; N, 3.77. Found: C, 77.70; H, 6.94; N, 3.72.
[4-({[ tert -Butyl(diphenyl)silyl]oxy}methyl)phenyl]aceto-nitrile (4i) White solid; mp 88-90 ˚C. IR (ATR): ν = 2930, 2857, 2245, 1588, 1514, 1427, 1112, 1083, 817, 704, 504, 490, 468 cm^-¹. ^¹H NMR (300 MHz, CDCl₃, TMS): δ = 1.10 (9 H, s), 3.73 (2 H, s), 4.76 (2 H, s), 7.11-7.46 (10 H, m), 7.67-7.70 (4 H, m). MS: m/z = 386 [M + H⁺]. Anal. Calcd for C₂₅H₂₇NOSi: C, 77.88; H, 7.06; N, 3.63. Found: C, 77.74; H, 7.04; N, 3.70.

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