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Synlett 2009(8): 1291-1294  
DOI: 10.1055/s-0028-1088129
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Osamu Yabe, Hideya Mizufune, Tomomi Ikemoto*
Chemical Development Laboratories, CMC Center, Pharmaceutical Production Division, Takeda Pharmaceutical Company Limited, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka, 532-8686, Japan
Fax: +81(6)63006251; e-Mail: Ikemoto_Tomomi@takeda.co.jp;
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Publication History

Received 8 January 2009
Publication Date:
08 April 2009 (online)

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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.

Key words

cyanation - trimethylsilyl cyanide - fluoride-free inorganic salt

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For cyanosilylation, the addition of a carbonyl compound with TMSCN using a catalytic amount of K2CO3 was already reported. [¹6]

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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.