A Facile and Efficient One-Pot Synthesis of Nitriles from Carboxylic Acids

Abstract

Direct transformation of aliphatic carboxylic acids to the corresponding nitriles can be easily performed with acetonitrile in the presence of sulfuric acid.

Key words

carboxylic acids - nitriles - acetonitriles - adamantane derivatives - one-pot procedure

References

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• 9a

  Similarly, when dicarboxamide 11 was subjected to the same reaction conditions, but the reaction time was reduced to 2 h, the mixture of 11, 12, and 4b was obtained in a 1:3:3 ratio.

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• 16a

  5b: ¹H NMR: δ = 1.42-1.61 (12 H, m), 2.10-2.19 (6 H, m, with a distinguishable singlet at 2.11); ¹³C NMR: δ = 28.17 (d), 31.44 (t), 32.74 (s), 34.78 (t), 40.40 (t), 45.58 (t), 117.09 (s);

• 16b For IR data of 5b see: Aigami K. Inamoto Y. Takaishi N. Hattori K. J. Med. Chem.  1975,  18:  713 
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• 22 Anderson GL. inventors; US  6,348,625 B1.  12:

10

General Procedure for the One-Pot Preparation of Nitriles. Concd H₂SO₄ (10 mmol) was added dropwise at r.t. to a well-stirred suspension of acid (1 mmol) in MeCN (5 mL) and then the mixture was stirred under reflux for the appropriate time (Table [1] ). The excess of acetonitrile was then evaporated and CH₂Cl₂ (15 mL) and H₂O (15 mL) were added. The layers were separated and the water layer was extracted with a fresh portion of CH₂Cl₂. The combined organic layers were washed with brine, dried over MgSO₄, and evaporated under reduced pressure to give the crude product, which was purified by chromatography using EtOAc-hexane as eluent.

11

1b: IR (KBr): 2919 (s), 2856 (m), 2252 (w), 2226 (w), 1453 (m), 1103 (m) cm^-1; ¹H NMR: δ = 1.71-1.77 (6 H, m), 2.00-2.08 (9 H, m); ¹³C NMR: δ = 26.92 (d), 35.56 (t), 39.75 (t), 125.01 (s).

14

4b: Mp 73-76 °C (lit. [15] 73-74 °C); IR (KBr): 2903 (s), 2850 (m), 2236 (w), 1442 (m), 1347 (m) cm^-1; ¹H NMR: δ = 1.58-1.77 (12 H, m), 2.00-2.06 (3 H, m), 2.09 (2 H, s, CH₂); ¹³C NMR: δ = 28.14 (d), 31.98 (s), 32.12 (t), 36.14 (t), 41.62 (t), 117.74 (s).

19

9: Mp 154-156 °C; R _f 0.44 (silica gel, EtOAc-hexane, 1:1). IR (KBr): 3273 (m), 2907 (s), 2856 (m), 1727 (s), 1696 (s), 1671 (s), 1470 (m), 1377 (m), 1289 (m), 1207 (m), 1016 (m) cm^-1. ¹H NMR: δ = 1.68-1.79 (6 H, m), 1.86-1.89 (6 H, m), 2.06-2.12 (3 H, m), 2.48 (3 H, s, CH₃), 8.26 (1 H, br s, NH). ¹³C NMR: δ = 25.45 (q, 1 C), 27.69 (d, 3 C), 36.03 (t, 3 C), 38.48 (t, 3 C), 41.80 (s, 1 C), 173.51 (s, 1 C), 176.55 (s, 1 C). Anal. Calcd for C₁₃H₁₉NO₂: C, 70.56; H, 8.65; N, 6.33. Found: C, 70.83; H, 8.63; N, 6.46.

21

11: Mp 142-144 °C; R _f 0.40 (silica gel, EtOAc-hexane, 1:1); IR (KBr): 3268 (m), 3175 (m), 2902 (s), 2845 (m), 1732 (s), 1531 (m), 1500 (m), 1238 (m), 1135 (m) cm^-1; ¹H NMR: δ = 1.60-1.75 (12 H, m), 1.98 (3 H, br s), 2.20 (2 H, s, CH₂), 2.42 (3 H, s, CH₃), 8.78 (1 H, br s, NH); ¹³C NMR: δ = 25.17 (q, 1 C), 28.43 (d, 3 C), 33.32 (s, 1 C), 36.51 (t, 3 C), 42.27 (t, 3 C), 51.50 (t, 1 C), 171.07 (s, 1 C), 172.67 (s, 1 C); Anal. Calcd for C₁₄H₂₁NO₂: C, 71.46; H, 8.99; N, 5.95. Found: C, 71.84; H, 8.88; N, 6.04.