Straightforward Conversion of Arene Carboxylic Acids into Aryl Nitriles by Palladium-Catalyzed Decarboxylative Cyanation Reaction

Abstract

A one-pot procedure to convert aromatic carboxylic acids into aromatic nitriles is described. The methodology is based on a palladium(II)-catalyzed decarboxylative cyanation reaction using cyanohydrins as soluble cyanide sources. The described reaction worked on a panel of substrates and is additionally of particular interest for the straightforward preparation of ^¹³C- or ^¹4C-labeled compounds.

Key words

palladium - cyanation - arene carboxylic acids - cyanohydrin - decarboxylation

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19

General Procedure for the Preparation of Aryl Nitriles 2
Arene carboxylic acid (250 mg, 1 equiv), Ag₂CO₃ (3 equiv), and palladium trifluoroacetate (0.2 equiv) were suspended in DMSO-DMF (95:5, 5 mL) under air. The reaction mixture is heated at 100 ˚C, then, cyclohexanone cyanohydrin
(1 equiv) diluted in DMSO-DMF (95:5, 5 mL) was added dropwise with a syringe pump. The reaction mixture rapidly turned black, was further heated for 1 h, then was cooled, poured into EtOAc, and filtered. The filtrate was washed sequentially with aq NaHCO₃ (1 M), H₂O and brine, then was dried over MgSO₄, filtered, and concentrated. Chromatography of the residue on silica gel (EtOAc-heptane) gave the desired product. Compounds 2a-l are known compounds.
Compound 2m: white solid, mp 69.6 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 2.47 (s, 3 H), 3.84 (s, 3 H), 3.88 (s, 3 H), 6.30 (s, 1 H), 6.38 (s, 1 H) ppm.^¹³C NMR (100 MHz, CDCl₃): δ = 20.81, 55.51, 55.90, 94.67, 95.70, 106.87, 116.05, 145.25, 163.81, 164.51 ppm. IR (NaCl): 2972, 2212, 1606, 1577, 1468, 1425, 1336, 1304, 1238, 1209, 1153, 1095, 1053, 935, 853, 830 cm^-¹. HRMS: m/z calcd for [M + H]⁺:178.0868; found:178.0863.
Compound 2n: white solid, mp 168.8 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 3.96 (s, 3 H), 3.97 (s, 3 H), 6.46 (s, 1 H), 7.68 (s, 1 H) ppm.^¹³C NMR (100 MHz, CDCl₃): δ = 56.28, 56.47, 94.68, 95.68, 102.20, 116.12, 138.78, 160.41, 162.52. IR (NaCl): 2989, 2224, 1595, 1561, 1492, 1471, 1433, 1386, 1317, 1284, 1221, 1161, 1020, 896, 838, 780 cm^-¹. HRMS: m/z calcd for [M + Na]⁺:263.9636; found:263.9644.

20

Procedure for the Preparation of 3h
^¹³C-Labeled 9-anthracenecarboxylic acid was prepared in two steps. ^¹³C-Labeled 9-anthracenecarbonitrile was first prepared from ^¹³C-labeled cyclohexanone cyanohydrin according to the procedure described above. After purification, the ^¹³C-labeled nitrile was hydrolyzed under basic conditions: ^¹³C-labeled nitrile (1 mmol) was reacted overnight at 80 ˚C with aq KOH (10 mL, 40% w/w) and abs. EtOH (10 mL). The mixture was acidified to pH 3 (HCl solution) and extracted by EtOAc. The organic phase was concentrated, and the residue was purified by reversed-phase chromatography with MeOH-H₂O (70:30) to afford product 3h; mp 212-214 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 8.61 (s, 1 H), 8.34 (d, 2 H, J = 8.8 Hz), 8.07 (d, 2 H, J = 8.8 Hz), 7.62 (t, 2 H, J = 7.2 Hz), 7.54 (t, 2 H, J = 7.2 Hz) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 171.38 (^¹³CO₂H), 131.23, 130.96, 129.96, 128.47, 127.68, 126.80, 125.50, 124.96 ppm. IR (KBr): 3200-2700, 2761, 2623, 1680, 1626, 1557, 1523, 1487, 1447, 1425, 1399, 1343, 1319, 1292, 1266, 1254, 1229, 1177, 1154, 1142, 1020, 992, 917, 891, 857, 847, 793, 738, 723, 639, 596, 559, 513 cm^-¹. HRMS: m/z calcd for C₁₄ ^¹³CH₁₀O₂Na: 246.0578; found: 246.0581.