Malononitrile: A Versatile d¹-Synthon for the Synthesis of Hetero-aromatic Carboxylic Acid Derivatives

Abstract

A convenient one-pot synthesis of heteroaromatic carboxylic acid derivatives from malononitrile substituted heteroaromatic compounds, namely pyridines, pyrimidines, and 1,3,5-triazines is described. In this procedure, the oxidation of malononitriles with anhydrous m-CPBA, followed by addition of different nucleophiles (alcohols, amines, thiols) under anhydrous conditions afforded the corresponding carboxylic acid derivatives in good to excellent yields.

Key words

malononitrile - oxidation - m-CPBA - carboxylic acids - heterocycles

• References and Notes

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For exemplary synthetic procedures please refer to:
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• 7 Anhydrous m-CPBA was always prepared and handled in solution only.
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• 10 Standard Procedure for the Preparation of Carboxylic Acid Derivatives from Malononitrile Systems: The reaction vessel was charged with the heteroaromatic malononitrile (1.0 equiv, prepared according to ref. 6) and the specified solvent (1 mL per 0.12 mmol). It was stirred at r.t. and 4 Å molecular sieve was added. Anhydrous m-CPBA (1.5 equiv) solution was prepared by dissolving in the specified solvent (1 mL per 0.22 mmol) and drying over molecular sieves (4 Å) for 10 min. This solution was added to the reaction mixture which was subsequently stirred for 10 min. After adding the nucleophile, the reaction mixture was stirred at r.t. The reaction was finally quenched with aq sodium thiosulfate solution and extracted with CH₂Cl₂. The combined organics were washed twice with saturated aqueous solution of NaHCO₃ and brine, dried over Na₂SO₄ and concentrated in vacuo. Further purification was carried out by preparative HPLC. Methyl 6-Chloro-2-phenylpyrimidine-4-carboxylate (2b): colorless solid. ¹H NMR (600 MHz, CDCl₃): δ = 8.51 (m, 2 H, ArH), 7.87 (s, 1 H, ArH), 7.52 (m, 3 H, ArH), 4.06 (s, 3 H, OMe). ¹³C NMR (150 MHz, CDCl₃): δ = 166.14, 163.97, 163.40, 156.67, 135.46, 132.04, 128.91, 128.76, 119.18, 55.53. HRMS (ES-TOF): m/z [M + H] calcd for C₁₂H₁₀ClN₂O₂: 249.0431; found: 249.0442. 6-Chloro-2-phenyl-N-propylpyrimidine-4-carboxamide (2e): colorless solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.43 (m, 2 H, ArH), 8.05 (br s, 1 H, NH), 8.00 (s, 1 H, ArH), 7.43 (m, 3 H, ArH), 3.49 (m, 2 H, NCH₂), 1.72 (m, 2 H, CH₂), 1.03 (t, J = 9.6 Hz, 3 H, Me). ¹³C NMR (100 MHz, CDCl₃): δ = 164.56, 163.76, 161.82, 158.40, 135.31, 131.96, 128.76, 128.56, 116.96, 41.42, 23.03, 11.45. HRMS (ES-TOF): m/z [M + H] calcd for C₁₄H₁₅ClN₃O: 276.0904; found: 276.0907. Methyl 6-Chloro-5-nitro-2-[(E)-styryl]pyrimidine-4-carboxylate (4k): yellow solid. ¹H NMR (600 MHz, CDCl₃): δ = 8.19 (d, J = 16.0 Hz, 1 H, CH=CH), 7.68 (m, 2 H, ArH), 7.46 (m, 3 H, ArH), 7.27 (d, J =16.0 Hz, 1 H, CH=CH), 4.07 (s, 3 H, OMe). ¹³C NMR (150 MHz, CDCl₃): δ = 163.71, 159.40, 151.72, 146.87, 143.19, 132.75, 128.95, 127.19, 126.47, 121.89, 52.38. HRMS (ES-TOF): m/z [M + H] calcd for C₁₄H₁₁ClN₃O₄: 320.0436; found: 320.0438.