Synlett 2015; 26(10): 1365-1370
DOI: 10.1055/s-0034-1380572
letter
© Georg Thieme Verlag Stuttgart · New York

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

Marco Brünjes*
Bayer CropScience AG, Small Molecules Research, Industriepark Höchst, 65926 Frankfurt am Main, Germany   Email: marco.bruenjes@bayer.com
,
Mark James Ford
Bayer CropScience AG, Small Molecules Research, Industriepark Höchst, 65926 Frankfurt am Main, Germany   Email: marco.bruenjes@bayer.com
,
Hansjörg Dietrich
Bayer CropScience AG, Small Molecules Research, Industriepark Höchst, 65926 Frankfurt am Main, Germany   Email: marco.bruenjes@bayer.com
,
Kirsty Wilson
Bayer CropScience AG, Small Molecules Research, Industriepark Höchst, 65926 Frankfurt am Main, Germany   Email: marco.bruenjes@bayer.com
› Author Affiliations
Further Information

Publication History

Received: 13 February 2015

Accepted after revision: 23 March 2015

Publication Date:
11 May 2015 (online)


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.

Supporting Information

 
  • References and Notes

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  • 5 Oleinik IV, Shkurko OP. Chem. Heterocycl. Compd. 1999; 35: 316

    • For exemplary synthetic procedures please refer to:
    • 6a Yamane A, Matsuda A, Ueda T. Chem. Pharm. Bull. 1980; 28: 150
    • 6b Kohra S, Ueda K, Tominaga Y. Heterocycles 1996; 43: 839
    • 6c Deboer M, Stewart M, Messersmith D, Duffy J, Martinez-Botella G, Come J, Gao H, Salituro F, Marone V, Pierce A. PCT Int. Appl WO2009085913, 2009
    • 6d Brünjes M, Dietrich H.-J, Ahrens H, Hoffmann MG, Dittgen J, Feucht D, Rosinger CH, Haeuser-Hahn I. PCT Int. Appl WO2010108611, 2010
  • 7 Anhydrous m-CPBA was always prepared and handled in solution only.
  • 8 Förster S, Tverskoy O, Helmchen G. Synlett 2008; 2803
  • 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.