A Green One-Pot Synthesis of vic-Amidino (Hetero)aromatic Acids from 1,2-Dinitriles

Abstract

Phthalonitrile undergoes partial hydration in MeOH–H₂O media in the presence of an equimolar amount of NaOH to afford 2-carbamimidoylbenzoic acid in good yield in one step. This and similar vic-amidino (hetero)aromatic acids also could be synthesized from corresponding 1,2-dinitriles by hydrolysis in aqueous MeOH catalyzed by an equimolar amount of NaOH of in situ generated 1,1-dimethoxy-1H-isoindol-3-amine or its counterparts. Protonation of the synthesized amidino acids, esterification, and reamination of the parent amidino benzoic acid with N-nucleophiles were performed.

Key words

green chemistry - phthalonitrile - partial hydration - 2-carbamimidoylaromatic acids - 3-carbamimidoyl-2-pyridinecarboxylic acid - protonation - esterification - reamination

• References and Notes

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• 22 Synthesis of Amidino Acids 5a,c–e; General Procedure
  Method A To a solution of NaOH (0.4 g, 10 mmol) in aq MeOH (25 mL; MeOH–H₂O, 3:2) 1,2-dinitrile (10 mmol) was added, and the obtained suspension was brought to reflux with stirring. The resulting clear solution was refluxed for 15–20 min before the elimination of ammonia began. Then the hot reaction mixture, if necessary, was filtered through cotton wool in order to separate the phthalocyanine impurities. The solution was left to cool at r.t. overnight during which time well-firmed crystals were formed. The crystals were filtered off, washed with MeOH (10 mL), and dried in air. Acidification of the mother liquior with AcOH (ca. 1 mL) to neutral pH produced an additional portion of target product. Method B To a freshly prepared solution of MeONa obtained by dissolving sodium metal (0.23 g, 10 mmol) in MeOH (15 mL), 1,2-dinitrile (10 mmol) was added. The resulting suspension was stirred at ambient temperature until TLC showed no starting nitrile. The obtained solution or suspension was diluted with distilled water (10 mL), brought to reflux with stirring, and kept under reflux for 20–25 min before the elimination of ammonia began. The further workup was as in method A. 2-Carbamimidoylbenzoic Acid (5а) Method А; colorless crystals of MeOH solvate (ca. 1:0.7) which lost MeOH on standing in air; yield 1.34 g (72%); mp 179–180 °С. IR (KBr): 3395, 3232, 3092, 2954, 2829, 1667, 1579, 1538, 1468, 1437, 1384 cm^–1. ¹H NMR of MeOH solvate (400 MHz, D₂O, 25 °С): δ = 3.32 (s, 2 H, MeOH), 7.52 (d, J = 7.6 Hz, J _m = 0.8 Hz, 1 H, H₃), 7.56 (dd, J ₁ = 7.6 Hz, J ₂ = 7.6 Hz, J _m =1.2 Hz, 1 H, H₄), 7.63 (dd, J ₁ = 7.6 Hz, J ₂ = 7.6 Hz, J _m =1.2 Hz, 1 H, H₅), 7.73 (d, J = 7.6 Hz, 1 H, H₆). ¹H NMR (400 MHz, D₂O, 25 °С): δ = 7.72–7.80 (m, 2 H, H₃ + H₄), 7.85 (dd, J ₁ = 7.2 Hz, J ₂ = 7.2 Hz, 1 H, H₅), 7.93 (d, J = 7.6 Hz, 1 H, H₆). ¹³C NMR (100 MHz, D₂O, 25 °С): δ = 171.3 (СООH), 166.9 (C(NH₂)=NH), 135.2 (С1), 129.8, 127.7, 126.7, 125.8 (С2), 125.7. Anal. Calcd for C₈H₈N₂O₂: C, 58.53; H, 4.91; N, 17.06. Found: C, 58.24; H, 4.99; N, 17.38. 2-Carbamimidoyl-3-methoxybenzoic Acid (5с) Method В; colorless crystals of MeOH solvate (ca. 1:1); yield 1.40 g (62%); mp 190–191 °С (subl.). IR (KBr): 3338, 3069, 1686, 1615, 1579, 1522, 1466, 1432, 1377 cm^–1. ¹H NMR (400 MHz, D₂O, 25 °С): δ = 3.33 (s, 3 H, CH₃OH), 3.89 (s, 3 Н, OСH₃), 7.25 (d, J = 8.4 Hz, 1 H, H_Ar), 7.36 (d, J = 8.0 Hz, 1 H, H_Ar), 7.58 (dd, J ₁ = 8.0 Hz, J ₂ = 8.4 Hz, 1 H, H₅). ¹³C NMR (100 MHz, D₂O, 25 °С): δ = 175.2 (СООH), 168.5 (C(NH₂)=NH), 157.9, 140.3, 134.8, 123.1, 119.4, 115.8, 58.5 (CH₃O), 50.9 (CH₃OH). Anal. Calcd for C₉H₁₀N₂O₃×СH₃OH: C, 53.09; H, 6.24; N, 12.38. Found: C, 53.30; H, 6.31; N, 12.76. 2-Carbamimidoyl-3-morpholin-4-ylbenzoic Acid (5d) Method В; pale yellow crystals of MeOH solvate (ca. 1:1); yield 1.71 g (61%); mp 194–195 °С (dec.). IR (KBr): 3360, 3244, 3064, 2962, 2924, 2858, 2826, 1688, 1610, 1574, 1520, 1430, 1386 cm^–1. ¹H NMR (400 MHz, D₂O, 25 °С): δ = 3.10 (m, 4 H, H_morph), 3.45 (s, 4 H, MeOH), 3.95 (m, 4 H, H_morph), 7.55 (d, J = 7.6 Hz, 1 H, H₄), 7.60 (d, J = 7.6 Hz, 1 H, H₆), 7.71 (2×d, J ₁ = 7.6 Hz, J₂ = 7.6 Hz, 1 H, H₅). ¹H NMR (400 MHz, D₂O + HCl, 25 °С): δ = 2.88 (m, 4 H, H_morph), 3.20 (s, 2 H, MeOH), 3.72 (m, 4 H, H_morph), 7.58–7.64 (m, 2 H, H₄,₅), 7.82 (d, J = 6.4 Hz, 1 H, H₆). ¹³C NMR (100 MHz, D₂O + HCl, 25 °С): δ = 168.0 (СООH), 167.0 (C(NH₂)=NH), 150.6, 132.8, 129.3, 128.2, 127.7, 127.6, 66.9, 52.7, 48.8. Anal. Calcd for C₁₂H₁₅N₃O₃·СH₃OH: C, 55.50; H, 6.81; N, 14.94. Found: C, 55.84; H, 6.78; N, 14.63. 3-Carbamimidoylpyridine-2-carboxylic Acid (5e) Method В; colorless crystals; yield 1.14 g (69%); mp 250–251 °С. IR (KBr): 3016, 2360, 1706, 1583, 1565, 1526, 1446, 1428, 1377 cm^–1. ¹H NMR (400 MHz, D₂O, 25 °С): δ = 7.61 (dd, J ₁ = 7.6 Hz, J ₂ = 7.6 Hz, 1 H, H₅), 8.04 (d, J = 8 Hz, J _M = 1.2 Hz, 1 H, H₄), 8.70 (d, J = 4.4 Hz, 1 H, H₆). ¹³C NMR (100 MHz, D₂O, 25 °С): δ = 170.3, 169.0, 162.5, 153.6, 139.6, 133.0, 126.7. ¹H NMR (400 MHz, D₂O + HCl, 25 °С): δ = 8.03–8.06 (m, 1 H, H₅), 8.49 (d, J = 7.2 Hz, 1 H, H₄), 8.80 (d, J = 4 Hz, 1 H, H₆). ¹³C NMR (100 MHz, D₂O + HCl, 25 °С): δ = 164.0 (СООH), 161.7 (C(NH₂)=NH), 146.6, 144.6, 143.1, 129.2, 128.2. Anal. Calcd for C₇H₇N₃O₂: C, 50.91; H, 4.27; N, 25.44. Found: C, 51.28; H, 4.34; N, 25.75. 2-(4,5-Dihydro-1H-imidazol-2-yl)benzoic Acid (26) To a suspension of 2-carbamimidoylbenzoic acid (5a, 0.328 g, 2 mmol) in EtOH (10 mL) was added an excess of 70% ethylenediamine solution in water (1.5 mL, 18 mmol). This reaction mixture was refluxed until no more ammonia gas was fixed by pH paper. The obtained clear solution was evaporated under reduced pressure to a volume of about 5 mL and acidified with a few drops of 10 M HCl to neutral pH with stirring. After standing for 2 h, fine colorless crystals were formed and separated by filtration, washed with EtOH (2 mL), and dried. Colorless crystals of hydrate (1:1); yield 0.277 g (73%); mp 222–223 °С. IR (KBr): 3382, 3218, 3106, 2944, 2896, 2686, 1628, 1604, 1577, 1556, 1380, 1286 cm^–1. ¹H NMR (400 MHz, D₂O, 25 °С): δ = 4.07 (s, 4 H, CH₂), 7.55 (d, J = 7.6 Hz, 1 H, H₃), 7.59 (2 × d, J ₁ = 7.6 Hz, J ₂ = 7.2 Hz, 1 H, H₄), 7.68 (2 × d, J ₁ = 7.2 Hz, J ₂ = 7.2 Hz, 1 H, H₅), 7.76 (d, J = 7.2 Hz, 1 H, H₆). ¹³C NMR (100 MHz, D₂O, 25 °С): δ = 173.6 (СООH), 168.7 (C(NH)=NH), 138.0, 132.8, 130.1, 129.0, 128.4, 122.0, 45.0 (2 CH₂). Anal. Calcd for C₁₀H₁₀N₂O₂·H₂O: C, 57.68; H, 5.81; N, 13.45. Found: C, 58.03; H, 6.19; N, 13.80. LC–MS: m/z (%) = 191 (100) [M + H]⁺.
• 23 X-ray diffraction studies of compounds 5c,e, 17, 20, 21a, and 4 were performed on an ‘Xcalibur 3’ diffractometer (graphite-monochromated Mo Kα radiation (λ = 0.71073), CCD detector, ω scans). Structure 4 was studied at both low and room temperature. Structures were solved by direct method and refined against F² within anisotropic approximation for all nonhydrogen atoms using OLEX2 program package²⁴ with SHELXS and SHELXL modules.²⁵ Crystallographic data, details of the data collection and processing, structure solution and refinement are summarized in Table S1 (see Supporting Information). CCDC numbers 1509778 (20) and 1509780–1509785 (5e, 4, 21a, 5c, 17) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
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