3-Formylchromones in Guareschi Synthesis of 5-(2-hydroxybenzoyl)-2-pyridones

Sergey V. Ryabukhin; Andrey S. Plaskon; Dmitriy M. Volochnyuk; Andrey A. Tolmachev

doi:10.1055/s-2004-832852

LETTER

3-Formylchromones in Guareschi Synthesis of 5-(2-hydroxybenzoyl)-2-pyridones

Sergey V. Ryabukhin^a,b, Andrey S. Plaskon^b, Dmitriy M. Volochnyuk*^a, Andrey A. Tolmachev^b
^a ‘Enamine Ltd.’, 23 A. Matrosova st., 01103 Kiev, Ukraine
^b National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33, 01033, Ukraine
Fax: +380(44)5373253; e-Mail: dov@fosfor.kiev.ua;

Abstract

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Abstract

A set of 5-(2-hydroxybenzoyl)-pyrid-2-ones, which are analogous to cardiotonic drugs such as milrinone, has been prepared in high yield by recyclization of 3-formylchromones with acetic acid amides having at the α-position an electron-withdrawing group. The best reaction conditions were found to be heating in DMF in the presence of Me₃SiCl as a promoter and water scavenger.

Key words

3-formylchromones - cyanoacetamides - 2-pyridones - recyclization - chlorotrimethylsilane - parallel synthesis

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References

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<A NAME="RD11604ST-6B">6b</A> The cyclization of 3-formylchromones with amidines and 5-aminopyrazole afforded 5-(2-hydroxybenzoyl)-pyrimidines. See: Löwe W. Synthesis 1976, 274

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<A NAME="RD11604ST-6D">6d</A> See further: Quiroga J. Mejia D. Insuasty B. Abonita R. Nogueras M. Sanches A. Cobo J. Low JN. J. Heterocycl. Chem. 2002, 35: 51

<A NAME="RD11604ST-6E">6e</A> The cyclization of 3-formylchromones with aminohetero-cycles afforded fused β-(2-hydroxybenzoyl)pyridines. See: Haas G. Stanton JL. von Srerecher A. Wenk P. J. Heterocycl. Chem. 1981, 18: 607

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For using Me₃SiCl as condensation agent see:

<A NAME="RD11604ST-8A">8a</A> Ryabykhin SV. Plaskon AS. Tverdokhlebov AV. Tolmachev AA. Synth. Commun. 2004, 34: 1483

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General Procedure: Amide 2-5 or 12 (2 mmol) and appropriate chromone 1 (2 mmol) were placed in a 10 mL flask and dissolved in DMF (5 mL). Chlorotrimethylsilane (10 mmol) was added dropwise to the solution. The flask was thoroughly sealed with a rubber stopper and heated on a water-bath for 10 h. After cooling the flask was opened (Caution! Excessive pressure inside!) and the reaction mixture was poured into H₂O (25 mL). The precipitate formed was filtered and washed with small amount of i-PrOH and than with MeOH. Recrystallization from an appropriate solvent yielded targeted compounds.

Typical ¹H MNR data (Varian Mercury-400 spectrometer) of pyridones obtained: Compound 6a: ¹H NMR (400 MHz, DMSO-d ₆): δ = 6.91-6.99 (2 H, m, CH), 7.34-7.41 (2 H, m, CH), 8.05 (1 H, d, ⁴ J _HH = 2.8 Hz, 4-H_Py), 8.31 (1 H, d, ⁴ J _HH = 2.8 Hz, 6-H_Py), 10.28 (1 H, s, NH), 13.11 (1 H, br s, OH). Compound 7bb: ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.42 [6 H, d, ³ J _HH = 7.6 Hz, (CH₃)₂CH], 2.30 (3 H, s, CH₃), 5.09 [1 H, hep, ³ J _HH = 7.6 Hz, (CH₃)₂CH], 6.86 (1 H, d, ³ J _HH = 8.4 Hz, CH), 7.16-7.20 (2 H, m, CH), 8.19 (1 H, d, ⁴ J _HH = 2.4 Hz, 4-H_Py), 8.35 (1 H, d, ⁴ J _HH = 2.4 Hz, 6-H_Py), 10.08 (1 H, s, OH). Compound 7ef: ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.77 (3 H, s, CH₃), 6.90-6.99 (3 H, m, CH), 7.50-7.60 (5 H, m, CH), 8.27 (1 H, d, ⁴ J _HH = 2.4 Hz, 4-H_Py), 8.42 (1 H, d, ⁴ J _HH = 2.4 Hz, 6-H_Py), 9.89 (1 H, s, OH). Compound 8ba: ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.28 (3 H, s, CH₃), 4.52 (2 H, d, ³ J _HH = 5.6 Hz, CH₂), 5.32 (2 H, s, CH₂), 6.87 (1 H, d, ³ J _HH = 8.4 Hz, CH), 7.15 (1 H, s, CH), 7.19-7.21 (2 H, m, CH), 7.25-7.38 (7 H, m, CH), 7.39 (2 H, d, ³ J _HH = 7.6 Hz, CH), 8.66 (1 H, ⁴ J _HH = 2.0 Hz, 4-H_Py), 8.72 (1 H, d, ⁴ J _HH = 2.0 Hz, 6-H_Py), 9.80 (1 H, t, ⁴ J _HH = 5.6 Hz, 6-H_Py), 10.18 (1 H, s, OH). Compound 9ea: ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.59 (3 H, s, COCH₃), 3.74 (3 H, s, OCH₃), 6.84 (1 H, d, ⁴ J _HH = 2.7 Hz, CH), 6.89 (1 H, d, ³ J _HH = 9.0 Hz, CH), 6.96 (1 H, dd, ³ J _HH = 9.0 Hz, ⁴ J _HH = 2.7 Hz, CH), 8.00 (1 H, d, ⁴ J _HH = 3.0 Hz, 4-H_Py), 8.39 (1 H, d, ⁴ J _HH = 3.0 Hz, 6-H_Py), 9.76 (1 H, s, OH), 12.55 (1 H, br s, NH). Compound 9eb: ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.57 (3 H, s, COCH₃), 3.63 (3 H, s, NCH₃), 3.74 (3 H, s, OCH₃), 6.84 (1 H, d, ⁴ J _HH = 2.7 Hz, CH), 6.89 (1 H, d, ³ J _HH = 9.0 Hz, CH), 6.96 (1 H, dd, ³ J _HH = 9.0 Hz, ⁴ J _HH = 2.7 Hz, CH), 8.29 (1 H, d, ⁴ J _HH = 3.0 Hz, 4-H_Py), 8.56 (1 H, d, ⁴ J _HH = 3.0 Hz, 6-H_Py), 9.75 (1 H, s, OH).

Typical ¹³C MNR data (Varian Mercury-400 spectrometer) of pyridones obtained: Compound 7bb: ¹³C NMR (100 MHz, DMSO-d ₆): δ = 20.4 [(CH₃)₂CH], 21.3 (CH₃), 50.3 [(CH₃)₂CH], 102.7 (3-C_Py), 116.4 (CN), 117.3 (5-C_Py), 117.4 (CH), 124.2 (C_q), 128.8 (CH), 131.1 (CH), 134.9 (C_q), 146.2 (4-CH_Py), 147.2 (6-CH_Py), 154.3 (2-C_Py), 159.5 (C_q), 190.7 (C=O). Compound 7ef: ¹³C NMR (100 MHz, DMSO-d ₆): δ = 56.1 (CH₃O), 104.3 (3-C_Py), 114.1 (5-C_Py), 116.1 (CN), 117.3 (CH), 118.5 (CH), 120.8 (CH), 124.6 (C_q), 127.2 (CH), 129.9 (CH), 130.0 (CH), 139.8 (C_q), 148.3 (4-CH_Py), 150.1 (6-CH_Py), 150.2 (2-C_Py), 152.8 (C_q), 159.5 (C_q), 190.1 (C=O). Compound 8ba: ¹³C NMR (100 MHz, DMSO-d ₆): δ = 20.4 (CH₃), 43.1 (CH₂), 53.5 (CH₂), 117.1 (3-C_Py), 118.2 (5-C_Py), 119.5 (CH), 124.9 (CH), 127.5 (CH), 128.0 (CH), 128.4 (CH), 128.5 (C_q), 128.6 (CH), 129.0 (CH), 129.3 (CH), 130.6 (CH), 134.3 (C_q), 136.5 (C_q), 139.5 (C_q), 143.9 (4-CH_Py), 148.9 (6-CH_Py), 154.1 (2-C_Py), 161.9 (C_q), 162.9 (CONH), 192.1 (C=O). Compound 9ea: ¹³C NMR (100 MHz, DMSO-d ₆): δ = 31.1 (COCH₃), 56.1 (CH₃O), 114.1 (CH), 116.8 (5-C_Py), 118.1 (CH), 119.6 (C_q), 125.7 (CH), 126.3 (3-C_Py), 142.9 (4-CH_Py), 146.9 (6-CH_Py), 149.9 (C_q), 152.6 (2-C_Py), 161.5 (C_q), 191.2 (COAr), 196.7 (COCH₃). Compound 9eb: ¹³C NMR (100 MHz, DMSO-d ₆): δ = 31.2 (COCH₃), 38.7 (NCH₃), 56.1 (CH₃O), 114.1 (CH), 116.5 (5-C_Py), 118.2 (CH), 119.8 (C_q), 124.8 (CH), 125.5 (3-C_Py), 142.6 (4-CH_Py), 149.8 (C_q), 150.2 (6-CH_Py), 152.6 (2-C_Py), 161.5 (C_q), 191.5 (COAr), 196.9 (COCH₃).

Typical IR data (Nexus-470 spectrometer) of pyridones obtained: Compound 7bb: IR (KBr): ν = 3400-2700 (br, OH), 3068, 2985, 2932, 2226 (C≡N), 1671 (C=O), 1654 (C=O_Py), 1630, 1577, 1532, 1482 cm^-1. Compound 7ef: IR (KBr): ν = 3470-3150 (br, OH), 2231 (C≡N), 1677 (C=O), 1660 (C=O_Py), 1539, 1508, 1417 cm^-1. Compound 8ba: IR (KBr): ν = 3600-3100 (br, OH), 3288 (NH), 3056, 3023, 2952, 1675 (C=O), 1664 (sh, C=O_Py), 1632 (CONHCH₂Ph), 1603, 1528 cm^-1. Compound 9ea: IR (KBr): ν = 3600-3200 (br, OH, NH), 3056, 2917, 2835, 1685 (COMe), 1665 (C=O_Ph), 1637, 1593, 1485, 1218 cm^-1. Compound 9eb: 3500-3100 (br, OH), 3078, 2960, 1677 (COMe), 1646 (C=O_Py), 1538, 1508, 1413 cm^-1.

Typical MS data (MX-1321 instrument) of pyridones obtained: Compound 6a: MS (EI, 70 eV): m/z (%) = 240 (39) [M⁺], 147 (19), 121 (86), 120 (100), 92 (45), 65 (54), 39 (43). Compound 7ef: MS (EI, 70 eV): m/z (%) = 346 (30) [M⁺], 254 (11), 150 (100). Compound 8ba: MS (EI, 70 eV): m/z (%) = 452 (19) [M⁺], 106 (100), 91 (54). Compound 9ea: MS (EI, 70 eV): m/z (%) = 287 (76) [M⁺], 272 (10), 150 (100), 135 (21), 43 (24).Compound 9eb: MS (EI, 70 eV): m/z (%) = 301 (64) [M⁺], 286 (17), 150 (100), 135 (12).

<A NAME="RD11604ST-14">14</A> For related interactions of enolates with nitrile groups affording 2-pyridone ring see: Bondavalli F. Bruno O. Lo Presty E. Menozzy G. Mosti L. Synthesis 1999, 1169