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

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

References

• 1a Scriven EFV. Pyridines and their Benzo Derivatives: (ii) Reactivity at Ring Atoms, In Comprehensive Heterocyclic Chemistry   Vol. 2:  Katritzky AR. Rees CW. Pergamon Press Ltd.; Oxford: 1984.  p.165 
• 1b Uff BC. Pyridines and their Benzo Derivatives: (iii) Reactivity of Substituents, In Comprehensive Heterocyclic Chemistry   Vol. 2:  Katritzky AR. Rees CW. Pergamon Press Ltd.; Oxford: 1984.  p.315 
• 2 Farah AE. Alousi AA. Life Sci.  1978,  22:  1139 
• 3 Alousi AA. Canter JM. Monterano MJ. Fort DJ. Ferrari RA. J. Cardiovasc. Pharmacol.  1983,  5:  792 
• 4a Fossa P. Boggia R. Presti EL. Dorigo P. Floreani M. Farmaco  1997,  52:  523 
• 4b Mosti L. Schenone P. Del Mar Mahiques M. Dorigo P. Fracarollo D. Santostasi G. D’Amico M. Falciani M. Lampa E. Farmaco  1994,  49:  559 
• 4c Dorigo P. Gaion RM. Belluco P. Fraccarollo D. Maragno I. Bombieri G. Benetollo F. Mosti L. Orsisns F. J. Med. Chem.  1993,  36:  2475 
• 5a Abu Shanab FA. Redhouse AD. Thompson JB. Wacefield BJ. Synthesis  1995,  557 
• 5b Mosti L. Schenone P. Menozzi G. J. Heterocycl. Chem.  1985,  22:  1503 
• For related cyclization reaction of 3-formylchromones, see:
• 6a Jones WD. Albrecht WL. J. Org. Chem.  1976,  41:  706 
• 6b The cyclization of 3-formylchromones with amidines and 5-aminopyrazole afforded 5-(2-hydroxybenzoyl)-pyrimidines. See: Löwe W. Synthesis  1976,  274 
• 6c See also: Petersen U. Heitzer H. Liebigs Ann. Chem.  1976,  1663 
• 6d See further: Quiroga J. Mejia D. Insuasty B. Abonita R. Nogueras M. Sanches A. Cobo J. Low JN. J. Heterocycl. Chem.  2002,  35:  51 
• 6e 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 
• 6f With hydrazines: Eiden F. Haverland H. Arch. Pharm. (Weinheim, Ger.)  1968,  301:  819 
• 6g See also: Ghosh CK. Mukhopadhyay KK. J. Indian Chem. Soc.  1978,  55:  386 
• 6h With NH₂OH·HCl: Hsung RP. Zificsak CA. Wei L.-L. Zehnder LP. Park F. Kim M. Tran TT. J. Org. Chem.  1999,  64:  8736 
• 6i With o-phenylenediamine: Ghosh CK. Khan S. Synthesis  1980,  701 
• 6j For conversion into pyrroles and thiofenes: Fitton AO. Frost JR. Suschitzky H. Houghton PG. Synthesis  1977,  133 
• 6k For conversation into 4-(2′-hydroxybenzoyl)salicylic esters see: Langer P. Holtz E. Synlett  2003,  402 
• 7a Nohara A. Ishiguro T. Sanno Y. Tetrahedron Lett.  1974,  1183 
• 7b Hishmat OH. El-Naem ShI. Magd-El-Din AA. Fawzy NM. Abd El.-AalAS. Egypt. J. Chem.  2000,  43:  87 
• For using Me₃SiCl as condensation agent see:
• 8a Ryabykhin SV. Plaskon AS. Tverdokhlebov AV. Tolmachev AA. Synth. Commun.  2004,  34:  1483 
• 8b Heaney H. Papageorgeogu G. Wilkins RF. Tetrahedron  1997,  53:  2941 
• 8c For using Me₃SiI as condensation agent see: Sabitha G. Reddy GSKK. Reddy KB. Yadav JS. Synthesis  2004,  263 
• 8d Sabitha G. Reddy GSKK. Reddy CS. Yadav JS. Synlett  2003,  858 
• 8e Sabitha G. Reddy GSKK. Reddy CS. Yadav JS. Tetrahedron Lett.  2003,  44:  4129 
• 14 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 

9

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.

10

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).

11

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).

12

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.

13

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).