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.

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 

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).

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