Efficient Synthesis of Functionalized 2-Pyridones from Malonyl Dichloride, Alkylamines and Dimethyl Acetylenedicarboxylate

Abstract

An efficient synthesis of dimethyl 1-alkyl-4-hydroxy-6-oxo-1,6-dihydropyridine-2,3-dicarboxylates is described. This involves a three-component reaction between primary alkylamines, malonyl dichloride, and dimethyl acetylenedicarboxylate.

malonyl dichloride - 2-pyridinone - acetylenic ester - multicomponent reaction

References and Notes

1a Lazaar J. Hoarau C. Mongin F. Trécourt F. Godard A. Quéguiner G. Marsais F. Tetrahedron Lett.  2005,  46:  3811 

1b Pemberton N. Jakobsson L. Almqvist F. Org. Lett.  2006,  8:  936 

1c Comins DL. Nolan JM. Org. Lett.  2001,  3:  4255 

1d Josein H. Ko S.-B. Bom D. Curran DP. Chem. Eur. J.  1998,  4:  67 

1e Comins DL. Saha JK. J. Org. Chem.  1996,  61:  9623 

1f Villemin D. Liao L. Tetrahedron Lett.  1996,  37:  8733 

2a Cutshall NS. Kucera KA. Ursion R. Latham J. Ihle NC. Bioorg. Med. Chem. Lett.  2002,  12:  1517 

2b Gaskell D. Chem. Br.  1998,  34:  27 

3a Henry GD. Tetrahedron  2004,  60:  6043 

3b Bevk D. Jakše R. Golobič L. Golič L. Meden A. Svete J. Stanovnik B. Heterocycles  2004,  63:  609 

3c Stanovnik B. Svete J. Chem. Rev.  2004,  104:  2433 

3d Coffey DS. Kolis SP. May SA. Prog. Heterocycl. Chem.  2003,  15:  284 

4a Arcadi A. Chiarani M. Di Giuseppe S. Marinelli F. Synlett  2003,  203 

4b Petrich SA. Hicks FA. Wilkinson DR. Tarrant JG. Bruno SM. Vargas M. Hosein KN. Gupton JT. Sikorski JA. Tetrahedron  1995,  51:  1575 

5 Varela JA. Saá C. Chem. Rev.  2003,  103:  3787 

6a Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 

6b Bienaymé H. Hulme C. Oddon G. Schmitt P. Chem. Eur. J.  2000,  6:  3321 

6c Lee D. Sello JK. Schreiber SL. Org. Lett.  2000,  2:  709 

6d Domling A. Chem. Rev.  2006,  106:  17 

6e Ugi I. J. Prakt. Chem.  1997,  339:  499 

6f Armstrong RW. Combs AP. Tempest PA. Brown SD. Keating TA. Acc. Chem. Res.  1996,  29:  123 

7a Yavari I. Nasiri F. Moradi L. Djahaniani H. Tetrahedron Lett.  2004,  45:  7099 

7b Yavari I. Anary-Abbasinejad M. Alizadeh A. Tetrahedron Lett.  2002,  43:  4503 

7c Yavari I. Adib M. Sayahi MH. Tetrahedron Lett.  2002,  43:  2927 

7d Yavari I. Alizadeh A. Anary-Abbasinejad M. Bijanzadeh HR. Tetrahedron  2003,  59:  6083 

8

Dimethyl 1-Benzyl-4-hydroxy-6-oxo-1,6-dihydro-2,3-pyridinedicarboxylate (4a): To a stirred solution of DMAD (0.34 g, 2.4 mmol) and benzyl amine (0.20 g, 2 mmol) in CH₂Cl₂ (10 mL) was added malonyl dichloride (0.19 mL, 2 mmol) at r.t. The reaction mixture was then stirred for 24 h. The solvent was removed under reduced pressure and the viscous residue was purified by flash column chromatography on silica gel (Merck 230-400 mesh) using n-hexane-EtOAc as eluent to give 4a as a white powder; mp 119-121 °C; yield: 0.53 g (85%). IR (KBr): 3445 (OH), 1732 (C=O), 1677, 1654, 1528, 1434 cm^-1. ¹H NMR (500.1 MHz, CDCl₃): δ = 3.69 (s, 3 H, OMe), 3.85 (s, 3 H, OMe), 5.19 (s, 2 H, CH₂), 6.05 (s, 1 H, CH), 7.16 (d, ³ J _HH = 6.9 Hz, 2 H, CH), 7.24-7.30 (m, 3 H, CH), 10.86 (s, 1 H, OH). ¹³C NMR (125.7 MHz, CDCl₃): δ = 48.9 (NCH₂), 53.0 (OMe), 53.2 (OMe), 97.8 (CH), 100.2 (C), 127.0 (2 × CH), 127.8 (CH), 128.5 (2 × CH), 135.4 (C), 147.4 (C), 162.3, 162.4, 165.3, 167.1 (COH, 3 × C=O). MS: m/z (%) = 317 (15) [M⁺], 241 (8), 211 (15), 196 (40), 179 (10), 91 (100), 77 (20), 57 (10). Anal. Calcd for C₁₆H₁₅NO₆ (317.29): C, 60.75; H, 4.76; N, 4.41. Found: C, 60.50; H, 4.70; N, 4.30. All other novel compounds isolated possessed spectroscopic and analytical data in agreement with their proposed structures.

9a Huisgen R. Herbig K. Siege1 A. Huber H. Chem. Ber.  1966,  99:  2526 

9b Herbig K. Huisgen R. Huber H. Chem. Ber.  1966,  99:  2540 

10a Yavari I. Hossein-Nia A. Magn. Reson. Chem.  1992,  30:  413 

10b Yavari I. Shaabani A. Soliemani H. Nourmohammadian F. Bijanzadeh HR. Magn. Reson. Chem.  1996,  34:  1003