Multicomponent Synthesis of Highly Substituted 2-Pyridones

Abstract

A novel synthesis of polyfunctionalised pyridones, ­structurally related to cardiotonic agent milrinone is described. The procedure consists of an Ugi four-component reaction of 3-formylchromones, followed by a base-promoted ring-opening/ring-closing process. Variation of three of the four components in the Ugi ­reaction allows access to the final products with a combinatorial distribution of ­substituents.

Key words

cyclisations - drugs - heterocycles - multicomponent ­reactions - pyridines

References and Notes

• 1 Dorigo P. Gaion RM. Belluco P. Fraccarollo D. Maragno I. Bombieri G. Benetollo F. Mosti L. Orsini F. J. Med. Chem.  1993,  36:  2475 
• For recent examples, see:
• 3a Chen YH. Zhang HJ. Nan FJ. J. Comb. Chem.  2004,  6:  684 
• 3b Hachiya L. Ogura K. Shimizu M. Synthesis  2004,  1349 ; and the references therein
• See, for example:
• 4a Fossa P. Menozzi G. Dorigo P. Floreani M. Mosti L. Bioorg. Med. Chem.  2003,  11:  4749 
• 4b Altomare C. Cellamare S. Summo L. Fossa P. Mosti L. Carotti A. Bioorg. Med. Chem.  2000,  8:  909 
• 4c Dorigo P. Fraccarollo D. Gaion RM. Santostasi G. Borea PA. Floreani M. Mosti L. Maragno I. Gen. Pharmacol.  1997,  28:  781 
• 4d Mosti L. Schenone P. Iester M. Dorigo P. Gaion RM. Fraccarollo D. Eur. J. Med. Chem.  1993,  28:  853 
• 5 Bossio R. Marcos CF. Marcaccini S. Pepino R. Heterocycles  1997,  45:  1589 
• 6 Beck B. Picard A. Herdtweck E. Dömling A. Org. Lett.  2004,  6:  39 
• 7a Marcaccini S. Pepino R. Marcos CF. Polo C. Torroba T. J. Heterocycl. Chem.  2000,  37:  1501 
• 7b Bossio R. Marcos CF. Marcaccini S. Pepino R. Synthesis  1997,  1389 
• 8 Ryabukhin SV. Plaskon AS. Volochnyuk DM. Tolmachev AA. Synlett  2004,  2287 
• 9 Jeon YH. Heo YS. Kim CM. Hyun YL. Lee TG. Ro S. Cho JM. CMLS, Cell. Mol. Life Sci.  2005,  62:  1198 
• Enamines 9 were identified by ¹H NMR and ¹³C NMR as the major products obtained in the reactions with 4-chloro-aniline, 3,5-dichloroaniline, 4-nitroaniline and 1-amino-naphthalene. For example ¹H NMR data of (Z)-3-[(4-chlorophenylamino)methylene]-2,3-dihydro-2-methoxy-chromen-4-one (9; R¹ = H, R² = 4-ClC₆H₄), obtained from 4-chloroaniline and 3-formylchromone, was identical to the published data:
• 14a Fitton AO. Frost JR. Suschitzky H. Tetrahedron Lett.  1975,  16:  2099 
• 14b Fitton AO. Frost JR. Houghton PG. Suschitzky H. J. Chem. Soc., Perkin Trans. 1  1979,  1691 
• 15 Cristau P. Vors JP. Zhu J. Tetrahedron  2003,  59:  7859 

2

Information obtained from the Investigational Drugs Database (IDDB, www.iddb3.com).

10

Synthesis of the Ugi adducts ( 7): General Procedure for Method A: 3-Formylchromone (3; R¹ = H) or 6-methyl-2-formylchromone (3; R¹ = CH₃, 5 mmol) was dissolved in MeOH (5 mL). Amine 4 (5 mmol) was added, and the mixture was stirred for 15 min at r.t. Isocyanide 5 (5 mmol) and cyanoacetic acid (6; 5 mmol) were successively added and the mixture was stirred for 24-48 h at r.t. An abundant precipitate was formed, which was filtered and successively washed with i-PrOH and i-Pr₂O, yielding a product pure enough to be used in the following reaction. For analytical purposes it may be further purified by recrystallisation from EtOH.

11

Representative Data: 2-Cyano- N -[cyclohexyl-carbamoyl(4-oxo-4 H -chromen-3-yl)methyl]- N -phenyl-acetamide ( 7a): Yield: 67%; white solid; mp 217-218 °C. IR: 3336, 2931, 2360, 1650, 1543, 1466, 761 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.15 (d, J = 8.1 Hz, 1 H), 8.03 (s, 1 H), 7.64 (t, J = 7.1 Hz, 1 H), 7.03-7.60 (m, 7 H), 6.47 (d, J = 8.4 Hz, 1 H), 6.31 (s, 1 H), 3.76-3.83 (m, 1 H), 3.33 (d, J = 18.5 Hz, 1 H), 3.17 (d, J = 18.5 Hz, 1 H,), 1.13-2.02 (m, 10 H). ¹³C NMR (100 MHz, CDCl₃): δ = 175.83 (C), 167.79 (C), 162.88 (C), 158.06 (CH), 155.75 (C), 138.34 (C), 134.03 (CH), 129.78 (CH), 129.51 (CH), 125.84 (CH), 125.57 (CH), 123.30 (C), 118.17 (CH), 117.93 (C), 113.81 (C), 55.84 (CH), 48.98 (CH), 32.66 (CH₂), 26.51 (CH₂), 25.39 (CH₂), 24.72 (CH₂). MS (EI): m/z (%) = 444 (<1) [M⁺ + 1], 318 (12), 250 (100), 172 (3), 130 (5), 77 (2). HRMS: m/z calcd for C₂₆H₂₅N₃O₄: 443.1849; found: 443.1845.

12

Cyclisation of the Ugi Adducts ( 7): General Procedure: A 0.5 M solution of KOH in EtOH (1 mL, 0.5 mmol) was added to a solution of the Ugi adduct (7, 0.5 mmol) in EtOH (1 mL). The mixture was stirred for 8 h at r.t. and the orange-yellow precipitate obtained was filtered and washed with i-Pr₂O, yielding compound 8 in an essentially pure form.

13

Representative Data for Potassium 5-Cyano-2-cyclohexylcarbamoyl-6-oxo-1-phenyl-1,6-dihydro-2 H -pyridin-3-ylidene(2-hydroxyphenyl)methanolate ( 8a): Yield: 75%; orange solid; mp 275 °C (dec.). IR: 3439, 2928, 2194, 1679, 1607, 1554, 1520, 1240, 771 cm^-1. ¹H NMR (400 MHz, DMSO): δ = 10.66 (s, 1 H), 7.56 (d, J = 8.1 Hz, 1 H), 7.31 (t, J = 8.0 Hz, 2 H), 7.23 (t, J = 7.1 Hz, 2 H), 7.11-7.19 (m, 3 H), 7.06 (s, 1 H), 6.86 (s, 1 H), 6.84 (s, 1 H), 5.28 (s, 1 H), 3.47-3.55 (m, 1 H), 1.04-1.75 (m, 10 H). ¹³C NMR (100 MHz, DMSO): δ = 183.28 (C), 169.91 (C), 164.31 (C), 156.83 (C), 147.65 (CH), 143.47 (C), 130.64 (CH), 129.59 (CH), 128.30 (CH), 125.68 (CH), 125.24 (C), 124.91 (CH), 122.21 (C), 118.34 (CH), 116.33 (CH), 105.83 (C), 78.28 (C), 62.07 (CH), 47.03 (CH), 32.34 (CH₂), 31.93 (CH₂), 25.42 (CH₂), 25.23 (CH₂), 23.85 (CH₂). MS (FAB): m/z (%) = 520 (100) [M⁺ + K], 482 (96) [M⁺ +1], 444 (18), 376 (29), 356 (19), 355 (72), 338 (62), 317 (29). HRMS (FAB): m/z calcd for C₂₆H₂₅KN₃O₄: 482.1482; found: 482.1487.

16

Synthesis of the Ugi Adducts; Method B: Equimolar amounts of the four components and NH₄Cl were stirred in toluene for 48 h at r.t. The resulting precipitate was filtered and successively washed with i-PrOH and hexanes.