Multicomponent Synthesis of Highly Substituted 2-Pyridones

Ana G. Neo; Rosa María Carrillo; Susana Barriga; Edelmiro Momán; Stefano Marcaccini; Carlos F. Marcos

doi:10.1055/s-2007-967992

LETTER

Multicomponent Synthesis of Highly Substituted 2-Pyridones

Ana G. Neo^a, Rosa María Carrillo^a, Susana Barriga^a, Edelmiro Momán^b, Stefano Marcaccini^c, Carlos F. Marcos*^a
^a Laboratorio de Química Orgánica y Bioorgánica, LOBO, Departamento de Química Orgánica, Facultad de Veterinaria, Universidad de Extremadura, 10071 Cáceres, Spain
^b Centre for Synthesis & Chemical Biology, Department of Pharmaceutical & Medicinal Chemistry, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland
^c Dipartimento di Chimica Organica ‘Ugo Schiff’, Università di Firenze, 50019 Sesto Fiorentino FI, Italy
Fax: +34(927)257110; e-Mail: cfernan@unex.es;

Abstract

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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

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References

References and Notes

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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.

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.

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.

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.

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:

<A NAME="RD17006ST-14A">14a</A> Fitton AO. Frost JR. Suschitzky H. Tetrahedron Lett. 1975, 16: 2099

<A NAME="RD17006ST-14B">14b</A> Fitton AO. Frost JR. Houghton PG. Suschitzky H. J. Chem. Soc., Perkin Trans. 1 1979, 1691

<A NAME="RD17006ST-15">15</A> Cristau P. Vors JP. Zhu J. Tetrahedron 2003, 59: 7859

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.