Solid-phase synthesis of 4-aryl substituted 5-carboxy-6-methyl-3,4-dihydropyridones

Article abstract of DOI:10.1016/S0040-4039(01)02172-4

Substituted 3,4-dihydro-2-pyridones have been efficiently prepared by solid-phase synthesis using Wang resin from the immobilised β-ketoester and further Hantzsch-type heterocyclisation.

Full text of DOI:10.1016/S0040-4039(01)02172-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 439–441
Solid-phase synthesis of 4-aryl substituted
5-carboxy-6-methyl-3,4-dihydropyridones
Hortensia Rodr´ıguez,a,* Osvaldo Reyes,b Margarita Suarez,a,* Hilda E. Garay,b Rolando Pe´rez,a
Luis Javier Cruz,b Yamila Verdecia,b Nazario Mart´ınc,* and Carlos Seoanec
aLaboratorio de S´ıntesis Orga´nica, Facultad de Qu´ımica, Universidad de La Habana, 10400 Ciudad Habana, Cuba
bCentro de Ingenieria Gene´tica y Biotecnologia, Apartado 6162, 10600 Ciudad Habana, Cuba
cDepartamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, Universidad Complutense, E-28040 Madrid, Spain
Received 25 July 2001; accepted 9 November 2001
Abstract—Substituted 3,4-dihydro-2-pyridones have been efficiently prepared by solid-phase synthesis using Wang resin from the
immobilised b-ketoester and further Hantzsch-type heterocyclisation. © 2002 Published by Elsevier Science Ltd.
The development of solid-phase synthetic methods is an
important aspect of todays drugs discovery process.1–4
There has been growing interest in such methodology
over the last 5 years, thus opening new horizons in the
search of suitable drug candidates. Due to their proper-
ties, heterocyclic systems play an important role as
potential active compounds. Some studies have been
published on the solid-phase synthesis of a wide variety
of heterocycles as pyrazole, pyridine and pyridone
derivatives,5 isoquinolines and imidazopyridines,6
trisubstituted indoles,7 2,3-dihydro-4-pyridones,8 1,3,5-
pyridin-2-ones,9 and 1,3,5-thiadiazine-2-thione deriva-
tives.10
further transformed in a wide variety of pyridine-fused
heterocyclic systems.15,16
The SPS of 2-pyridones takes place from a previous
preparation of immobilised b-ketoesters 2, as shown in
Scheme 1. Simple acetoacetylation can be performed by
treatment of hydroxyl functionalised polymers 1 (Wang
resin) with 1,3-dioxin-4-one (toluene, 111°C, 5 h).17 The
qualitative conversion of 1 to 2 was observed following
the disappearance of the OH group present in 1, and
detecting the presence of the CꢀO group present in 2 in
the IR spectra. Thus, the reaction of 2 with ammonium
acetate (AcOH, 118°C, 6 h) gave rise to the correspond-
ing enamine 3. To confirm the presence of the enamine,
a sample of 318 was treated with a solution of TFA/
DCM (95%) (Scheme 2) and the crude solution contain-
ing 7 was analysed by HPLC and NMR.19 We have
also obtained the solid-phase NMR spectrum of 3 and
detected the enamine linked to the Wang resin by the
presence in the spectra of the CꢀO signal at l 169
(CP-MAS).
The research on the 1,4-dihydropyridine (1,4-DHP) sys-
tems is of current interest due to their exceptional
properties as calcium antagonists.11 Gordeev et al.
developed an efficient solid-phase synthesis of diverse
pyridines and pyrido[2,3-d]pyrimidines12 and 1,4-
dihydropyridines.13
In a previous work we have described the synthesis of
3,4-dihydropyridones in solution.14 In this paper we
report on the solid-phase synthesis (SPS) of 4-aryl
The intermediate 3 was further reacted with Knove-
nagel derivatives20 (DMF, 150°C, 5 h) by a Hantzsch-
type heterocyclisation,21 to afford the expected
immobilised 2-pyridones 5a–h. The desired products 6
were cleaved from the resin using TFA 95% in DCM.
The products were obtained in 71–85% yield and 82–
95% of purity determined by HPLC,22 as shown in
Table 1. The impurities of the cleaved products could
not be identified. One- and two-dimensional NMR
experiments confirmed the formation of the pyridone
ring.23
substituted
5-carboxy-6-methyl-3,4-dihydropyridone
derivatives from readily available starting materials.
These 3,4-dihydro-2-oxopyridines are important key
intermediates for the preparation of o-chloroformyl
1,4-DHPs by Vilsmeier–Haack reaction, which can be
Keywords: solid-phase synthesis; 5-carboxy-6-methyl-3,4-dihydropyri-
dones; Wang resin.
* Corresponding authors.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(01)02172-4

440
H. Rodr´ıguez et al. / Tetrahedron Letters 43 (2002) 439–441
Scheme 1. (i) 1,3-Dioxin-4-one, toluene, 111°C; (ii) NH4AcO, AcOH, 118°C; (iii) DMF, 150°C; (iv) TFA 95% in DCM; (v) TFA
95% in DCM, MeOH.
Scheme 2.
Table 1. 4-Aryl substituted 5-carboxy-6-methyl-3,4-dihy-
resin. The 3,4 dihydropyridones were prepared in four
synthetic steps and 71–85% overall yields. Since these
nitrogen heterocycles are key intermediates for the
preparation of o-chloroformyl derivatives, this method-
ology paves the way for the solid-phase synthesis of
related bicyclic–fused systems.
dropyridone derivatives
Compound
Ar
Yielda (%)
Purityb (%)
6a
6b
6c
6d
6e
6f
C6H5
82
73
65
85
71
85
81
95
88
85
78
95
82
92
89
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
2-ClC6H4
2,4-diClC6H3
4-CH3OC6H4
Acknowledgements
6g
6h
2,4-diCH3OC6H3 75
Supports of this work by Proyectos Alma Mater
(CUBA) and DGESIC of Spain (PB98-0818 and
BQU2000-0790) are gratefully acknowledged. M.S. is
indebted to Programa de Cooperacio´n Cient´ıfica con
Iberoame´rica, Proyectos de Investigacio´n Conjunta
2001, M.E.C. of Spain.
a Yields are based on the calculated loading after coupling of diketene
acetone adduct to Wang resin.
b Purity of the compounds was based on the integration area of
HPLC for crude products, at 226 nm.
The cleavage of 6 from the resin in the presence of
MeOH gave the corresponding methyl ester 8 and their
spectroscopical data were identical to those obtained
from the products synthesised by following the method
previously reported.14
References
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In conclusion, an efficient and general solid-phase syn-
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dihydropyridones has been developed using Wang
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(5 mL), and dried in a vacuum desiccator. The resulted
resin was stirred with 95% TFA in CH2Cl2 (20 mL, 2 h;
for cleavage from Wang resin). Acetone (5 mL) was
added, and quickly evaporated in vacuo with addition of
acetone to ensure complete TFA removal.
19. Data for compound 7:
1H NMR (DMSO-d6): l 7.78 (2H, brs, NH2), 4.30 (1H, s,
CH), 1.83 (3H, s, CH3); 13C NMR (DMSO-d6): l 167.7
(C1), 161.6 (C3), 89.5 (C2), 20.6 (C4). Anal. calcd for
C4H7NO2 (101.11) C, 47.52; H, 6.98; N, 13.85. Found C,
47.74; H, 7.21; N, 13.96%.
20. Rodr´ıguez, R.; Sua´rez, M.; Ochoa, E.; Morales, A.;
Gonza´lez, L.; Mart´ın, M.; Quinteiro, M.; Seoane, C.;
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21. General procedure for synthesis of 4-aryl substituted
5-carboxyl-6-methyl-3,4-dihydropyridones 6: Resin O-
immobilised enamine 3 and the different Knovenagel
derivatives 4a–i in DMF was refluxed for 5 h. The resin
was filtered, washed sequentially with DMF (4×5 mL),
DCM (3×7 mL), and diethyl ether (5 mL), and dried in a
vacuum desiccator. The resulting resin was stirred with
95% TFA in CH2Cl2 (20 mL, 2 h; for cleavage from
Wang resin). Acetone (5 mL) was added, and quickly
evaporated in vacuo with addition of acetone to ensure
complete TFA removal, the residue obtained is precipi-
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22. HPLC analyses were performed using 10 mm 4.6×100 mm
reverse phase column (gradient from 100% of the
aqueous 0.1% TFA (eluent A) to 60% eluent A-40% of
0.5% TFA in acetonitrile (eluent B) over 35 min, flow rate
0.8 mL/min).
17. General procedure for preparation of O-immobilised b-
ketoesters 2: Appropriate hydroxyl functionalised poly-
mers 1 (Wang resin, 0.46 mmol) and 1,3-dioxin-4-one
(0.92 mmol) in toluene (5 mL) was refluxed for 6 h. The
resulting immobilised b-ketoesters 2 was filtered, washed
sequentially with toluene (4×5 mL), acetonitrile (3×5
mL), ethanol (3×5 mL), and diethyl ether (5 mL), and
dried in a vacuum desiccator.
23. Data for compound 6a:
1H NMR (DMSO-d6): l 9.98 (1H, brs, NH), 7.48–7.05
(5H, m, Ph), 4.01 (d, 1H, H4, J=7.5 Hz), 2.91 (dd, 1H,
H3a, J=7.5 Hz, J=0.9 Hz), 2.40 (d, 1H, H3b, J=0.9
Hz), 1.82 (3H, s, CH3); 13C NMR (DMSO-d6): l 171.5
(C2), 170.0 (COOH), 145.3 (C6), 141.2 (C1%), 128.2 (C2%,
C6%), 126.2 (C4%), 123.4 (C3%, C5%), 109.7 (C5), 40.3 (C3),
38.4 (C4), 18.7 (CH3). Anal. calcd for C13H13NO3
(231.25) C, 67.52; H, 5.67; N, 6.06. Found C, 67.81; H,
5.76; N, 6.17%.
18. General procedure for preparation of 3: Appropriate
resin O-immobilised b-ketoesters
2 (0.5 mmol) and
ammonium acetate (5 mmol) in acetic acid was refluxed
for 6 h. The resin was filtered, washed sequentially with
acetic acid (4×5 mL), DMF (3×7 mL), and diethyl ether