Efficient synthesis of 2-aryl-6-methyl-2,3-dihydro-1H-pyridin-4-ones

Article abstract of DOI:10.1016/S0040-4039(99)02164-4

Syntheses of 2-aryl-6-methyl-2,3-dihydro-1H-pyridin-4-ones were achieved starting from corresponding β-arylβ-amino acids. This reaction sequence involved, as a key step, the condensation of an acid chloride with a diketone using SmI₃ as catalyst. A final intramolecular cyclization furnished the attempted product. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02164-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 681–683
Efficient synthesis of 2-aryl-6-methyl-2,3-dihydro-1H-pyridin-
4-ones
Olivier Renault,a Jean Guillon,b Patrick Dallemagne a,∗ and Sylvain Rault a
aCentre d’Etudes et de Recherche sur le Médicament de Normandie, UFR des Sciences Pharmaceutiques, 1 rue Vaubénard,
14032 Caen Cedex, France
bSYNTHEVAL, 5 rue Vaubénard, 14032 Caen Cedex, France
Received 18 October 1999; accepted 17 November 1999
Abstract
Syntheses of 2-aryl-6-methyl-2,3-dihydro-1H-pyridin-4-ones were achieved starting from corresponding β-aryl-
β-amino acids. This reaction sequence involved, as a key step, the condensation of an acid chloride with a diketone
using SmI3 as catalyst. A final intramolecular cyclization furnished the attempted product. © 2000 Elsevier Science
Ltd. All rights reserved.
Dihydropyridones of the type 1 (Scheme 1) are interesting building blocks for a large variety of
heterocycle syntheses,1 because their amino-enone moiety can be used in various reactions, such as
1,2- and 1,4-additions, electrophilic substitutions and enolate alkylations. This type of compound can
be prepared according to two general routes, cyclization of triketones with ammonia,2,3 or addition of
organometallics to 1-acyl salts of 4-methoxypyridines.4–6 Moreover, they are also of great interest in
medicinal chemistry to design ligands for the neuronal nicotinic receptor.7
Scheme 1.
We wish to present herein a new efficient pathway which starts from β-amino-β-arylpropionic acids
and, in five steps, authorizes the preparation of a large diversity of compounds of the type 2. Thus,
the sequence depicted in Scheme 2 is as follows: the β-amino acids 3 were prepared according to
the Rodionow–Johnson’s method8,9 from the corresponding arylaldehydes. The amino function was
then protected by the trifluoroacetyl group, and then the acid chlorides were prepared in refluxing
∗
Corresponding author. Fax 00 (33) 2/31/93/11/88; e-mail: dallemagne@pharmacie.unicaen.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02164-4
tetl 16092

682
thionyl chloride. The latter were converted into the trifluoroacetylamino-β-diketones 4 by reaction
with acetylacetone in the presence of samarium iodide according to the method recently described by
Hao.10 Deprotection of the amino group in boiling hydrochloric acid gave the stable ammonium salts
5 which underwent an intramolecular cyclization in alkaline medium to give the 2-aryl-6-methyl-1,2-
dihydropyridin-4-ones 2 in high yield (Scheme 2). Furthermore, we have demonstrated that this sequence
can be applied to obtain enantiopure pyridones 2 using chiral β-amino acids.11
Scheme 2. (i) (CF3CO)2O; (ii) SOCl2; (iii) Sm/I2/CH3COCH2COCH3/CH3CN; (iv) HCl (6N)/∆; (v) NH4OH
Thus, application of this sequence to (–)-(2R)-2-(3-chlorophenyl)-3-aminopropionic acid 3e11
(Scheme 3) gave (–)-(2R)-2-(3-chlorophenyl)-6-methyl-1,2-dihydropyridin-4-one 2e12 without
racemization (ee >95%, determined by chiral HPLC analysis).
Scheme 3. (vi) C6H5CH2COCl/Et3N/CH3COCH3/H2O; (vii) penicillin acylase (E. coli)/NaHCO3/H2O
References
1. Chen, C.; McDonald, I. A.; Munoz, B. Tetrahedron Lett. 1998, 39, 217–220.
2. Work, S. D.; Hauser, C. R. J. Org. Chem. 1963, 28, 725–730.
3. Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223–243.
4. Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1986, 27, 4549–4552.
5. Comins, D. L.; Killpack, M. O. J. Am. Chem. Soc. 1992, 114, 10972–10974.
6. Comins, D. L.; Joseph, S. P.; Goehring, R. R. J. Am. Chem. Soc. 1994, 116, 4719–4728.
7. Holladay, M. W.; Dart, M. J.; Lynch, J. K. J. Med. Chem. 1997, 40, 4170–4194.
8. Rodionow, W. M.; Malewinskaja, E. T. Chem. Ber. 1926, 59, 2952–2958.
9. Johnson, T.; Livak, J. E. J. Am. Chem. Soc. 1936, 58, 299–303.
10. Hao, W.; Zhang, Y.; Ying, T.; Lu, P. Synth. Commun. 1996, 26, 2421–2427.
11. Soloshonok, V. A.; Fokina, N. A.; Rybakova, A. V.; Shishkina, I. P.; Galushko, S. V.; Sorochinsky, A. E.; Kukhar, V. P.;
Savchenko, M. V.; Svedas, V. K. Tetrahedron: Asymmetry 1995, 6, 1601–1610.
12. The experiment is as follows: Synthesis of 2e. A mixture of powdered samarium (0.037 mol) and iodine (0.061 mol) in dry
acetonitrile (300 mL) was stirred at room temperature until the samarium disappeared. To the cooled resulting suspension of
SmI3 were added the acid chloride (0.034 mol) and pentane-2,4-dione (0.037 mol). The reaction mixture was stirred for 6 h
at 0°C. It was then treated with dilute hydrochloric acid and extracted with diethyl ether (3×100 mL). The combined organic
layers were washed with saturated aqueous NaHCO3 and Na2S2O3 solutions, dried over magnesium sulfate and evaporated

683
to dryness. The residue was refluxed for 12 h in aqueous HCl solution (6N), then filtered and evaporated to dryness to give
the ammonium salt 5e. A suspension of 5e (0.0072 mol) in 100 mL of methylene chloride was made alkaline to pH=10 with
an ammonium hydroxide solution. It was then extracted with methylene chloride (2×50 mL). The combined organic layers
were dried over calcium chloride and evaporated to dryness. The oily residue was triturated in diethyl ether to give 2e as
beige crystals: mp: 129°C; IR (KBr) 3220, 1615 cm−1; 1H NMR (CDCl3) δ 1.86 (3H, s, CH3), 2.26 (1H, dd, J=105.9 and
5.6, H-3a), 2.36 (1H, dd, J=15.9 and 11.2, H-3b), 4.65 (2H, m, H-20 and H-50), 7.29 (3H, m, Harom), 7.39 (1H, s, Harom),
7.72 (1H, broad s, NH); 13C NMR (CDCl3) δ 20.2, 42.8, 55.7, 97.7, 125.5, 126.7, 127.6, 130.4, 133.2, 143.7, 162.5, 189.0;
[α]D25=−176.92 (c, 0.004 CH3OH); anal. calcd for C12H12ClNO: C, 65.02; H, 5.91; N, 6.32. Found: C, 64.89; H, 6.02; N,
6.25.