Synthesis of Hydroxylated 3,4-Dihydropyridine-2-ones
from Intramolecular Nucleophilic Addition Reaction of Oxirane-Containing
Tertiary Enamides

Luo Yang; Shuo Tong; De-Xian Wang; Zhi-Tang Huang; Jieping Zhu; Mei-Xiang Wang

doi:10.1055/s-0030-1259703

LETTER

Synthesis of Hydroxylated 3,4-Dihydropyridine-2-ones from Intramolecular Nucleophilic Addition Reaction of Oxirane-Containing Tertiary Enamides

Luo Yang^a, Shuo Tong^a, De-Xian Wang^a, Zhi-Tang Huang^a, Jieping Zhu^b,c, Mei-Xiang Wang*^a,b
^a Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. of China
^b The Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, P. R. of China
Fax: +86(10)62796761; e-Mail: wangmx@mail.tsinghua.edu.cn;
^c Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, EPFL-SB-ISIC-LSPN, 1015, Lausanne, Switzerland

Abstract

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Abstract

Catalyzed by p-toluenesulfonic acid in dry acetonitrile, oxirane-containing tertiary enamides underwent efficient cyclization via intramolecular addition to produce 3-hydroxy-3,4-dihydropyridin-2(1H)-one derivatives in moderate to good yields.

Key words

enamides - oxiranes - nucleophilic addition - cyclization - 3,4-dihydropyridin-2-ones

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References

References and Notes

1 For example of anti-HIV activity, see: Medina-Franco JL. Martinez-Mayorga K. Juárez-Gordiano C. Castillo R. ChemMedChem 2007, 2: 1141

2 Yang M.-H. Chen Y.-Y. Huang L. Phytochemistry 1988, 27: 445

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3b Polyak F. Lubell WD. J. Org. Chem. 2001, 66: 1181

4 Keller PA. Pyridinones and Related Systems, In Science of Synthesis Vol. 15: Thieme; Stuttgart: 2005. p.285

5a Yadav LDS. Kapoor R. Tetrahedron Lett. 2008, 49: 4840

5b Yadav LDS. Kapoor R. Synlett 2008, 2348

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6d The Chemistry of Enamines Rappoport Z. John Wiley and Sons; Chichester: 1994.

7 Carbery DR. Org. Biomol. Chem. 2008, 6: 3455

8a Matsubara R. Kobayashi S. Acc. Chem. Res. 2008, 41: 292 ; and references cited therein

8b Brønsted acid catalyzed reaction of secondary enamides with imines is also known. See: Terada M. Machioka K. Sorimachi K. Angew. Chem. Int. Ed. 2006, 45: 2254

8c Terada K. Machioka K. Sorimachi K. J. Am. Chem. Soc. 2007, 129: 10336

For examples of enaminic reactions of tertiary enamides, see:

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Typical Procedure for the Conversion of 4a into Compound 6
Refluxing a suspension of enamide 4a (0.4 mmol, 111 mg) in deionized H₂O (12 mL) for 4 h under argon protection gave rise to a homogeneous solution. After addition of brine (30 mL), the mixture was extracted with EtOAc (3 × 20 mL). The organic layer was dried with anhyd Na₂SO₄, filtered, and concentrated under vacuum. The residue was subjected to chromatography using a silica gel (200-300 mesh) column eluting with a mixture of PE and EtOAc (1:1) as mobile phase to give product 6.
Mp 130-132 ˚C. IR (KBr): ν = 3307, 1637 cm^-¹. ^¹H NMR (300 MHz, CDCl₃, 300 K): δ = 7.23-7.98 (m, 10 H), 6.26 (s, 1 H), 4.38 (dd, J = 3.9, 5.2 Hz, 1 H), 3.73-3.85 (m, 2 H), 3.41-3.47 (m, 1 H), 3.29 (d, J = 5.6 Hz, 1 H), 2.71 (d, J = 2.7 Hz, 3 H). ^¹³C NMR (75 MHz, CDCl₃, 300 K): δ = 199.5, 172.8, 139.2, 136.8, 133.4, 128.76, 128.7, 128.4, 128.2, 127.3, 73.6, 44.8, 40.7, 25.7. ESI-MS: 298 (52) [M + 1]⁺, 320 (100) [M + Na]⁺. Anal. Calcd for C₁₈H₁₉NO₃: C, 72.71; H, 6.44; N, 4.71. Found: C, 72.94; H, 6.59; N, 4.86.

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General Procedure for the Synthesis of Compounds 5 and 8
To a solution of 4 or 7 (0.4 mmol) in dry MeCN (12 mL) was added PTSA (0.08 mmol, 14 mg) while stirring at 0 ˚C. The mixture was then kept stirring until the starting material was completely consumed. Water (100 mL) was added, and the mixture was extracted with EtOAc (3 × 50 mL). The organic layer was dried with anhyd MgSO₄ and concentrated. The residue was subjected to a silica gel (200-300 mesh) column eluted with a mixture of PE and EtOAc (3:1) to afford pure 5 or 8.
Selected Data for Compound 5a
Mp 143-145 ˚C. IR (KBr): ν = 3442, 1668 cm^-¹. ^¹H NMR (300 MHz, CDCl₃, 300 K): δ = 7.25-7.40 (m, 10 H), 5.35 (d, J = 2.4 Hz, 1 H), 4.38 (dd, J = 1.0, 13.7 Hz, 1 H), 3.88 (d, J = 1.8 Hz, 1 H), 3.78 (dd, J = 2.4, 13.7 Hz, 1 H), 3.04 (s, 3 H). ^¹³C NMR (75 MHz, CDCl₃, 300 K): δ = 172.9, 141.6, 140.6, 135.0, 128.9, 128.7, 128.66, 128.0, 127.7, 127.3, 113.3, 71.3, 45.8, 32.7. ESI-MS: m/z = 280 (26) [M + 1]⁺, 302 (100) [M + Na]⁺. Anal. Calcd for C₁₈H₁₇NO₂: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.25; H, 6.39; N, 4.94.

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