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Synlett 2008(4): 509-512  
DOI: 10.1055/s-2008-1032093
LETTER
© Georg Thieme Verlag Stuttgart · New York

One-Pot Synthesis of 1,4-Dihydropyridines via a Phenylboronic Acid Catalyzed Hantzsch Three-Component Reaction

Abdelmadjid Debache*a, Raouf Boulcinaa, Ali Belfaitaha, Salah Rhouatia, Bertrand Carbonib
a Laboratoire des Produits Naturels d’Origine Végétale et de Synthèse Organique, Département de Chimie, Faculté des Sciences, Université Mentouri de Constantine, 25000 Constantine, Algérie
Fax: +213(31)818862; e-Mail: a_debache@yahoo.fr;
b Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France
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Publikationsverlauf

Received 21 August 2007
Publikationsdatum:
12. Februar 2008 (online)

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Abstract

A simple, inexpensive, and efficient one-pot synthesis of 1,4-dihydropyridine derivatives was achieved in good yields via the three-component reaction of aromatic aldehydes, ethyl acetoacetate, and ammonium acetate using PhB(OH)2 as catalyst.

Key words

1,4-dihydropyridines - Hantzsch reaction - one-pot condensation - phenylboronic acid

24

General Procedure for the Synthesis of 1,4-Dihydro-pyridines 4
A mixture of aldehyde 1 (5 mmol), ethyl acetoacetate 2 (10 mmol), NH4OAc (3, 10 mmol), and PhB(OH)2 (10 mol%) was refluxed in EtOH (10 mL) for 4-5 h. The reaction mixture was poured into cold H2O and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by recrystallization from EtOH to afford 1,4-dihydropyr-idines 4 in 75-95% yields. The aqueous layer containing the catalyst could be evaporated under reduced pressure to give a white solid, which could be reused.
All compounds were fully characterized by mp, IR, 1H NMR and 13C NMR spectroscopy. These data are in full agreement with those previously reported in the literature. [26]
Diethyl 4-(Phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4a) Mp 156-158 °C. 1H NMR (250 MHz, CDCl3): δ = 1.25 (t, J = 7.1 Hz, 6 H), 2.33 (s, 3 H), 2.32 (s, 6 H), 4.11 (q, J = 7.1 Hz, 4 H), 5.01 (s, 1 H), 5.97 (s, 1 H), 7.11-7.32 (m, 5 H). 13C NMR (62.9 MHz, CDCl3): δ = 14.1, 19.5, 39.4, 59.3, 104.1, 127.5, 128.8, 135.7, 144.1, 145.9, 167.8. FT-IR (KBr): 3334, 1690, 1654, 1494, 1243, 1127, 721 cm-1.
Diethyl 4-(3-Methylphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4b) Mp 122-124 °C. 1H NMR (250 MHz, CDCl3): δ = 1.28 (t, J = 7.1 Hz, 6 H), 2.31 (s, 3 H), 2.34 (s, 6 H), 4.10 (q, J = 7.1 Hz, 4 H), 4.98 (s, 1 H), 5.96 (s, 1 H), 6.94-6.99 (m, 1 H), 7.09-7.15 (m, 3 H). 13C NMR (62.9 MHz, CDCl3): δ = 14.2, 19.5, 21.6, 39.5, 59.8, 104.0, 125.1, 127.7, 127.8, 128.0, 128.8, 144.1, 147.7, 167.6. FT-IR (KBr): 3344, 1692, 1648, 1490, 1212, 1130, 723 cm-1.
Diethyl 4-(4-Methylphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4c) Mp 135-137 °C. 1H NMR (250 MHz, CDCl3): δ = 1.28 (t, J = 7.1 Hz, 6 H), 2.30 (s, 3 H), 2.32 (s, 6 H), 4.14 (q, J = 7.1 Hz, 4 H), 4.98 (s, 1 H), 6.09 (s, 1 H), 7.04 (d, J = 7.8 Hz, 2 H), 7.23 (d, J = 7.8 Hz, 2 H). 13C NMR (62.9 MHz, CDCl3): δ = 14.3, 19.4, 21.2, 39.1, 59.7, 103.9, 127.8, 128.9, 135.2, 144.3, 145.0, 168.0. FT-IR (KBr): 3343, 1690, 1651, 1491, 1213, 1122, 772 cm-1.
Diethyl 4-(3-Chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4d) Mp 130-132 °C. 1H NMR (250 MHz, CDCl3): δ = 1.25 (t, J = 7.1 Hz, 6 H), 2.33 (s, 6 H), 4.12 (q, J = 7.1 Hz, 4 H), 4.98 (s, 1 H), 6.03 (s, 1 H), 7.12-7.29 (m, 4 H). 13C NMR (62.9 MHz, CDCl3): δ = 14.2, 19.5, 39.6, 59.9, 103.4, 126.2, 127.8, 128.2, 133.5, 143.4, 144.6, 149.8, 167.6. FT-IR (KBr): 3323, 1703, 1649, 1491, 1215, 1124, 802 cm-1.
Diethyl 4-(4-Chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4e) Mp 144-146 °C. 1H NMR (250 MHz, CDCl3): δ = 1.24 (t, J = 7.2 Hz, 6 H), 2.33 (s, 6 H), 4.11 (q, J = 7.2 Hz, 4 H), 4.97 (s, 1 H), 5.88 (s, 1 H), 7.23-7.19 (m, 4 H). 13C NMR (62.9 MHz, CDCl3): δ = 14.3, 19.6, 39.2, 59.9, 103.8, 127.9, 129.4, 131.7, 144.1, 146.3, 167.5. FT-IR (KBr): 3360, 1695, 1651, 1487, 1212, 1122, 789 cm-1.
Diethyl 4-(4-Hydroxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4f)
Mp 230-232 °C. 1H NMR (250 MHz, CDCl3): δ = 1.25 (t, J = 7.1 Hz, 6 H), 2.34 (s, 6 H), 4.12 (q, J = 7.1 Hz, 4 H), 5.32 (s, 1 H), 5.77 (s, 1 H), 7.24-7.41 (m, 4 H). 13C NMR (62.9 MHz, CDCl3): δ = 14.1, 19.3, 39.4, 59.8, 103.9, 127.9, 130.9, 130.4, 142.3, 148.5, 167.8. FT-IR (KBr): 3331, 1689, 1656, 1490, 1244, 1126, 720 cm-1.
Diethyl 4-(3-Nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4g) Mp 164-166 °C. 1H NMR (250 MHz, CDCl3): δ = 1.33 (t, J = 7.1 Hz, 6 H), 2.36 (s, 6 H), 4.12 (q, J = 7.1 Hz, 4 H), 5.10 (s, 1 H), 6.20 (s, 1 H), 7.31 (t, J = 7.9 Hz, 1 H), 7.66 (d, J = 7.8 Hz, 1 H), 8.03 (d, J = 7.9 Hz, 1 H), 8.15 (s, 1 H). 13C NMR (62.9 MHz, CDCl3): δ = 14.2, 19.5, 39.9, 60.0, 103.0, 121.3, 123.1, 128.6, 134.6, 145.1, 148.1, 150.0, 167.3. FT-IR (KBr): 3344, 1705, 1645, 1527, 1487, 1215, 1123, 704 cm-1.
Diethyl 4-(4-Nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4h) Mp 130-132 °C. 1H NMR (250 MHz, CDCl3): δ = 1.23 (t, J = 7.1 Hz, 6 H), 2.35 (s, 6 H), 4.13 (q, J = 7.1 Hz, 4 H), 5.10 (s, 1 H), 6.16 (s, 1 H), 7.50 (d, J = 8.6 Hz, 2 H), 8.14 (d, J = 8.6 Hz, 2 H). 13C NMR (62.9 MHz, CDCl3): δ = 14.2, 19.5, 40.1, 60.3, 103.0, 123.6, 128.9, 145.0, 146.2, 155.2, 167.2. FT-IR (KBr): 3317, 1705, 1647, 1521, 1348, 1215, 1122, 707 cm-1.
Diethyl 4-(4-Methoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4i)
Mp 157-159 °C. 1H NMR (250 MHz, CDCl3): δ = 1.25 (t, J = 7.2 Hz, 6 H), 2.31 (s, 6 H), 3.76 (s, 3 H), 4.12 (q, J = 7.2 Hz, 4 H), 4.95 (s, 1 H), 6.13 (s, 1 H), 6.76 (d, J = 8.6 Hz, 2 H), 7.23 (d, J = 8.6 Hz, 2 H). 13C NMR (62.9 MHz, CDCl3): δ = 14.2, 19.4, 38.7, 55.1, 59.7, 104.2, 113.1, 128.9, 140.4, 143.9, 157.8, 167.8. FT-IR (KBr): 3342, 1690, 1651, 1491, 1211, 1124, 750 cm-1 Diethyl 4-(4-Bromophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4j)
Mp 160-162 °C. 1H NMR (250 MHz, CDCl3): δ = 1.24 (t, J = 7.1 Hz, 6 H), 2.34 (s, 6 H), 4.12 (q, J = 7.1 Hz, 4 H), 5.32 (s, 1 H), 5.77 (s, 1 H), 7.18 (d, J = 8.4 Hz, 2 H), 7.34 (d, J = 8.4 Hz, 2 H). 13C NMR (62.9 MHz, CDCl3): δ = 14.1, 19.3, 39.4, 59.8, 103.9, 127.9, 130.9, 130.4, 142.3, 148.5, 167.8. FT-IR (KBr): 3340, 1690, 1643, 1492, 1211, 1120, 770 cm-1.
Diethyl 4-(3,5-Dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4k)
Mp 128-130 °C. 1H NMR (250 MHz, CDCl3): δ = 1.25 (t, J = 7.1 Hz, 6 H), 2.34 (s, 6 H), 4.13 (q, J = 7.1 Hz, 4 H), 4.95 (s, 1 H), 6.07 (s, 1 H), 7.13-7.23 (m, 3 H). 13C NMR (62.9 MHz, CDCl3): δ = 14.2, 19.5, 39.8, 60.0, 103.0, 126.2, 126.8, 134.1, 144.8, 151.0, 167.2. FT-IR (KBr): 3315, 1701, 1645, 1492, 1217, 1124, 785 cm-1.
Diethyl 4-(2-Thienyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4l)
Mp 172-174 °C. 1H NMR (250 MHz, CDCl3): δ = 1.31 (t, J = 7.1 Hz, 6 H), 2.35 (s, 6 H), 4.18 (q, J = 7.1 Hz, 4 H), 5.37 (s, 1 H), 6.06 (s, 1 H), 6.80-6.93 (m, 2 H), 7.06-7.12 (m, 1 H). 13C NMR (62.9 MHz, CDCl3): δ = 14.3, 19.4, 34.3, 60.0, 103.3, 123.1, 126.3, 143.5, 144.8, 151.6, 167.5. FT-IR (KBr): 3344, 1696, 1652, 1487, 1367, 1211, 1132, 723 cm-1.
Diethyl 4-(2-Furyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4m)
Mp 160-162 °C. 1H NMR (250 MHz, CDCl3): δ = 1.26 (t, J = 7.1 Hz, 6 H), 2.31 (s, 6 H), 4.17 (q, J = 7.1 Hz, 4 H), 5.20 (s, 1 H), 5.86-5.89 (m, 1 H), 6.23-6.25 (m, 1 H), 6.37 (s, 1 H), 7.21-7.23 (m, 1 H). 13C NMR (62.9 MHz, CDCl3): δ = 14.3, 19.4, 33.3, 59.9, 100.4, 104.4, 110.0, 140.8, 145.6, 158.7, 167.5. FT-IR (KBr): 3342, 1697, 1648, 1480, 1361, 1211, 1132, 750 cm-1.