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Synlett 2007(18): 2897-2901  
DOI: 10.1055/s-2007-990839
LETTER
© Georg Thieme Verlag Stuttgart · New York

Magnesium Perchlorate as Efficient Lewis Acid: A Simple and Convenient Route to 1,4-Dihydropyridines

Giuseppe Bartoli, Krzysztof Babiuch, Marcella Bosco, Armando Carlone, Patrizia Galzerano, Paolo Melchiorre, Letizia Sambri*
Dipartimento di Chimica Organica ‘A. Mangini’, Università di Bologna, V. le Risorgimento 4, 40136 Bologna, Italy
Fax: +39(051)2093654; e-Mail: letizia.sambri@unibo.it;
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Publication History

Received 31 July 2007
Publication Date:
12 October 2007 (online)

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Abstract

A new protocol for the synthesis of various 1,2,3,4-tetrasubstituted 1,4-dihydropyridines from enamino or carbonylic derivatives promoted by Mg(ClO4)2 is presented.

Key words

magnesium perchlorate - 1,4-dihydropyridines - domino reaction - Michael addition - cyclization

1

Erasmus student from Uniwersytet Jagielloński, ul. Golebia 24, 31-007 Cracow, Poland

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General Procedure for the Synthesis of Dihydropyridine 3 from Enamino Derivatives 1: In a two-necked flask equipped with a magnetic stirring bar, Mg(ClO4)2 (0.10 mmol), MgSO4 (0.20 mmol), and the enamino derivative 1 (1.0 mmol) were suspended in anhyd CH2Cl2 (2 mL) and the aldehyde 2 (1.2 mmol) was added. The mixture was stirred at r.t. until completion of the reaction or for 70 h. The crude reaction mixture was filtered on celite and the solvent was removed by rotary evaporation. The dihydropyridine 3 was purified by flash chromatography on silica gel pretreated with the solvent mixture of PE-acetone (95:5) added with 5% Et3N.
General Procedure for the Synthesis of Dihydropyridine 3 from Carbonyl Derivatives 5: In a two-necked flask equipped with a magnetic stirring bar, Mg(ClO4)2 (0.10 mmol), MgSO4 (0.20 mmol), and the carbonyl derivative 5 (1.0 mmol) were suspended in anhyd CH2Cl2 (2 mL) and the amine (1.1 mmol) was added. When the reaction was completed (check with TLC), the aldehyde 2 (1.2 mmol) was added. The mixture was stirred at r.t until completion of the reaction or for 70 h. The crude reaction mixture was filtered on celite and the solvent was removed by rotary evaporation. The dihydropyridine 3 was purified by flash chromatography on silica gel pre-treated with the solvent mixture of PE-acetone (95:5) added with 5% Et3N.
Spectroscopic data for selected compounds are as follows:
1-(4-Isopropyl-2-methyl-1-phenyl-1,4-dihydropyridin-3-yl)ethanone (3ba): 1H NMR: δ = 0.91 (d, J H,H = 6.9 Hz, 6 H), 1.50-1.60 (m, 1 H), 2.00 (s, 3 H), 2.27 (s, 3 H), 3.41 (dd, J H,H = 4.4, 6.0 Hz, 1 H), 4.93 (dd, J H,H = 6.2, 7.5 Hz, 1 H), 6.30 (d, J H,H = 7.5 Hz, 1 H), 7.05-7.15 (m, 2 H), 7.25-7.30 (m, 1 H), 7.35-7.45 (m, 2 H). 13C NMR: δ = 16.8 (Me), 18.6 (Me), 19.1 (Me), 29.0 (Me), 35.5 (CH), 40.6 (CH), 103.5 (CH), 111.1 (C), 126.96 (CH), 126.99 (CH), 129.3 (CH), 131.3 (CH), 143.6 (C), 146.4 (C), 200.9 (C). HRMS: m/z calcd for C17H21NO: 255.1623; found: 255.1623.
1-[2-Methyl-4-(2-nitrophenyl)-1-phenyl-1,4-dihydro-pyridin-3-yl]ethanone (3bd): 1H NMR: δ = 1.99 (s, 3 H), 2.18 (s, 3 H), 5.26 (dd, J H,H = 5.5, 7.5 Hz, 1 H), 5.32 (d, J H,H = 5.5 Hz, 1 H), 6.10 (d, J H,H = 7.5 Hz, 1 H), 7.15-7.20 (m, 2 H), 7.35-7.40 (m, 2 H), 7.40-7.45 (m, 2 H), 7.60-7.65 (m, 2 H), 7.80-7.85 (m, 1 H). 13C NMR: δ = 19.6 (Me), 29.8 (Me), 37.3 (CH), 106.4 (CH), 108.9 (C), 124.3 (CH), 127.4 (CH), 127.8 (CH), 128.1 (CH), 130.0 (CH), 130.3 (CH), 131.1 (CH), 134.0 (CH), 141.7 (C), 143.3 (C), 147.7 (C), 149.2 (C), 199.0 (C). HRMS: m/z calcd for C20H18N2O3: 334.1317; found: 334.1315.
tert -Butyl 1-Butyl-2-methyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (3cd): 1H NMR: δ = 0.95 (t, J H,H = 7.3 Hz, 3 H), 1.10 (s, 9 H), 1.35-1.40 (m, 2 H), 1.55-1.60 (m, 2 H), 2.49 (s, 3 H), 3.20-3.30 (m, 1 H), 3.40-3.50 (m, 1 H), 5.04 (d, J H,H = 4.9 Hz, 1 H), 5.15 (dd, J H,H = 4.9, 7.7 Hz, 1 H), 5.82 (d, J H,H = 7.7 Hz, 1 H), 7.10-7.15 (m, 1 H), 7.55-7.60 (m, 2 H), 7.80-7.85 (m, 1 H). 13C NMR: δ = 13.8 (Me), 15.3 (Me), 19.8 (CH2), 27.8 (3 × Me), 32.4 (CH2), 37.3 (CH), 50.1 (CH2), 78.9 (C), 99.7 (C), 106.2 (CH), 123.4 (CH), 126.2 (CH), 129.3 (CH), 130.9 (CH), 133.2 (CH), 144.2 (C), 147.4 (C), 149.6 (C), 167.8 (C). HRMS: m/z calcd for C21H28N2O4: 372.2049; found: 372.2048.
Ethyl 1-Butyl-2-methyl-4-propyl-1,4-dihydropyridine-3-carboxylate (3fc): 1H NMR: δ = 0.87 (t, J H,H = 6.8 Hz, 3 H), 0.93 (t, J H,H = 7.3 Hz, 3 H), 1.26 (t, J H,H = 7.1 Hz, 3 H), 1.20-1.40 (m, 6 H), 1.45-1.55 (m, 2 H), 2.36 (s, 3 H), 3.10-3.20 (m, 1 H), 3.30-3.40 (m, 1 H), 3.40-3.50 (m, 1 H), 4.05-4.20 (m, 2 H), 4.86 (dd, J H,H = 6.3, 7.4 Hz, 1 H), 5.84 (d, J H,H = 7.4 Hz, 1 H). 13C NMR: δ = 14.0 (Me), 14.5 (Me), 14.6 (Me), 15.8 (Me), 18.2 (CH2), 20.0 (CH2), 32.6 (CH2), 33.0 (CH), 41.6 (CH2), 50.0 (CH2), 59.2 (CH2), 99.7 (C), 107.5 (CH), 130.0 (CH), 149.3 (C), 169.7 (C). HRMS: m/z calcd for C16H27NO2: 265.2042; found: 265.2043.
1,4-Diphenyl-3-(ethoxycarbonyl)-2-methylpyridinium Perchlorate (4db): 1H NMR (CD2Cl2): δ = 1.06 (t, J H,H = 7.2 Hz, 3 H), 2.60 (s, 3 H), 4.25 (q, J H,H = 7.2 Hz, 2 H), 7.60-7.70 (m, 7 H), 7.75-7.80 (m, 3 H), 8.11 (d, J H,H = 6.6 Hz, 1 H), 8.78 (d, J H,H = 6.6 Hz, 1 H). 13C NMR (CD2Cl2): δ = 13.6 (Me), 19.9 (Me), 63.8 (CH2), 125.7 (CH), 127.1 (CH), 128.5 (CH), 129.7 (CH), 131.3 (CH), 131.7 (CH), 132.3 (CH), 134.0 (C), 135.3 (C), 140.8 (C), 146.3 (CH), 153.6 (C), 158.3 (C), 164.6 (C). MS (ESI+): m/z = 318. MS (ESI-): m/z = 99.
1-Benzyl-3-(ethoxycarbonyl)-2-methyl-4-isopropyl-pyridinium Perchlorate (4ea): 1H NMR: δ = 1.33 (t, J H,H = 7.1 Hz, 6 H), 1.40 (t, J H,H = 7.0 Hz, 3 H), 2.72 (s, 3 H), 3.00-3.10 (m, 1 H), 4.48 (q, J H,H = 7.1 Hz, 2 H), 5.83 (s, 2 H), 7.25-7.30 (m, 2 H), 7.35-7.45 (m, 3 H), 7.93 (d, J H,H = 7.0 Hz, 1 H), 8.92 (d, J H,H = 7.0 Hz, 1 H). 13C NMR: δ = 13.8 (Me), 18.2 (Me), 22.3 (2 × Me), 47.3 (CH), 61.9 (CH2), 63.4 (CH2), 123.7 (CH), 127.9 (CH), 129.5 (CH), 129.6 (CH), 131.2 (C), 134.7 (C), 146.5 (CH), 151.8 (C), 164.2 (C), 165.4 (C). MS (ESI+): m/z = 298. MS (ESI-): m/z = 99.

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We compared our results with those from the previously reported procedure, employing Sc(OTf)3 as Lewis acid (see ref. 6b) and we found conversion yields similar to those obtained with our method facing the same separation problems. These results mean that the perchlorate anion is not responsible in any way for the low recovered yields.