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Synlett 2002(1): 0100-0104
DOI: 10.1055/s-2002-19344
LETTER
© Georg Thieme Verlag Stuttgart · New York

Diels-Alder Reactions of 6-Substituted 1-(p-Nitrobenzoyl)-5,6-dihydro-2-pyridinones

Luiz C. Dias*a, Anna M. A. P. Fernandesa, J. Zukerman-Schpectorb
a Instituto de Química, Universidade Estadual de Campinas/UNICAMP, C.P. 6154, CEP: 13083-970, Campinas, SP, Brazil
Fax: +55(19)37883023; e-Mail: ldias@iqm.unicamp.br;
b Departamento de Química/UFSCar, C.P. 676, CEP: 13565-905, São Carlos, SP, Brazil
Further Information

Publication History

Received 4 October 2001
Publication Date:
01 February 2007 (online)

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Abstract

The first examples of Diels-Alder cycloaddition reactions of 6-substituted 1-(p-nitrobenzoyl)-5,6-dihydro-2-pyridinones are described. This reaction benefits from the fact that the diene adopts an endo orientation trans to the axial substituent at C-6 due to A [1] [3] allylic type strain with the N-PNB protecting group.

Key words

heterocycles - cycloadditions - α,β-unsaturated lactams - A1,3 allylic strain - cis-hydroisoquinoline

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Initial attempts at Diels-Alder reactions with a N-tert-butoxycarbonyl (BOC) derivative and the highly reactive Danishefsky’s diene failed to afford the expected adducts under either thermal or Lewis acid conditions. Under both conditions we observed loss of the BOC group. In an attempt to carry out these reactions under the influence of various Lewis acids, unsatisfactory results were obtained.

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It is interesting that we observed no loss of MeOH under these conditions.

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6-Methyl-2-piperidinone (+/-)-4: White powder; mp: 84.1-84.3 °C; IR (KBr): 3426, 3208, 2929, 1634, 797 cm-1; 1H NMR (500 MHz, CDCl3): δ = 1.16 (d, J = 6.3 Hz, 3 H, CH3), 1.29 (m, 1 H, H-4), 1.65 (m, 1 H, H-4), 1.85 (m, 2 H, H-5), 2.23 (ddd, J = 17.5, 10.7 and 6.1 Hz, 1 H, H-3), 2.33 (bd, J = 17.8 Hz, 1 H, H-3), 3.47 (m, 1 H, H-6), 6.92 (bs, 1 H, NH); 13C NMR (125 MHz, CDCl3): δ = 19.6 (C-4), 22.5 (CH3), 30.3 (C-5), 30.8 (C-3), 48.5 (C-6), 172.5 (C-2); MS: m/z (rel. intensity) = 113(25) [M+], 98(100), 85(4), 70(8), 55(51), 42(31); TLC: Rf = 0.42 (EtOAc-MeOH, 90:10). 6-Methyl-1-(4-nitrobenzoyl)-2-piperidinone (+/-)-5: Yellow oil; IR (KBr): 3112, 3076, 2957, 1709, 1681, 1520, 1259, 1163 cm-1; 1H NMR (500 MHz, CDCl3): δ = 1.38 (d, J = 6.6 Hz, 3 H, CH3), 1.89 (m, 2 H, H-4), 2.10 (m, 2 H, H-5), 2.55 (m, 2 H, H-3), 4.60 (m, 1 H, H-6), 7.60 (dt, J = 2.0 and 8.8 Hz, 2 H, NO2-m-H), 8.21 (dt, J = 2.0 and 8.8 Hz, NO2-o-H); 13C NMR (125 MHz, CDCl3): δ = 17.3 (C-4), 19.8 (CH3), 28.9 (C-5), 34.1 (C-3), 51.5 (C-6), 123.4 (C-m-NO2), 127.9 (C-o-NO2), 142.9 (C-p-NO2), 148.7 (C-i-NO2), 172.2 (C-2, CO), 174.1 (COPhNO2); MS: m/z (rel. intensity) = 262(9) [M+], 245(8), 219(13), 150(100), 112(52), 104(34), 76(25); Anal. Calcd for C13H14N2O4: C, 59.54; H, 5.38; N, 10.68. Found: C, 59.47; H, 5.46; N, 10.71; HRMS calcd 262.0953, found 262.0952; TLC: Rf = 0.49 (Et2O-hexanes, 90:10). 6-Methyl-1-(4-nitrobenzoyl)-5,6-dihydro-2-pyridinone (+/-)-6a: Yellow powder; mp: 113.7-114.6 °C; IR (KBr): 3118, 2975, 1690, 1681, 1604, 1532, 1303, 850 cm-1; 1H NMR (300 MHz, CDCl3): δ = 1.43 (d, J = 6.6 Hz, 3 H, CH3), 2.41 (ddt, J = 0.7, 6.2 and 18.7 Hz, 1 H, H-5), 2.94 (ddt, J = 2.7, 6.3 and 18.6 Hz, 1 H, H-5), 4.84 (qt, J = 7.5 Hz, 1 H, H-6), 5.99 (ddd, J = 0.7, 2.6 and 9.9 Hz, 1 H, H-3), 6.92 (m, 1 H, H-4), 7.62 (dt, J = 2.1 and 8.9 Hz, 2 H, NO2-m-H), 8.24 (dt, J = 2.9 and 9.0 Hz, 2 H, NO2-o-H); 13C NMR (75 MHz, CDCl3): δ = 18.9 (CH3), 31.0 (C-5), 49.6 (C-6), 123.3 (C-m-NO2), 124.3 (C-3), 128.3 (C-o-NO2), 142.5 (C-p-NO2), 144.2 (C-4), 148.8 (C-i-NO2), 164.6 (C-2), 171.4 (COPhNO2); MS: m/z (rel. intensity) = 260(11) [M+], 243(6), 232(11), 217(15), 150(100), 110(44), 68(55); HRMS calcd 260.0797, found 260.0796; TLC: Rf = 0.29 (hexanes-EtOAc, 50:50). 8-Methoxy-3-methyl-2-(4-nitrobenzoyl)perhydro-1,6-isoquinolinedione (+/-)-8a: General procedure: A mixture of the dienophile (6a) (50 mg, 0.19 mmol), 2,6-di-tert-butyl-4-methylphenol (42 mg, 0.19 mmol) and Danishefsky’s diene (0.40 mL, 10 equiv) in degassed dry xylene (3 mL) was refluxed for 20 h under Ar. After being cooled to r.t., the mixture was concentrated under reduced pressure to afford a crude residue, which was taken into THF (3 mL) and H2O (1 mL) and treated with KF (40 mg) at r.t. for 2 h. The mixture was diluted with CH2Cl2 (100 mL) and extracted. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to give, after chromatography (flash, SiO2, 100% Et2O) 8a as a pale yellow powder: Mp: 188.6-189.4 °C; IR (KBr): 3118, 3071, 2963, 1716, 1693, 1670, 1608, 1528, 1344, 1264 and 858 cm-1; 1H NMR (500 MHz, CDCl3): δ = 1.46 (d, J = 6.6 Hz, 3 H, CH3), 1.77 (ddd, J = 1.9, 4.1 and 13.6 Hz, 1 H, H-4), 2.40 (dt, J = 4.9 and 13.6 Hz, 1 H, H-4), 2.44 (dd, J = 3.2 and 16.1 Hz, 1 H, H-7), 2.52 (dd, J = 5.2 and 15.5 Hz, 1 H, H-5), 2.70 (dd, J = 7.6 and 15.5 Hz, 1 H, H-5), 2.89 (dd, J = 3.0 and 8.3 Hz, 1 H, H-9), 2.92 (bd, J = 16.1 Hz, 1 H, H-7), 2.97 (m, 1 H, H-10), 3.40 (s, 3 H, OCH3), 4.33 (dd, J = 3.0 and 5.9 Hz, 1 H, H-8), 4.60 (qdd, J = 1.9, 6.6 and 4.9, 1 H, H-3), 7.69 (dt, J = 2.1 and 9.1 Hz, 2 H, NO2-m-H), 8.24 (dt, J = 2.1 and 9.2 Hz, 2 H, NO2-o-H); 13C NMR (125 MHz, CDCl3): δ = 20.3 (CH3), 28.4 (C-10), 34.7 (C-4), 41.8 (C-5), 44.1 (C-7), 46.4 (C-9), 50.9 (C-3), 56.8 (OCH3), 81.2 (C-8), 123.4 (C-m-NO2), 128.1 (C-o-NO2), 142.5 (C-p-NO2), 148.8 (C-i-NO2), 172.2 (C-1, CO), 173.7 (COPhNO2), 207.6 (C-6, CO); MS: m/z (rel. intensity) = 360(10) [M+], 210(82), 178(12), 150(100), 120(12), 57(40); Anal. Calcd for C18H20N2O6: C, 59.99; H, 5.59; N, 7.77. Found: C, 59.93; H, 5.66; N, 7.64; HRMS calcd 360.1321, found 360.1324; TLC: Rf = 0.20 (Et2O). (-)-(6 S )-(4-Methoxybenzyloxymethyl)-2-piperidinone ( S )-(+)-12: Colorless oil; [α]D 25 +14.6 (c 1.75, CHCl3); IR (KBr): 3397, 2944, 1658, 1514, 1462, 1247, 1092, 1032 cm-1; 1H NMR (300 MHz, CDCl3): δ = 1.26 (m, 1 H, H-5), 1.68 (m, 1 H, H-4), 1.84 (m, 2 H, H-5), 2.26 (ddd, J = 17.5, 11.0 and 6.2 Hz, 1 H, H-3), 2.40 (brd, J = 17.5 Hz, 1 H, H-3), 3.23 (t, J = 9.1 Hz, 1 H, CH2O), 3.47 (dd, J = 3.6 and 9.2 Hz, 1 H, CH2O), 3.60 (ddd, J = 4.0, 9.6 and 13.6 Hz, 1 H, H-6), 3.80 (s, 3 H, OCH3), 4.41 (d, J = 11.4 Hz, 1 H, CH2Ph), 4.46 (d, J = 11.4 Hz, 1 H, CH2Ph), 6.24 (brs, 1 H, NH), 6.89 (dt, J = 2.5 and 8.8 Hz, 2 H, OCH3-m-H), 7.23 (dt, J = 2.2 and 8.8 Hz, 2 H, OCH3-o-H); 13C NMR (75 MHz, CDCl3): δ = 19.5 (C-5), 24.6 (C-4), 31.4 (C-3), 52.5 (C-6), 55.2 (OCH3), 72.9 (CH2O), 73.4 (CH2Ph), 113.8 (C-m-OCH3), 129.3 (C-o-OCH3), 129.5 (C-p-OCH3), 159.3 (C-i-OCH3), 171.8 (C-2); MS: m/z (rel. intensity) = 249(3) [M+], 121(41), 113(48), 98(100), 78(9), 69(28), 55(35); HRMS calcd 249.1364, found 249.1362; TLC: Rf = 0.30 (hexanes-EtOAc, 10:90). (-)-(6 S )-(4-Methoxybenzyloxymethyl)-1-(4-nitro-benzoyl)-2-piperidinone ( S )-(-)-13: Yellow oil; [α]D 25 -11.4 (c 2.24, CHCl3); IR (KBr): 3112, 3071, 2959, 1710, 1676, 1613, 1522, 1350, 1300, 1253 cm-1; 1H NMR (300 MHz, CDCl3): δ = 1.86 (m, 1 H, H-5), 2.00-2.20 (m, 3 H, H-4 and H-5), 2.53 (m, 2 H, H-3), 3.65 (dd, J = 3.5 and 9.7 Hz, 1 H, CH2O), 3.72 (dd, J = 6.0 and 9.3 Hz, 1 H, CH2O), 3.80 (s, 3 H, OCH3), 4.40 (d, J = 11.7 Hz, 1 H, CH2Ph), 4.44 (d, J = 11.4 Hz, 1 H, CH2Ph) 4.64 (m, 1 H, H-6), 6.85 (dt, J = 2.4 and 9.2 Hz, 2 H, OCH3-o-H), 7.17 (dt, J = 2.4 and 9.3 Hz, 2 H, OCH3-m-H) 7.61 (dt, J = 2.1 and 8.9 Hz, 2 H, NO2-m-H), 8.20 (dt, J = 2.2 and 9.1 Hz, 2 H, NO2-o-H); 13C NMR (75 MHz, CDCl3): δ = 18.2 (C-4), 25.2 (C-5), 34.1 (C-3), 54.3 (C-6), 55.1 (OCH3), 70.1 (CH2O), 73.0 (CH2Ph), 113.8 (C-m-OCH3), 123.5 (C-m-NO2), 128.3 (C-o-NO2), 129.3 (C-o-OCH3), 129.7 (C-p-OCH3) 142.4 (C-p-NO2), 149.0 (C-i-NO2), 159.4 (C-i-OCH3), 172.6 (C-2), 174.4 (COPhNO2); MS: m/z (rel. intensity) = 398(3) [M+], 248(12), 150(60), 121(100), 98(50), 78(10), 55(14); HRMS calcd 398.1477, found 398.1474; TLC: Rf = 0.35 (hexanes-EtOAc, 65:35). (8a S ,3 R )-3-(4-Methoxyphenyl)-1,5,8,8a-tetrahy-dro[1,3]oxazolo[3,4-a]pyridin-5-one (-)-14: Light brown oil; [α]D 25 -113 (c 1.0, CHCl3); IR (KBr): 2928, 1656, 1519, 1448 cm-1; 1H NMR (500 MHz, CDCl3): δ = 2.34 (m, 1 H), 2.55 (dt, J = 6.1 and 17.3, 1 H), 3.77 (t, J = 8.2 Hz, 1 H), 3.80 (s, 3 H), 4.20 (m, 1 H), 4.43 (dd, J = 6.3 and 8.3 Hz, 1 H), 5.96 (dd, J = 2.9 and 10.0 Hz, 1 H), 6.32 (s, 1 H), 6.53 (ddd, J = 2.5, 6.7 and 9.4 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 2 H), 7.40 (d, J = 8.8 Hz, 2 H); 13C NMR (75 MHz, CDCl3): δ = 27.3, 53.8, 55.2, 72.8, 88.7, 113.7, 125.8, 127.8, 130.7, 137.0, 159.7, 160.5; MS: m/z (rel. intensity) = 245(70) [M+], 214(6), 176(8), 135(100), 122(17), 96(50), 77(10); HRMS calcd 245.1051, found 245.1055; TLC: Rf = 0.33 (hexanes-EtOAc, 20:80). (-)-(6 S )-(4-Methoxybenzyloxymethyl)-2-oxo-1,2,3,6-tetrahydro-1-pyridinyl-4-nitrophenylmethanone( S )-(-)-6b: Light brown oil; IR (KBr): 3065, 2935, 2861, 1691, 1609, 1520, 1348, 1290, 1233, 1176, 1110 cm-1; 1H NMR (300 MHz, CDCl3): δ = 2.81 (m, 2 H, H-5), 3.61 (t, J = 8.8 Hz, 1 H, CH2O), 3.70 (dd, J = 4.7 and 9.5 Hz, 1 H, CH2O), 3.82 (s, 3 H, OCH3), 4.46 (d, J = 11.4 Hz, 1 H, CH2Ph), 4.52 (d, J = 11.4 Hz, 1 H, CH2Ph), 4.89 (m, 1 H, H-6), 5.95 (dt, J = 2.0 and 9.9 Hz, 1 H, H-3), 6.83 (m, 1 H, H-4), 6.89 (dt, J = 2.3 and 8.4 Hz, 2 H, OCH3-m-H), 7.24 (dt, J = 2.2 and 8.4 Hz, 2 H, OCH3-o-H) 7.61 (dt, J = 2.2 and 8.8 Hz, 2 H, NO2-m-H), 8.24 (dt, J = 2.2 and 9.1 Hz, 2 H, NO2-o-H); 13C NMR (75 MHz, CDCl3): δ = 26.1 (C-5), 52.2 (C-6), 55.2 (OCH3), 68.4 (OCH2), 73.0 (CH2Ph), 113.8 (C-m-OCH3), 123.4 (C-m-NO2), 124.3 (C-3), 128.4 (C-o-NO2), 129.3 (C-o-OCH3), 129.7 (C-p-OCH3) 142.2 (C-p-NO2), 144.0 (C-4), 148.9 (C-i-NO2), 159.4 (C-i-OCH3), 164.4 (C-2), 171.4 (COPhNO2); MS: m/z (rel. intensity) = 396(2) [M+], 245(6), 150(41), 121(100), 104(27), 78(23); HRMS calcd 396.1321, found 396.1358; TLC: Rf = 0.38 (hexanes-EtOAc, 60:40). 8-Methoxy-3-(4-methoxybenzyloxymethyl)-2-(4-nitro-benzoyl)perhydro-1,6-isoquinolinedione (-)-8b: Light brown oil; IR (KBr): 3110, 2960, 1711, 1680, 1521, 1350, 1300, 1230, 1110 cm-1; 1H NMR (500 MHz): δ = 2.02 (ddd, J = 1.9, 4.3 and 13.6 Hz, 1 H, H-4eq), 2.28 (dt, J = 5.0 and 13.6 Hz, 1 H, H-4ax), 2.36 (dd, J = 2.7 and 16.5 Hz, 1 H, H-7ax), 2.47 (dd, J = 6.1 and 15.0 Hz, 1 H, H-5), 2.61 (dd, J = 7.4 and 15.0 Hz, 1 H, H-5), 2.81 (dd, J = 2.7 and 6.9 Hz, 1 H, H-9), 2.86 (dd, J = 1.5 and 16.5 Hz, 1 H, H-7eq), 3.05 (m, 1 H, H-10), 3.38 (s, 3 H, OCH3 in C-8), 3.72 (dd, J = 2.7 and 9.7 Hz, 1 H, CH2O), 3.80 (m, 4 H, OCH3 and CH2O), 4.29 (m, 1 H, H-8), 4.41 (d, J = 11.6 Hz, 1 H, CH2Ph) 4.46 (d, J = 11.6 Hz, 1 H, CH2Ph), 4.60 (m, 1 H, H-3), 6.86 (d, J = 8.5 Hz, 2 H, OCH3-m-H), 7.17 (d, J = 8.5 Hz, OCH3-o-H), 7.71 (d, J = 8.8 Hz, 2 H, NO2-m-H), 8.23 (d, J = 8.8 Hz, 2 H, NO2-o-H); 13C NMR (75 MHz, CDCl3): δ = 29.7 (C-10), 32.9 (C-4), 41.7 (C-5), 44.4 (C-7), 46.8 (C-9), 53.9 (C-3), 55.3 (CH3OPh) 56.7 (OCH3), 70.6 (OCH2), 73.3 (CH2Ph), 81.1 (C-8), 113.9 (C-m-OCH3), 123.4 (C-m-NO2), 128.4 (C-o-NO2), 129.4 (C-o-OCH3) 129.5 (C-p-OCH3), 142.2 (C-p-NO2), 149.0 (C-i-NO2), 159.4 (C-i-OCH3), 172.4 (C-1), 174.3 (COPhNO2), 208.1 (C-6, CO); HRMS calcd 496.1845, found 496.1841; TLC: Rf = 0.28 (hexanes-EtOAc, 50:50).