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

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.

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

References

1a Ornstein PL. Augenstein NK. Arnold MB. J. Org. Chem.  1994,  59:  7862 

1b Ornstein PL. Arnold MB. Allen NK. Bleish T. Borromeo PS. Lugar CW. Leander JD. Lodge D. Schoepp DD. J. Med. Chem.  1996,  39:  2232 

2a Imbroisi DO. Simpkins NS. Tetrahedron Lett.  1989,  30:  4309 

2b Nakagawa M. Lai Z. Torisawa Y. Hino T. Heterocycles  1990,  31:  999 

2c Imbroisi DO. Simpkins NS. J. Chem. Soc., Perkin Trans 1  1991,  1815 

2d Torisawa Y. Nakagawa M. Hosaka T. Tanabe K. Lai Z. Ogata K. Nakata T. Oishi T. Hino T. J. Org. Chem.  1992,  57:  5741 

3a Torisawa Y. Nakagawa M. Takami H. Nagata T. Ali MA. Hino T. Heterocycles  1994,  39:  277 

3b Torisawa Y. Ali MA. Tavet F. Kageyama K. Aikawa M. Fukui N. Hino T. Nakagawa M. Heterocycles  1996,  42:  677 

3c Torisawa Y. Hosaka T. Tanabe K. Suzuki N. Motohashi Y. Hino T. Nakagawa M. Tetrahedron  1996,  32:  10597 

4 Casamitjana N. López V. Jorge A. Bosch J. Molins E. Roig A. Tetrahedron  2000,  56:  4027 

5a Uchida H. Nishida A. Nakagawa M. Tetrahedron Lett.  1999,  40:  113 

5b Nakagawa M. Torisawa Y. Ushida H. Nishida A. J. Synth. Org. Chem. Jpn.  1999,  57:  1004 

5c Nakagawa M. J. Heterocycl. Chem.  2000,  37:  567 

6 Maldaner AO. Pilli RA. Tetrahedron  1999,  55:  13321 

7 Hoffmann RW. Chem. Rev.  1989,  89:  1841 

8A complete crystal structure description of 6a and 8a is being published elsewhere:

8 Zukerman-Schpector J. Vega M. Caracelli I. Dias LC. Fernandes AMAP. Acta Cryst.  2001,  C57:  1089 

9

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.

10a Dias LC. J. Braz. Chem. Soc.  1997,  8:  289 

10b Brocksom TJ. Nakamura J. Ferreira ML. Brocksom U. J. Braz. Chem. Soc.  2001,  12:  597 

11

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

12a Hermitage SA. Moloney MG. Tetrahedron: Asymmetry  1994,  5(8):  1463 

12b Davies CE. Heightman TD. Hermitage SA. Moloney MG. Synth. Commun.  1996,  26:  687 

13 D’Aniello F. Taddei M. J. Org. Chem.  1992,  57:  5247 

14

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: R_f = 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: R_f = 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: R_f = 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: R_f = 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: R_f = 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: R_f = 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: R_f = 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: R_f = 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-4_eq), 2.28 (dt, J = 5.0 and 13.6 Hz, 1 H, H-4_ax), 2.36 (dd, J = 2.7 and 16.5 Hz, 1 H, H-7_ax), 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-7_eq), 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: R_f = 0.28 (hexanes-EtOAc, 50:50).