Access to Eight-Membered Ring Lactams from Five-Membered Ring 1,4-Diketones and Primary Amines

Abstract

Unsaturated eight-membered ring lactams are obtained by expansion of the five-membered ring of a 1,4-diketone with primary amines. Azabicyclo[3.3.0]octanes are the proposed reaction intermediates; there has been a single azabicyclo[3.3.0]octane isolated. Reaction of the 1,4-diketone with phenylhydrazine yields a new cyclopenta[c]pyridazine.

ketones - lactams - pyrroles - ring expansion - hetero­cycles

References and Notes

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8

Ethyl 1-Butyl-8-oxo-2-phenyl-1,4,5,6,7,8-hexahydro-azocine-4-carboxylate ( 2c): A suspension of ester 1 (100 mg, 365 µmol), n-BuNH₂ (133 mg, 1.83 mmol, 5 equiv), and Bi(NO₃)₃·5H₂O (9 mg, 18 µmol, 0.05 equiv) in THF (1.0 mL) was stirred in a closed reaction vial for 2 d at 70 °C. After cooling to ambient temperature, the reaction mixture was chromatographed (basic alumina; hexanes-EtOAc, 2:1) to give lactam 2c (74 mg, 223 µmol, 61%) as a yellowish oil; R _f (silica) 0.32. IR (ATR): 2956 (m), 2931 (s), 2862 (m), 1733 (vs), 1654 (vs), 1446 (s), 1399 (s), 1179 (s) cm^-1. ¹H NMR (CDCl₃, 500 MHz): δ = 0.83 (t, J = 7.4 Hz, 3 H), 1.19-1.26 (m, 2 H), 1.30 (t, J = 7.1 Hz, 3 H), 1.33-1.37 (m, 1 H), 1.41-1.55 (m, 1 H), 1.75-1.85 (m, 1 H), 1.99-2.04 (m, 1 H), 2.13-2.18 (m, 2 H), 2.44 (dt, J = 1.4 Hz, J = 12.3 Hz, 1 H), 2.51 (ddd, J = 1.4 Hz, J = 8.0 Hz, J = 11.9 Hz, 1 H), 2.65 (ddd, J = 5.0 Hz, J = 10.0 Hz, J = 13.6 Hz, 1 H), 3.04 (ddd, J = 0.9 Hz, J = 10.2 Hz, J = 10.6 Hz, 1 H), 4.09 (ddd, J = 6.0 Hz, J = 9.9 Hz, J = 13.4 Hz, 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 6.02 (d, J = 9.9 Hz, 1 H), 7.36-7.38 (m, 5 H) ppm. ¹³C NMR (CDCl₃, 125 MHz): δ = 13.79 (CH₃), 14.20 (CH₃), 20.31 (CH₂), 24.13 (CH₂), 29.39 (CH₂), 29.60 (CH₂), 33.59 (CH₂), 43.79 (CH), 44.65 (CH₂), 61.03 (CH₂), 124.34 (CH), 126.28 (2 × CH), 128.84 (2 × CH), 128.94 (CH), 135.73 (C), 140.44 (C), 173.85 (C), 173.87 (C) ppm. MS (70 eV, EI): m/z (%) = 329 (100) [M⁺]. Anal. Calcd for C₂₀H₂₇NO₃: C, 72.92; H, 8.26; N, 4.25. Found: C, 73.07; H, 8.35; N, 4.31.

9

Ethyl 4,5,6,6a-Tetrahydro-6a-hydroxy-2-phenyl-3 H -cyclopenta[ b ]pyrrole-3a-carboxylate ( 3): A mixture of ester 1 (56 mg, 0.20 mmol), molecular sieves (4 Å, ca. 90 mg) and liquid NH₃ (ca. 4 mL) was stirred for 7 h at -75 °C. After evaporation of the solvent upon warming to ambient temperature the residue was suspended in CHCl₃ (ca. 2 mL), filtered, the solvent again evaporated, and the residue chromatographed (silica; hexanes-EtOAc-Et₃N, 8.3:1.7:1) to give 3 (35 mg, 0.13 mmol, 63%) as light brown crystals. Mp 142 °C; R _f (silica; hexanes-EtOAc, 2:1) 0.18. IR (ATR): 3066 (br, m), 2962 (m), 2929 (m), 2799 (m), 1724 (vs), 1627 (s), 1577 (m), 1450 (m), 1362 (m), 1345 (m), 1322 (m), 1298 (s), 1284 (s), 1235 (m), 1184 (s), 1146 (s), 1125 (s), 1087 (s), 1023 (m), 942 (w) cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.30 (t, J = 7.1 Hz, 3 H), 1.32-1.42 (m, 1 H), 1.73 (ddt, J = 13.1 Hz, J = 6.2 Hz, J = 2.0 Hz, 1 H), 1.77-1.84 (m, 1 H), 2.05 (dt, J = 12.5 Hz, J = 6.6 Hz, 1 H), 2.26 (ddt, J = 12.9 Hz, J = 6.0 Hz, J = 2.0 Hz, 1 H), 2.66 (dt, J = 12.3 Hz, J = 6.6 Hz, 1 H), 2.89 (d, J = 18.0 Hz, 1 H, CHH), 4.02 (d, J = 18.0 Hz, 1 H, CHH), 4.07 (s, br, 1 H, OH), 4.19-4.26 (m, 2 H), 7.40-7.44 (m, 2 H), 7.46-7.50 (m, 1 H), 7.85-7.89 (m, 2 H) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 14.26 (CH₃), 22.85 (CH₂), 37.47 (CH₂), 39.96 (CH₂), 48.13 (CH₂), 58.92 (C), 61.29 (CH₂), 116.03 (C), 128.24 (2 × CH), 128.52 (2 × CH), 131.37 (CH), 133.21 (C), 171.99 (C), 174.25 (C) ppm. MS (EI, 70 eV): m/z (%) = 273 (78) [M⁺], 244 (30) [M⁺ - Et], 231 (36), 200 (100) [M⁺ - CO₂Et]. Anal. Calcd C₁₆H₁₉NO₃: C, 70.36; H, 7.01; N, 5.13. Found: C, 70.05; H, 7.07; N, 4.99.

10

Ethyl 1-(Benzoylmethyl)-2-phenylhydrazonocyclo-pentane-1-carboxylate ( 5): A solution of ester 1 (400 mg, 1.46 mmol) in EtOH (2.0 mL) was added to a mixture of phenylhydrazine (176 mg, 1.63 mmol, 1.1 equiv), AcOH (0.68 mL), and EtOH (4.0 mL). After stirring for 30 min at 23 °C the mixture was poured onto ice and H₂O (ca. 25 g). After filtration the residue was dried in vacuo to give a yellow solid (500 mg, 1.37 mmol, 94%). Mp 106 °C. IR (ATR): 3320 (m), 2968 (m), 1700(vs), 1685 (vs), 598 (vs), 1494 (m), 1229 (vs), 1180 (s), 1128 (s) cm^-1. ¹H NMR (CDCl₃, 500 MHz): δ = 1.20 (t, J = 7.1 Hz, 3 H), 1.83 (ddd, J = 7.7 Hz, J = 9.8 Hz, J = 13.1 Hz, 1 H), 1.94-2.00 (m, 1 H), 2.16-2.25 (m, 1 H), 2.35-2.42 (m, 1 H), 2.48 (ddd, J = 3.9 Hz, J = 9.4 Hz, J = 17.2 Hz, 1 H), 2.77 (ddd, J = 3.4 Hz, J = 7.3 Hz, J = 13.0 Hz, 1 H), 3.23 (d, J = 18.1 Hz, 1 H), 4.11 (d, J = 18.1 Hz, 1 H), 4.16 (q, J = 7.0 Hz, 2 H), 6.80-6.83 (m, 1 H), 6.98-7.01 (m, 2 H), 7.17-7.21 (m, 2 H), 7.36 (s, 1 H), 7.44-7.48 (m, 2 H), 7.54-7.57 (m, 1 H), 7.98-8.00 (m, 2 H) ppm. ¹³C NMR (CDCl₃, 125 MHz): δ = 14.08 (CH₃), 22.46 (CH₂), 26.25 (CH₂), 35.60 (CH₂), 45.69 (CH₂), 54.44 (C), 61.00 (CH₂), 112.90 (2 × CH), 119.92 (CH), 128.06 (2 × CH), 128.54 (2 × CH), 129.11 (2 × CH), 133.03 (CH), 137.09 (C), 145.36 (C), 153.46 (C), 173.27 (C), 197.97 (C) ppm. MS (EI, 70 eV): m/z calcd for C₂₂H₂₄N₂O₃ [M⁺], 364.1787; found, 364.1788.

11

Ethyl 2,3-Diphenyl-2,5,6,7-tetrahydrocyclo-penta[ c ]pyridazine-4a-carboxylate ( 6): TFA (1 drop, ca. 10 mg) was added to a suspension of hydrazone 5 (60 mg, 0.16 mmol) and MgSO₄ (150 mg) in CH₂Cl₂ (2.0 mL). After stirring the mixture for 4 h at 23 °C all volatile materials were removed in vacuo and the residue chromatographed (basic alumina; hexanes-EtOAc, 10:1) to give pyridazine 6 (30 mg, 87 µmol, 54%) as a yellow oil. R _f (silica; hexanes-EtOAc, 2:1) 0.64. IR (ATR): 2976 (m), 1719 (vs), 1597 (s), 1495 (m), 1355 (m), 1221 (s), 1026 (m) cm^-1. ¹H NMR (CDCl₃, 500 MHz): δ = 1.14 (t, J = 7.1 Hz, 3 H), 1.78-1.86 (m, 1 H), 1.93-2.06 (m, 2 H), 2.64-2.71 (m, 2 H), 2.89 (ddd, J = 6.5 Hz, J = 9.0 Hz, J = 16.8 Hz, 1 H), 4.05-4.12 (m, 2 H), 4.79 (s, 1 H), 6.85-6.89 (m, 1 H), 7.03-7.05 (m, 2 H), 7.07-7.11 (m, 2 H), 7.18-7.23 (m, 5 H) ppm. ¹³C NMR (CDCl₃, 125 MHz): δ = 14.05 (CH₃), 22.50 (CH₂), 30.17 (CH₂), 37.06 (CH₂), 51.05 (C), 61.17 (CH₂), 101.22 (CH), 121.16 (2 × CH), 122.55 (CH), 127.99 (3 × CH), 128.20 (2 × CH), 128.69 (2 × CH), 135.51 (C), 140.38 (C), 143.52 (C), 153.38 (C), 172.89 (C) ppm. MS (CI, CH₄): m/z calcd for C₂₂H₂₃N₂O₂ [M + H⁺], 347.1759; found, 347.1766.

12 Yamasaki T. Yoshihara Y. Okamoto Y. Okawara T. Furukawa M. Heterocycles  1996,  43:  1613