General synthetic
Melting points (m.p.) were determined by using a Mel-Temp from Electrothermal. TLC was performed using TLC Silica gel 60 F254 aluminium sheets from Merck. 1H NMR and 13C NMR spectra were measured by using a Bruker Avance 500 (500 MHz, 125 MHz) or a Bruker Avance 600 (600 MHz, 150 MHz) NMR spectrometer. Signals were assigned by two-dimensional methods (COSY, HMQC, HMBC). The IR spectra were recorded in KBr pellets by using a Nicolet 6700 FT-IR spectrometer from Thermo Electron Corporation. Elemental analysis was performed on a Vario EL III elemental analyzer. All starting materials were used as purchased without further purification.
γ-Spirolactams 1a, cis-1b, and trans-1b
Benzoic acid (2a) (12.21 g, 100 mmol) or p-toluic acid (13.62 g, 100 mmol) were introduced into a three-necked flask (500 mL), equipped with a dry-ice condenser and cooled to − 78 °C by a dry-ice acetone bath. Ammonia (200 mL) was condensed into the three-necked flask, and lithium (1.39 g, 200 mmol) was added in small pieces to the solution at − 78 °C, until it remained blue. After stirring for 1 h at − 78 °C, chloroacetonitrile (10.0 mL, 160 mmol) was added via syringe within 2 min and the ammonia was allowed to evaporate overnight at RT. The solid residue was dissolved in water (70 mL), cooled to 0 °C, acidified with 6 M HCl to pH 2 and extracted with dichloromethane (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered over a small pad of silica gel, and the solvent was removed in vacuo. The crude products were crystallized from n-hexane to obtain the intermediate cyclohexadienes 4a (15.7 g, 96%) or 4b (16.3 g, 92%) as white solids. Cyclohexadiene 4b was obtained as a 55:45 mixture of diastereomers, which were separated by column chromatography (silica gel, hexane/ethyl acetate/methanol 3:1:0.25) to afford 4.9 g (28%) of cis-4b, 5.2 g (29%) of trans-4b and 5.9 g (33%) of a mixture fraction. This fraction was separated again under same conditions to afford additionally 2.5 g (14%) of cis-4b and 3.0 g (17%) of trans-4b in analytically pure forms.
Cyclohexadiene 4a
Rf = 0.55 (CH2Cl2/MeOH/HOAc 9:1:0.1); m.p. 122–123 °C; 1H NMR (500 MHz, CDCl3): δ 10.08 (brs, 1 H, O–H), 6.13 (dt, J = 10.3, 3.3 Hz, 2 H, 3-H, 5-H), 5.75 (dt, J = 10.3, 1.9 Hz, 2 H, 2-H, 6-H), 2.72–2.79 (m, 2 H, 4-H), 2.74 (s, 2 H, CH2CN); 13C NMR (125 MHz, CDCl3): δ 26.2 (t, CH2CN), 28.4 (t, C-4), 46.0 (s, C-1), 116.5 (s, CN), 123.5 (d, C-2, C-6), 129.3 (d, C-3, C-5), 177.7 (s, CO2H); IR (KBr) \(\widetilde{v}\) = 3164, 2965, 2270, 1724, 1227, 754 cm−1; elemental analysis calcd (%) for C9H9NO2 (163.18): C 66.25, H 5.56, N 8.58; found: C 65.93, H 5.66, N 8.56.
Cyclohexadiene cis-4b
Rf = 0.58 (CH2Cl2/MeOH/HOAc 9:1:0.1); m.p. 143–144 °C; 1H NMR (500 MHz, CDCl3): δ 10.32 (brs, 1 H, O–H), 6.04 (dd, J = 10.3, 3.4, Hz, 2 H, 3-H, 5-H), 5.69 (dd, J = 10.3, 2.0 Hz, 2 H, 2-H, 6-H), 2.83–2.89 (m, 1 H, 4-H), 2.73 (s, 2 H, CH2CN), 1.14 (d, J = 7.4 Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3): δ 21.0 (q, CH3), 28.2 (t, CH2CN), 30.7 (t, C-4), 46.1 (s, C-1), 116.6 (s, CN), 122.3 (d, C-2, C-6), 135.6 (d, C-3, C-5), 177.8 (s, CO2H); IR (KBr) \(\widetilde{v}\) = 3140, 2939, 2272, 1726, 1227, 755 cm−1; elemental analysis calcd (%) for C10H11NO2 (177.20): C 67.78, H 6.28, N 7.90; found: C 67.74, H 6.06, N 7.90.
Cyclohexadiene trans-4b
Rf = 0.52 (CH2Cl2/MeOH/HOAc 9:1:0.1); m.p. 161–162 °C; 1H NMR (500 MHz, CDCl3): δ 11.42 (brs, 1 H, O–H), 6.06 (dd, J = 10.3, 3.3, Hz, 2 H, 3-H, 5-H), 5.70 (dd, J = 10.3, 2.0 Hz, 2 H, 2-H, 6-H), 2.85–2.92 (m, 1 H, 4-H), 2.78 (s, 2 H, CH2CN), 1.22 (d, J = 7.4 Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3): δ 21.4 (q, CH3), 28.5 (t, CH2CN), 30.8 (t, C-4), 46.3 (s, C-1), 116.7 (s, CN), 122.4 (d, C-2, C-6), 135.6 (d, C-3, C-5), 176.6 (s, CO2H); IR (KBr) \(\widetilde{v}\) = 3164, 2965, 2270, 1725, 1227, 754 cm−1; elemental analysis calcd (%) for C10H11NO2 (177.20): C 67.78, H 6.28, N 7.90; found: C 67.66, H 6.21, N 7.94.
The cyclohexadienes 4a (3.26 g, 20 mmol), cis-4b (3.54 g, 20 mmol), or trans-4b (3.54 g, 20 mmol) were dissolved in methanol (300 mL) at RT and platinum(iv) oxide (50 mg, 1 mol%) and 37% HCl (1.5 mL) was added. The solution was purged with hydrogen gas for 5 min, equipped with a balloon filled with hydrogen gas and hydrogenated under stirring for 48 h. The solution was filtered through a pad of Celite, washed with methanol (2 × 50 mL) and the solvent was removed in vacuo. The residue was dissolved in pyridine (500 mL) and heated for 8 h under reflux. The pyridine was removed in vacuo and the residue was dissolved in dichloromethane (200 mL), extracted with 1 N HCl (100 mL), dried over sodium sulfate, and concentrated in vacuo. The solid γ-spirolactams 1 crystallized from n-hexane in analytically pure form and afforded single crystals for X-ray measurements.
γ-Spirolactam 1a
White solid (3.00 g, 98%). Rf = 0.21 (EtOAc); m.p. 107–108 °C; 1H NMR (500 MHz, CDCl3): δ 7.45 (brs, 1 H, N–H), 3.24 (t, J = 7.0 Hz, 2 H, 3-H), 1.94 (t, J = 7.0 Hz, 2 H, 4-H), 1.18–1.70 (m, 10 H, 6-H–10-H); 13C NMR (125 MHz, CDCl3): δ 22.4 (t, C-7, C-9), 25.6 (t, C-8), 31.7 (t, C-4), 32.2 (t, C-6, C-10), 39.2 (t, C-3), 44.2 (s, C-5), 183.7 (s, C-1); IR (KBr) \(\widetilde{v}\) = 3292, 2928, 1686, 1650, 1279, 1071, 739 cm−1; elemental analysis calcd (%) for C9H15NO (153.22): C 70.55, H 9.87, N 9.14; found: C 70.29, H 9.99, N 9.07.
γ-Spirolactam cis-1b
White solid (3.20 g, 96%). Rf = 0.26 (EtOAc); m.p. 128–129 °C; 1H NMR (600 MHz, CDCl3): δ 7.69 (brs, 1 H, N–H), 3.22 (t, J = 7.0 Hz, 2 H, 3-H), 1.89 (t, J = 7.0 Hz, 2 H, 4-H), 1.54–1.40 (m, 4 H, 7-Hax., 9-Hax., 6-Hequ., 10-Hequ.), 1.37–1.41 (m, 2 H, 7-Hequ., 9-Hequ.), 1.27–1.34 (m, 1 H, 8-H), 0.89 (ddd, J = 15.7, 9.8, 4.7 Hz, 2 H, 6-Hax., 10-Hax.), 0.81 (d, J = 6.7 Hz, 3 H, CH3); 13C NMR (75 MHz, CDCl3): δ 22.6 (q, CH3), 31.1 (t, C-7, C-9), 31.3 (t, C-4), 31.9 (d, C-8), 32.1 (t, C-6, C-10), 39.2 (t, C-3), 44.0 (s, C-5), 184.0 (s, C-1); IR (KBr) \(\widetilde{v}\) = 3201, 2918, 1680, 1287, 753 cm−1; elemental analysis calcd (%) for C10H17NO (167.25): C 71.81, H 10.24, N 8.38; found: C 71.60, H 10.31, N 8.44.
γ-Spirolactam trans-1b
White solid (3.24 g, 97%). Rf = 0.35 (EtOAc); m.p. 114–115 °C; 1H NMR (600 MHz, CDCl3): δ 6.70 (brs, 1 H, N–H), 3.26 (t, J = 6.9 Hz, 2 H, 3-H), 1.89 (t, J = 6.9 Hz, 2 H, 4-H), 1.85 (ddd, J = 13.3, 8.1, 3.0 Hz, 2 H, 6-Hequ., 10-Hequ.), 1.48–1.57 (m, 5 H, 7-H, 8.H, 9-H), 1.24 (ddd, J = 13.3, 8.4, 4.1 Hz, 2 H, 6-Hax., 10-Hax.), 0.96 (d, J = 6.2 Hz, 3 H, CH3); 13C NMR (75 MHz, CDCl3): δ 20.0 (q, CH3), 29.3 (t, C-7, C-9), 29.8 (d, C-8), 31.2 (t, C-6, C-10), 35.3 (t, C-4), 38.8 (t, C-3), 42.2 (s, C-5), 183.0 (s, C-1); IR (KBr) \(\widetilde{v}\) = 3211, 2924, 1677, 1289, 755 cm−1; elemental analysis calcd (%) for C10H17NO (167.25): C 71.81, H 10.24, N 8.38; found: C 71.71, H 10.12, N 8.37.
X-ray structure analysis
The crystals were embedded in perfluoropolyalkylether oil and mounted within a MicroGripper. The data collections were performed at 210 K on a STOE StadiVari diffractometer equipped with a four-circle goniometer (open Eulerian cradle), a Genix Microfocus X-ray source (Mo) with a graded multilayer mirror and a Dectris 200 K detector (Δω = 0.5°; detector distance 60 mm; 1a: 4110 frames, 5 s exposure time per frame; cis-1b: 2488 frames, 10 s exposure time per frame; trans-1b: 2516 frames, 10 s exposure time per frame). The data were corrected for absorption as well as for Lorentz and polarization effects using the program X-Area [16]. The structures were solved by direct methods using SHELXS-2013/2 [17] and refined by full-matrix least squares on F2 using the program SHELXL-2014/7 [18]. All non-hydrogen atoms were refined anisotropically. The hydrogen atoms of the N–H groups were located from the difference Fourier maps and free refined. The other hydrogen atoms were calculated in their expected positions using a riding model with C–H = 0.98 Å (–CH2) and C–H = 0.97 Å (–CH3), allowing for rotation), and Uiso(H) = 1.2Ueq(CH2) and Uiso(H) = 1.5Ueq(CH3). For the visualization the programs ORTEP-3 for windows [19] and DIAMOND [20] were used.
Crystal data of 1a
C9H15NO, M = 153.22, monoclinic, a = 20.4582(6), b = 11.8454(4), c = 28.4142(10) Å, β = 106.017(5)°, V = 6815.2(4) Å3, T = 210(2) K, space group C2/c (no. 15), Z = 32, μ(MoKα) = 0.077 mm−1; 92,264 reflections measured, 5983 unique (Rint = 0.0616) which were used in all calculations. Final R values: wR2(F2) = 0.1079, R1 = 0.0697 (all data); wR2(F2) = 0.0969, R1 = 0.0373 [I > 2σ(I)].
Crystal data of cis-1b
C10H17NO, M = 167.24, monoclinic, a = 14.7946(9), b = 6.4589(2), c = 10.5769(7) Å, β = 105.199(5)°, V = 975.34(10) Å3, T = 210(2) K, space group P21/c (no. 14), Z = 4, μ(MoKα) = 0.073 mm−1; 15,495 reflections measured, 1713 unique (Rint = 0.0236) which were used in all calculations. Final R values: wR2(F2) = 0.0940, R1 = 0.0391 (all data); wR2(F2) = 0.0913, R1 = 0.0336 [I > 2σ(I)].
Crystal data of trans-1b
C10H17N O, M = 167.24, monoclinic, a = 11.1386(5), b = 10.5587(5), c = 8.3892(7) Å, V = 948.34(10) Å3, T = 210(2) K, space group P21/c (no. 14), Z = 4, μ(MoKα) = 0.073 mm−1; 14,814 reflections measured, 1655 unique (Rint = 0.0261) which were used in all calculations. Final R values: wR2(F2) = 0.0847, R1 = 0.0368 (all data); wR2(F2) = 0.0816, R1 = 0.0313 [I > 2σ(I)].