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DOI: 10.1055/s-2006-941595
Serendipitous Synthesis of Unusual Cyclic and Acyclic Enaminone Esters from Tröger’s Base and Conjugated Esters
Publication History
Publication Date:
22 May 2006 (online)
Abstract
The reaction of Tröger’s base and methyl propiolate in the presence of ZnBr2 in CH3CN serendipitously afforded unusual cyclic enaminone ester derivatives in moderate to good yields.
Key words
Tröger’s base - methyl propiolate - iminium salt - enaminone esters
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References and Notes
Compound 3a; Typical Procedure. To a stirred mixture of 1 (250 mg, 1 mmol) and 2a (84 mg, 1 mmol) in CH3CN (2 mL) was added ZnBr2 (225 mg, 1 mmol) and the resulting mixture was heated to 50-60 °C for 4 h. After the usual work-up and column chromatography (hexanes-Et2O, 6:1), 3a was obtained as a colorless oil; 302 mg (90%). IR (film): 1720, 1493 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 2.16 (s, 3 H), 2.19 (s, 3 H), 3.78 (s, 3 H), 3.97 (d, J = 16.8 Hz, 1 H), 4.22 (d, J = 16.5 Hz, 1 H), 4.25 (d, J = 16.8 Hz, 1 H), 4.72 (d, J = 16.5 Hz, 1 H), 5.11 (s, 1 H), 5.59 (s, 1 H), 6.10 (s, 1 H), 6.57 (s, 1 H), 6.69 (s, 1 H), 6.91-7.08 (m, 4 H). 13C NMR (CDCl3, 75 MHz): δ = 20.92 (2 C), 52.18, 53.19, 61.39, 72.22, 124.93, 125.07, 127.04, 127.15, 127.22, 127.43, 127.49, 128.09, 128.59, 133.31, 133.45, 137.79, 143.53, 147.17, 167.28. EIMS (70 eV): m/z (%) = 132 (100), 215 (44), 275 (30), 334 (M+, 86). Anal. Calcd for C21H22N2O2: C, 75.42; H, 6.63; N, 8.38. Found: C, 75.65; H, 6.87; N, 8.35.
Compound 3b: Yield: 87%; colorless oil. IR (film): 1728, 1493 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 1.27 (t, J = 7.2 Hz, 3 H), 2.14 (s, 3 H), 2.18 (s, 3 H), 3.96 (d, J = 17.1 Hz, 1 H), 4.18-4.33 (m, 4 H), 4.71 (d, J = 16.5 Hz, 1 H), 5.11 (s, 1 H), 5.58 (s, 1 H), 6.07 (s, 1 H), 6.56 (s, 1 H), 6.68 (s, 1 H), 6.90-7.08 (m, 4 H). 13C NMR (CDCl3, 75 MHz): δ = 14.25, 20.86 (2 C), 53.18, 60.92, 61.31, 72.22, 124.91, 125.03, 126.58, 126.99, 127.16, 127.44, 127.49, 128.03, 128.51, 133.20, 133.33, 138.17, 143.55, 147.20, 166.81. EIMS (70 eV): m/z (%) = 77 (100), 103 (89), 132 (97), 275 (24), 348 (M+, 29). Anal. Calcd for C22H24N2O2: C, 75.83; H, 6.94; N, 8.04. Found: C, 75.85; H, 6.81; N, 8.11.
Compound 3c: Yield: 65%; colorless oil. IR (film): 1724, 1493 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 1.28 (t, J = 7.2 Hz, 3 H), 1.70 (s, 3 H), 2.16 (s, 3 H), 2.20 (s, 3 H), 4.02 (d, J = 17.4 Hz, 1 H), 4.15 (d, J = 17.1 Hz, 1 H), 4.16-4.38 (m, 3 H), 4.70 (d, J = 17.1 Hz, 1 H), 5.95 (s, 2 H), 6.55 (s, 1 H), 6.67 (s, 1 H), 6.89-7.08 (m, 4 H). 13C NMR (CDCl3, 75 MHz): δ = 14.39, 21.05 (2 C), 24.65, 55.29, 56.59, 60.82, 74.60, 125.45, 126.59, 126.61, 126.96, 127.80, 127.84, 128.27, 128.40, 133.26, 133.27, 143.07, 145.47, 146.41, 167.01. EIMS (70 eV): m/z (%) = 43 (100), 77 (81), 132 (84), 230 (52), 289 (15), 362 (M+, 23). Anal. Calcd for C23H26N2O2: C, 76.21; H, 7.23; N, 7.73. Found: C, 76.41; H, 7.19; N, 7.58.
Compound 3d: Yield: 61%; colorless oil. IR (film): 1728, 1493 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 1.45 (t, J = 7.2 Hz, 3 H), 2.09 (s, 3 H), 2.18 (s, 3 H), 4.00 (d, J = 17.1 Hz, 1 H), 4.01-4.11 (m, 2 H), 4.19 (d, J = 17.1 Hz, 1 H), 4.24 (d, J = 17.1 Hz, 1 H), 4.45 (d, J = 17.1 Hz, 1 H), 5.96 (s, 1 H), 6.14 (s, 1 H), 6.34 (s, 1 H), 6.62 (s, 1 H), 6.92-7.28 (m, 7 H), 7.57-7.71 (m, 2 H). 13C NMR (CDCl3, 75 MHz): δ = 14.20, 20.98, 21.05, 56.31, 56.65, 60.62, 79.33, 125.44, 125.65, 126.61, 126.95, 126.97, 127.58, 128.16, 128.36, 128.38, 128.65, 128.68, 130.46, 133.00, 133.25, 140.09, 142.74, 146.05, 146.12, 166.13. EIMS (70 eV): m/z (%) = 43 (100), 77 (86), 292 (28), 351 (11), 424 (M+, 19). Anal. Calcd for C28H28N2O2: C, 79.22; H, 6.65; N, 6.60. Found: C, 79.16; H, 6.67; N, 6.69.
Compound 3e: Yield: 79%; colorless oil. IR (film): 1763, 1732, 1493 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 2.17 (s, 6 H), 3.72 (s, 3 H), 3.78 (s, 3 H), 4.10 (d, J = 17.4 Hz, 1 H), 4.22 (d, J = 17.4 Hz, 1 H), 4.31 (d, J = 17.4 Hz, 1 H), 4.47 (d, J = 17.4 Hz, 1 H), 6.01 (s, 1 H), 6.08 (s, 1 H), 6.58 (s, 2 H), 6.95-6.98 (m, 2 H), 7.12-7.17 (m, 2 H). 13C NMR (CDCl3, 75 MHz): δ = 20.71, 20.76, 52.23, 53.12, 56.08, 56.97, 80.19, 124.71, 125.02, 125.78, 126.28, 126.73, 127.26, 128.37, 128.50, 129.66, 133.11, 133.70, 137.94, 144.54, 145.68, 166.56, 168.51. ESIMS: m/z = 393 (M+ + H). Anal. Calcd for C23H24N2O4: C, 70.39; H, 6.16; N, 7.14. Found: C, 70.51; H, 6.27; N, 7.25.
Compound 5a; Typical Procedure. To a stirred mixture of 1 (250 mg, 1 mmol) and 2f (530 mg, 10 mmol) in CH3CN (2 mL) was added ZnBr2 (45 mg, 0.2 mmol) and the resulting mixture was heated to 50-60 °C for 19 h. After the usual work-up and column chromatography (hexanes-Et2O, 10:1) 5a was obtained as colorless oil, 185 mg (61%). We could not obtain the exact 13C NMR spectra for 5a-c due to the line-broadening effect of the nitrogen atom.
[4a]
In order to assign more precisely the stereochemistry we took the 1H NMR spectrum of 5a in CDCl3 at elevated temperature, 50 °C (500 MHz). Fortunately, the vinyl peak (δ = 3.94 ppm) at the α-position of the nitrile split into a doublet (J = 14.0 Hz), which corresponded to trans stereochemistry. However, the other vinyl peak (δ = 6.86 ppm) appeared as a broad doublet. We also acquired NOE difference spectra. Irradiation of either proton at δ = 3.94 ppm or δ = 6.86 ppm did not show any NOE enhancement. From these supple-mentary experiments we believe the geometry to be trans.
IR (film): 2924, 2198, 1620, 1504 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 2.30 (s, 3 H), 2.36 (s, 3 H), 2.82 (s, 3 H), 3.94 (br s, 1 H), 4.12 (br s, 2 H), 4.56 (s, 2 H), 6.86 (br s, 1 H), 6.98-7.16 (m, 6 H). 13C NMR (CDCl3, 75 MHz): δ = 20.41, 20.77, 39.20, 57.87, 65.44, 116.69, 121.75, 123.39, 129.10, 129.46, 130.97, 131.78, 135.54, 142.29, 147.88, 150.94. ESIMS: m/z = 304 (M+ + H). Anal. Calcd for C20H21N3: C, 79.17; H, 6.98; N, 13.85. Found: C, 79.35; H, 6.79; N, 13.75.
Compound 5b: Yield: 43%; colorless oil. IR (film): 1693, 1601, 1504, 1149 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 2.30 (s, 3 H), 2.35 (s, 3 H), 2.81 (s, 3 H), 3.59 (s, 3 H), 4.14 (br s, 2 H), 4.59 (s, 2 H), 4.72 (br s, 1 H), 6.84 (br s, 1 H), 7.00-7.11 (m, 5 H), 7.68 (d, J = 13.5 Hz, 1 H). 13C NMR (CDCl3, 75 MHz): δ = 20.45, 20.75, 39.37, 50.54, 53.83, 58.07, 88.59, 116.62, 123.44, 128.97, 129.16, 130.75, 132.04, 134.92, 143.50, 149.26, 169.72. ESIMS: m/z = 337 (M+ + H). Anal. Calcd for C21H24N2O2: C, 74.97; H, 7.19; N, 8.33. Found: C, 75.15; H, 7.27; N, 8.35.
Compound 5c: Yield: 42%; colorless oil. IR (film): 1689, 1601, 1504, 1142 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 1.21 (t, J = 6.9 Hz, 3 H), 2.30 (s, 3 H), 2.35 (s, 3 H), 2.82 (s, 3 H), 4.07 (q, J = 6.9 Hz, 2 H), 4.11 (br s, 2 H), 4.58 (br s, 2 H), 4.72 (br s, 1 H), 6.84 (br s, 1 H), 7.00-7.11 (m, 5 H), 7.68 (d, J = 13.5 Hz, 1 H). ESIMS: m/z = 351 (M+ + H). Anal. Calcd for C22H26N2O2: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.61; H, 7.38; N, 7.91.
Compound 6a. A mixture of 3a (334 mg, 1 mmol) and Pd/C (5 wt.%, 30 mg) in a MeOH-CH2Cl2 (1:1, 3 mL) was stirred under a H2 atmosphere (balloon) for 44 h at r.t. After filtration through a pad of Celite, removal of the solvent, and column chromatography (hexanes-Et2O, 20:1), two diastereomers of 6a were obtained as colorless oils; fast-moving isomer (98 mg, 29%) and slow-moving isomer
(163 mg, 48%).
6a (minor isomer): IR (film): 1739, 1493 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 1.25 (d, J = 6.9 Hz, 3 H), 2.19 (s, 3 H), 2.20 (s, 3 H), 2.72 (dq, J = 10.8, 6.9 Hz, 1 H), 3.73 (s, 3 H), 3.94 (d, J = 17.7 Hz, 1 H), 4.12 (d, J = 10.8 Hz, 1 H), 4.14 (d, J = 16.5 Hz, 1 H), 4.63 (d, J = 16.5 Hz, 1 H), 4.67 (d, J = 17.7 Hz, 1 H), 6.68 (s, 2 H), 6.89-7.00 (m, 4 H). 13C NMR (CDCl3, 75 MHz): δ = 15.01, 21.01, 21.04, 41.41, 52.06, 52.74, 61.08, 75.70, 125.34, 126.01, 127.21, 127.23, 127.34, 127.90, 128.07, 128.45, 133.49, 133.52, 142.89, 148.25, 175.37. EIMS (70 eV): m/z (%) = 84 (47), 120 (100), 249 (54), 336 (M+, 30).
6a (major isomer): IR (film): 1740, 1493 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 1.34 (d, J = 6.9 Hz, 3 H), 2.19 (s, 6 H), 2.70 (dq, J = 11.1, 6.9 Hz, 1 H), 3.66 (s, 3 H), 3.98 (d, J = 17.4 Hz, 1 H), 4.06 (d, J = 16.5 Hz, 1 H), 4.22 (d, J = 11.1 Hz, 1 H), 4.32 (d, J = 17.4 Hz, 1 H), 4.61 (d, J = 16.5 Hz, 1 H), 6.66 (d, J = 9.0 Hz, 2 H), 6.89-7.01 (m, 4 H). 13C NMR (CDCl3, 75 MHz): δ = 14.37, 21.00, 21.03, 41.38, 51.80, 52.16, 60.94, 75.34, 125.12, 126.11, 126.70, 126.94, 127.42, 128.08, 128.16, 128.57, 133.23, 133.59, 143.30, 147.86, 175.44. EIMS (70 eV): m/z (%) = 77 (98), 132 (100), 249 (66), 336 (M+, 41). Anal. Calcd for C21H24N2O2: C, 74.97; H, 7.19; N, 8.33. Found: C, 75.05; H, 7.17; N, 8.47.
Compound 7a. A mixture of 3a (167 mg, 0.5 mmol) and NaBH4 (57 mg, 1.5 mmol) in MeOH-CH2Cl2 (1:1, 2 mL) was stirred for 4 h at r.t. After the usual workup and column chromatography (hexanes-Et2O, 4:1) we obtained 6a as a mixture of two isomers, 148 mg (88%). During the separation we isolated also a low yield of 7a.
7a: Yield: 9%; white solid; mp 163-164 °C. IR (KBr): 3363, 1682, 1620, 1504, 1119 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 1.19 (d, J = 0.9 Hz, 3 H), 2.26 (s, 3 H), 2.31 (s, 3 H), 3.65 (s, 3 H), 4.25 (s, 2 H), 4.61 (s, 2 H), 6.61 (d, J = 7.8 Hz, 1 H), 6.89-7.03 (m, 5 H), 7.45 (q, J = 0.9 Hz, 1 H). 13C NMR (CDCl3, 75 MHz): δ = 12.27, 20.41, 20.85, 51.07, 51.65, 60.56, 99.66, 119.44, 126.10, 126.75, 128.11, 129.13, 129.74, 130.08, 131.58, 134.22, 134.74, 142.64, 145.52, 146.92, 170.84. ESIMS: m/z = 337 (M+ + H). Anal. Calcd for C21H24N2O2: C, 74.97; H, 7.19; N, 8.33. Found: C, 74.88; H, 7.39; N, 8.16.
Compound 7a slowly converted to 6a. We found that the conversion of 7a (as a solution in CDCl3) to 6a was complete, almost quantitatively, within two weeks (TLC).