Serendipitous Synthesis of Unusual Cyclic and Acyclic Enaminone Esters from Tröger’s Base and Conjugated Esters

Ka Young Lee; Saravanan Gowrisankar; Jae Nyoung Kim

doi:10.1055/s-2006-941595

LETTER

Serendipitous Synthesis of Unusual Cyclic and Acyclic Enaminone Esters from Tröger’s Base and Conjugated Esters

Ka Young Lee, Saravanan Gowrisankar, Jae Nyoung Kim*
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
Fax: +82(62)5303389; e-Mail: kimjn@chonnam.ac.kr;

Abstract

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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

References and Notes

For the synthesis and applications of Tröger’s base derivatives in host-guest chemistry:

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For the synthesis and synthetic applications of enaminone esters, see:

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<A NAME="RU02306ST-6">6</A> Recently Voskressensky and co-workers reported an interesting tetrahydropyridine ring expansion under the action of activated terminal alkynes via similar mechanism to ours: Voskressensky LG. Borisova TN. Kostenev IS. Kulikova LN. Varlamov AV. Tetrahedron Lett. 2006, 47: 999 ; and references cited therein

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).

<A NAME="RU02306ST-12A">12a</A> Northrop RC. Russ PL. J. Org. Chem. 1975, 40: 558

<A NAME="RU02306ST-12B">12b</A> Szmuszkovicz J, and Cerda ES. inventors; US Patent 3,714,186. ; Chem. Abstr. 1973, 78, 136055