Synthesis of 7,8-Benzo-3-hydroxy-9-azabicyclo[3.3.1]non-3-enes by Cyclocondensation of 1,3-Bis-Silyl Enol Ethers with Isoquinolines

Abstract

Several functionalized 7,8-benzo-3-hydroxy-9-azabicyclo[3.3.1]non-3-enes were prepared by two-step cyclocondensation of 1,3-bis-silyl enol ethers with isoquinolinium salts.

alkaloids - cyclizations - iminium salts - isoquinoline - ­silyl enol ethers

References

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General Procedure.
To a CH₂Cl₂ solution (40 mL) of isoquinoline (0.520 g, 4.0 mmol) was added the 1,3-bis-silyl enol ether (8.0 mmol) and methyl chloroformate (0.460 g, 4.8 mmol) at 0 °C. The solution was stirred for 2 h at 0 °C and for 12 h at 20 °C. A sat. aq solution of NH₄Cl (20 mL) was added and the organic and the aqueous layers were separated. The latter was extracted with CH₂Cl₂ (3 × 100 mL). The combined organic layers were dried (Na₂SO₄), filtered and the filtrate was concentrated in vacuo. The residue was purified by chro-matography (silica gel, hexane → hexane-EtOAc = 2:1).
Synthesis of 3e.
Starting with 1a (0.520 g, 4.0 mmol), 2e (2.196 g, 8.0 mmol) and methyl chloroformate (0.460 g, 4.8 mmol), 3e was prepared as a yellow oil (0.700 g, 55%). Due to the amide resonance and formation of E/Z-isomers, doubling of some signals was observed. ¹H NMR (300 MHz, CDCl₃): δ = 2.41-2.72 (m, 2 H, NCHCH ₂, isomer 1, isomer 2), 3.36 (s, 3 H, OCH₃, isomer 1), 3.37 (s, 3 H, OCH₃, isomer 2), 3.78 (s, 3 H, CO₂CH₃, isomer 1), 3.80 (s, 3 H, CO₂CH₃, isomer 2), 3.93 (s, 2 H, COCH ₂, isomer 1), 3.94 (s, 2 H, COCH ₂, isomer 2), 5.58 (s, 1 H, COCH, isomer 1), 5.61 (s, 1 H, COCH, isomer 2), 5.71 (t, ³ J = 7.0 Hz, 1 H, NCH, isomer 1), 5.82 (t, ³ J = 7.0 Hz, 1 H, NCH, isomer 2), 5.88 (d, ³ J = 7.8 Hz, 1 H, CH, isomer 1), 5.98 (d, ³ J = 7.8 Hz, 1 H, CH, isomer 2), 6.80 (d, ³ J = 7.8 Hz, 1 H, CH, isomer 1), 6.96 (d, ³ J = 7.8 Hz, 1 H, CH, isomer 2), 7.03-7.24 (m, 4 H, Ar), 15.04 (br s, 1 H, OH). ¹³C NMR (75 MHz, CDCl₃): δ = 42.73/43.04 (NCHCH₂), 53.42 (CO₂CH₃), 53.97 (NCH), 59.37 (OCH₃), 74.04 (COCH₂), 98.22 (COCH), 108.97/109.28 (CH), 124.27/124.97 (CH), 126.09/126.32, 126.54, 127.17, 128.16/128.27 (Ar-CH), 130.03/130.23, 131.29, 153.28, 187.21/187.92, 193.57/194.52 (C). IR (neat): 775 (s), 947 (s), 981 (s), 2827 (s), 2950 (s), 2994 (s), 3070 (w), 3106 (w) cm^-1. MS (EI, 70 eV): m/z (%) = 317 (2) [M⁺], 189 (12), 188 (100), 144 (37), 129 (13). Anal. Calcd for C₁₇H₁₉NO₅ (317.34): C, 64.34; H, 6.03; N, 4.41. Found: C, 64.46; H, 6.01; N, 4.28. All new compounds gave satisfactory spectroscopic and analytical and/or high resolution mass data.

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General Procedure.
To a CH₂Cl₂ solution (6 mL) of 3 (1.5 mmol) was added TFA (3.0 mmol) and the solution was stirred for 12 h at 20 °C.
For 4a-c:
A sat. aq solution of NaHCO₃ (2 mL) was added and the organic and the aqueous layers were separated. The latter was extracted with CH₂Cl₂ (3 × 30 mL). The combined organic layers were dried (Na₂SO₄), filtered and the filtrate was concentrated in vacuo.
For 4d-j: the solvent and TFA were removed in vacuo.
For 4a-j: the residue was purified by chromatography (silica gel, hexane → hexane-EtOAc = 2:1). The product was dried for 16 h at 50 °C and 0.01 mbar to remove hydrolyzed 2.
Synthesis of 4e (typical example).
Starting with 3e (0.531 g, 1.67 mmol) and TFA (0.380 g, 3.35 mmol), 4e was isolated as a colorless solid (0.364 g, 69%). Due to the amide resonance and formation of E/Z isomers, doubling of some signals was observed. In all products, the 1,3-dicarbonyl moiety resides in the enolic form. ¹H NMR (300 MHz, CDCl₃): δ = 2.49 (dd, ² J = 18.0 Hz, ³ J = 1.1 Hz, 1 H, CHCH ₂), 2.74 (d, ² J = 16.4 Hz, 1 H, CHCH ₂), 3.00-3.08 (m, 1 H, CHCH ₂), 3.32-3.45 (m, 1 H, CHCH ₂), 3.51 (s, 3 H, OCH₃), 3.75 (s, 3 H, CO₂CH₃, isomer 1), 3.77 (s, 3 H, CO₂CH₃, isomer 2), 4.22-4.43 (m, 2 H, CH₂), 5.38-5.40 (m, 1 H, NCH), 5.48-5.52 (m, 1 H, NCH), 7.08-7.21 (m, 4 H, Ar-H), 15.59 (s, 1 H, OH, isomer 1), 15.65 (s, 1 H, OH, isomer 2). ¹³C NMR (75 MHz, CDCl₃): δ = 34.93/35.43 (CHCH₂), 39.34/39.60 (CHCH₂), 44.23/44.81 (CH), 48.17/48.80 (CH), 53.11 (CO₂CH₃), 59.65 (OCH₃), 72.99/73.13 (CH₂), 108.57 (C), 126.44, 126.72/126.86, 127.67/127.81, 129.72/130.0 (Ar-CH), 130.98/131.42, 136.05/136.20, 154.50, 180.89/182.16, 193.18/193.82 (C). IR (neat): 765 (w), 1029 (w), 1121 (s), 1458 (s), 1702 (s), 3439 (br) cm^-1. MS (EI, 70 eV): m/z (%) = 317 (10) [M⁺], 272 (94), 226 (26), 194 (19), 188 (100). Anal. Calcd for C₁₇H₁₉NO₅ (317.34): C, 64.34; H, 6.03; N, 4.41. Found: C, 64.10; H, 6.03; N, 4.30.

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