Novel Three-Step Synthesis of (±)-Harmicine

Abstract

A three-step synthesis of (±)-harmicine from 3,4-di­hydro-β-carboline is achieved by addition of a 3-trimethylsilyl­propargyl Grignard reagent, Ag(I)-promoted oxidative cyclization to a pyrrole, and chemoselective hydrogenation of the pyrrole ring.

alkaloids - cyclizations - hydrogenations - pyrroles - ­nucleophilic additions

References

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<A NAME="RG13304ST-11">11</A>

Silver(I)-Promoted Oxidative Cyclization of Compound 4: Silver acetate (90 mg, 0.54 mmol) was added to a solution of 1-(3-trimethylsilylpropargyl)-1,2,3,4-tetrahydro-β-carboline (4, 138 mg, 0.49 mmol) in anhyd CH₂Cl₂ (20 mL). In the absence of light, the solution was stirred at r.t. under an argon atmosphere. Filtration over a short path of neutral alumina (CH₂Cl₂) provided compound 5 as a light green powder; yield: 78 mg (77%); mp: 161-163 °C. UV (MeOH): λ = 224, 281, 290 nm. IR (DRIFT): ν = 3425, 3383, 1624, 1603, 1480, 1438, 1369, 1353, 1332, 1320, 1307, 1272, 1244, 1234, 1070, 844, 747, 712 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 3.18 (t, J = 7.0 Hz, 2 H), 4.22 (t, J = 7.0 Hz, 2 H), 6.26 (dd, J = 3.4, 2.7 Hz, 1 H), 6.33 (dd, J = 3.4, 1.4 Hz, 1 H), 6.80 (dd, J = 2.7, 1.4 Hz, 1 H), 7.18 (m, 2 H), 7.39 (m, 1 H), 7.54 (m, 1 H), 8.10 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, CDCl₃): δ = 21.25 (CH₂), 45.36 (CH₂), 101.87 (CH), 105.17 (C), 108.14 (CH), 110.93 (CH), 117.81 (CH), 119.94 (CH), 121.44 (CH), 121.77 (CH), 124.62 (C), 127.13 (C), 128.96 (C), 136.38 (C). MS (65 °C): m/z (%) = 208 (100) [M⁺], 207 (68), 206 (18), 205 (3), 115 (4), 104 (3). HRMS: m/z calcd for C₁₄H₁₂N₂ [M⁺]: 208.1000; found: 208.0994.

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<A NAME="RG13304ST-13">13</A>

(±)-Harmicine [(±)-(1)]: Light yellow solid. IR (ATR): ν = 3185, 3059, 2925, 2853, 1610, 1558, 1520, 1450, 1384, 1302, 1233, 1147, 1059, 1008, 923, 738 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.77-1.87 (m, 1 H), 1.88-1.97 (m, 2 H), 2.28-2.36 (m, 1 H), 2.69-2.74 (m, 1 H), 2.89-2.97 (m, 2 H), 2.99-3.03 (m, 1 H), 3.10-3.16 (m, 1 H), 3.31 (ddd, J = 12.9, 5.0, 2.3 Hz, 1 H), 4.41 (m, 1 H), 7.07 (dt, J = 1.0, 7.5 Hz, 1 H), 7.12 (dt, J = 1.2, 7.5 Hz, 1 H), 7.31 (br d, J = 7.5 Hz, 1 H), 7.45 (br d, J = 7.5 Hz, 1 H), 8.73 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, CDCl₃): δ = 17.38 (CH₂), 23.14 (CH₂), 29.51 (CH₂), 45.64 (CH₂), 49.06 (CH₂), 56.99 (CH), 107.03 (C), 110.95 (CH), 117.98 (CH), 119.30 (CH), 121.51 (CH), 126.90 (C), 133.96 (C), 136.21 (C). MS (150 °C): m/z (%) = 212 (62) [M⁺], 211 (100), 184 (21), 183 (9), 170 (7), 169 (6), 168 (7), 156 (12), 106 (6), 84 (11). HRMS: m/z calcd for C₁₄H₁₆N₂ [M⁺]: 212.1313; found: 212.1332.