Direct Phosphonylation of N-Carbamate-tetrahydroisoquinoline by Convergent Paired Electrolysis

Abstract

Mild experimental conditions for a direct phosphonylation of an easily cleavable N-carbamate-tetrahydroisoquinoline have been described under constant current electrolysis. The developed electrochemical process allowed to prepare α-aminophosphonates in moderate to good yields. On the basis of the experimental results, a mechanism proceeding through a convergent paired electrochemical process was enabled to be postulated.

Key words

electrosynthesis - convergent paired electrolysis - phosphonylation - aminophosphonates - N-Boc-tetrahydroisoquinoline

• References and Notes


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• 14 Experimental Procedure for Phosphonylation of N-Carbamate-tetrahydroisoquinoline In an electrochemical cell fitted with two graphite plate electrodes (thickness: 2 mm, submerged area: 8.78 cm², distance between the electrodes: 3–5 mm) was added a solution of tetraethylammonium tetrafluoroborate (109 mg, 0.50 mmol, 0.5 equiv) in MeCN/THF (3:1, 10 mL, v/v). The solution was bubbled with argon for 5 min before the successive addition of N-Boc-tetrahydroisoquinoline (233 mg, 1.00 mmol, 1.0 equiv) and dialkyl phosphite (1.20 mmol, 1.2 equiv). After 161 min (3.0 F/mol) of electrolysis (30 mA of current giving rise to a density of 3.42 mA cm^–2) under stirring at 20 °C, the reaction mixture was quenched with a 1 M HCl aqueous solution (20 mL) and diluted with Et₂O (20 mL). After layers separation, the aqueous layer was extracted by Et₂O (2 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by flash chromatography on silica gel column to afford the pure phosphonylated compound.
• 15 Characterization Data of Compounds 3a–f tert-Butyl 1-(Dimethoxyphosphoryl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3a) Colorless oil, yield 70% (237 mg). FC: ethyl acetate/petroleum ether (60:40). ¹H NMR (400 MHz, CDCl₃): δ (mixture of rotamers in 55:45 ratio) = 7.45–7.41 (m, 1 H), 7.24–7.08 (m, 3 H), 5.71 (d, J = 20.5 Hz, 0.55 H), 5.52 (d, J = 20.6 Hz, 0.45 H), 4.28 (m, 0.45 H), 4.00 (m, 0.55 H), 3.83–3.37 (m, 7 H), 2.92–8.81 (m, 2 H), 1.48 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ (mixture of rotamers) = 154.5 (d, J = 3.4 Hz), 153.9 (d, J = 1.1 Hz), 135.0 (d, J = 4.1 Hz), 135.0 (d, J = 4.0 Hz), 130.8 (s), 129.4 (s), 128.9 (d, J = 1.9 Hz), 128.8 (s), 128.0 (d, J = 3.8 Hz), 127.7 (d, J = 3.6 Hz), 127.5 (d, J = 3.1 Hz), 127.3 (d, J = 3.1 Hz), 126.1 (d, J = 2.8 Hz), 126.1 (d, J = 2.8 Hz), 80.8 (s), 80.5 (s), 53.6 (d, J = 7.2 Hz), 53.4 (d, J = 6.7 Hz), 53.3 (d, J = 6.2 Hz), 53.2 (d, J = 149.7 Hz), 53.0 (d, J = 7.4 Hz), 51.8 (d, J = 152.3 Hz), 40.0 (s), 38.2 (s), 28.7 (s), 28.3 (s), 28.2 (s), 27.9 (s). ³¹P NMR (162 MHz, CDCl₃): δ (mixture of rotamers) = 24.44, 23.99. HRMS (ESI⁺): m/z calcd for C₁₆H₂₅NO₅P [M + H]⁺: 342.1465; found: 342.1467. tert-Butyl 1-(Diethoxyphosphoryl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3b) Colorless oil, yield 65% (240 mg). FC: ethyl acetate/petroleum ether (60:40). ¹H NMR (400 MHz, CDCl₃): δ (mixture of rotamers in 55:45 ratio) = 7.47–7.43 (m, 1 H), 7.22–7.11 (m, 3 H), 5.70 (d, J = 20.7 Hz, 0.55 H), 5.51 (d, J = 20.7 Hz, 0.45 H), 4.32–4.27 (m, 0.45 H), 4.15–3.93 (m, 4.4 H), 3.82–3.68 (m, 1 H), 3.55–3.48 (m, 0.45 H), 2.95–2.79 (m, 2 H), 1.49 and 4.48 (2 s, 9 H), 1.40–1.27 (m, 3 H), 1.19 (t, J = 7.1 Hz, 1.7 H), 1.12 (t, J = 7.0 Hz, 1.3 H). ¹³C NMR (100 MHz, CDCl₃): δ (mixture of rotamers) = 154.5 (d, J = 4.0 Hz), 154.1 (d, J = 1.9 Hz), 135.2 (d, J = 5.6 Hz), 135.1 (d, J = 6.0 Hz), 129.8 (s), 129.4 (d, J = 1.1 Hz), 129.2 (s), 128.9 (d, J = 2.3 Hz), 128.2 (d, J = 3.9 Hz), 127.9 (d, J = 3.3 Hz), 127.4 (d, J = 3.3 Hz), 127.3 (d, J = 3.0 Hz), 126.0 (d, J = 2.7 Hz), 126.0 (d, J = 3.2 Hz), 80.7 (s), 80.30 (s), 63.2 (d, J = 7.3 Hz), 63.0 (d, J = 7.1 Hz), 62.6 (d, J = 7.0 Hz), 62.4 (d, J = 7.6 Hz), 53.6 (d, J = 153.0 Hz), 52.1 (d, J = 152.9 Hz), 40.0 (s), 38.2 (s), 28.4 (s), 28.2 (s), 27.9 (s), 16.4 (s). ³¹P NMR (162 MHz, CDCl₃): δ (mixture of rotamers) = 21.92, 21.87. HRMS (ESI⁺): m/z calcd for C₁₈H₂₉NO₅P [M + H]⁺: 370.1778; found: 370.1780. tert-Butyl 1-(Diisopropoxyphosphoryl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3c) Colorless oil, yield 50% (198 mg). FC: ethyl acetate/petroleum ether (30:70). ¹H NMR (400 MHz, CDCl₃): δ (mixture of rotamers in 55:45 ratio) = 7.49–7.40 (m, 1 H), 7.18–7.05 (m, 3 H), 5.64 (d, J = 21.7 Hz, 0.54 H), 5.45 (d, J = 21.1 Hz, 0.46 H), 4.70–4.59 (m, 1 H), 4.58–4.50 (m, 0.53 H), 4.45–4.35 (m, 0.47 H), 4.27 (dd, J = 13.4, 5.8 Hz, 0.45 H), 4.05–3.97 (m, 0.55 H), 3.73–3.64 (m, 0.53 H), 3.45 (ddd, J = 13.3, 11.6, 4.5 Hz, 0.47 H), 2.98–2.71 (m, 2 H), 1.45 and 1.44 (2 s, 9 H), 1.31–1.25 (m, 5 H), 1.25–1.20 (m, 4 H), 0.99 (d, J = 6.2 Hz, 1.6 H), 0.81 (d, J = 6.2 Hz, 1.4 H). ¹³C NMR (100 MHz, CDCl₃): δ (mixture of rotamers) = 154.5 (d, J = 4.6 Hz), 154.1 (d, J = 1.8 Hz), 135.2 (d, J = 5.6 Hz), 135.1 (d, J = 5.7 Hz), 130.3 (s), 129.7 (s), 129.3 (s), 128.9 (s), 128.4 (d, J = 3.5 Hz), 128.0 (d, J = 3.3 Hz), 127.3 (d, J = 2.9 Hz), 127.1 (d, J = 2.9 Hz), 126.2 (s), 125.8 (d, J = 2.9 Hz), 80.5 (s), 80.1 (s), 72.0 (d, J = 7.4 Hz), 71.7 (d, J = 7.6 Hz), 71.1 (d, J = 7.5 Hz), 70.8 (d, J = 8.0 Hz), 54.1 (d, J = 151.2 Hz), 52.9 (d, J = 155.7 Hz), 39.9 (s), 38.0 (s), 28.4 (s), 28.19 (s), 27.9 (s), 24.41 (s), 24.2 (d, J = 3.0 Hz), 24.1 (s), 24.0 (d, J = 3.4 Hz), 23.8 (d, J = 5.7 Hz), 23.3 (d, J = 5.4 Hz), 23.1 (d, J = 5.2 Hz). ³¹P NMR (162 MHz, CDCl₃): δ (mixture of rotamers) = 20.31, 20.17. HRMS (ESI⁺): m/z calcd for C₂₀H₃₃NO₅P [M + H]⁺: 398.2091; found: 398.2092. tert-Butyl 1-(Dibutoxyphosphoryl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3d) Colorless oil, yield 71% (302 mg). FC: ethyl acetate/petroleum ether (20:80). ¹H NMR (400 MHz, CDCl₃): δ (mixture of rotamers in 55:45 ratio) = 7.49–7.38 (m, 1 H), 7.21–7.10 (m, 3 H), 5.70 (d, J = 20.8 Hz, 0.55 H), 5.51 (d, J = 20.8 Hz, 0.45 H), 4.30 (dd, J = 13.5, 5.2 Hz, 0.46 H), 4.06–3.97 (m, 3 H), 3.93 (dd, J = 10.0, 6.8 Hz, 0.4 H), 3.88–3.81 (m, 0.6 H), 3.75–3.62 (m, 1 H), 3.48 (ddd, J = 13.3, 11.4, 4.4 Hz, 0.54 H), 3.00–2.75 (m, 2 H), 1.66–1.57 (m, 2 H), 1.48 and 1.47 (2 s, 9 H), 1.43–1.33 (m, 3 H), 1.28–1.21 (m, 2 H), 0.95–0.86 (m, 4 H), 0.86–0.79 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ (mixture of rotamers) = 154.5 (d, J = 4.4 Hz), 154.1 (d, J = 2.9 Hz), 135.1 (d, J = 5.6 Hz), 129.9 (s), 129.4 (s), 129.4 (s), 128.9 (s), 128.2 (d, J = 3.8 Hz), 127.9 (s), 127.4 (s), 127.3 (s), 127.2 (s), 126.0 (s), 126.0 (s), 80.7 (s), 80.3 (s), 66.9 (d, J = 8.0 Hz), 66.6 (d, J = 7.2 Hz), 66.2 (d, J = 7.0 Hz), 66.1 (d, J = 7.5 Hz), 53.7 (d, J = 151.8 Hz), 52.2 (d, J = 154.4 Hz), 40.9 (s), 40.1 (s), 38.2 (s), 32.5 (d, J = 5.7 Hz), 28.4 (s), 28.2 (s), 27.9 (s), 23.9 (s), 18.7 (s), 18.6 (s), 13.6 (s). ³¹P NMR (162 MHz, CDCl₃): δ (mixture of rotamers) = 21.94, 21.86. HRMS (ESI⁺): m/z calcd for C₂₂H₃₇NO₅P [M + H]⁺: 426.2404; found: 426.2406. tert-Butyl 1-[Bis(benzyloxy)phosphoryl]-3,4-dihydroisoquinoline-2(1H)-carboxylate (3e) Off-white solid, yield 45% (220 mg). FC: ethyl acetate/petroleum ether (20:80); mp 87–89 °C. ¹H NMR (400 MHz, CDCl₃): δ (mixture of rotamers in 55:45 ratio) = 7.52–7.37 (m, 1 H), 7.39–7.01 (m, 13 H), 5.86 (d, J = 20.5 Hz, 0.55 H), 5.62 (d, J = 20.8 Hz, 0.45 H), 5.09–4.94 (m, 2.45 H), 4.94–4.80 (m, 1 H), 4.64 (dd, J = 20.4, 11.8 Hz, 0.55 H), 4.32–4.22 (m, 0.45 H), 4.03–3.93 (m, 0.55 H), 3.74– 3.62 (m, 0.55 H), 3.56–3.43 (m, 0.45 H), 2.95–2.72 (m, 2 H), 1.43 (s, 4.9 H), 1.37 (s, 4.1 H). ¹³C NMR (100 MHz, CDCl₃): δ (mixture of rotamers) = 154.6 (d, J = 3.4 Hz), 154.0 (d, J = 2.0 Hz), 136.3 (d, J = 6.2 Hz), 136.1 (d, J = 5.8 Hz), 135.3 (d, J = 6.6 Hz), 135.2 (d, J = 6.3 Hz), 129.5 (d, J = 1.8 Hz), 129.4 (s), 129.1 (d, J = 1.7 Hz), 128.9 (s), 128.6 (s), 128.5 (s), 128.4 (s), 128.3 (s), 128.2 (s), 128.1 (s), 128.1 (s), 127.9 (s), 127.8 (s), 127.7 (s), 127.6 (d, J = 3.7 Hz), 127.5 (d, J = 3.3 Hz), 126.2 (s), 126.1 (d, J = 2.8 Hz), 80.9 (s), 80.5 (s), 68.5 (d, J = 7.2 Hz), 68.2 (d, J = 7.1 Hz), 67.9 (d, J = 6.5 Hz), 67.8 (d, J = 7.5 Hz), 53.8 (d, J = 149.2 Hz), 52.4 (d, J = 152.3 Hz), 40.1 (s), 38.3 (s), 28.4 (s), 28.3 (s), 28.2 (s), 27.9 (s). ³¹P NMR (162 MHz, CDCl₃): δ (mixture of rotamers) = 22.74, 22.64. HRMS (ESI⁺): m/z calcd for C₂₈H₃₃NO₅P [M + H]⁺: 494.2091; found: 494.2091. tert-Butyl 1-(Diphenoxyphosphoryl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3f) Off-white solid, yield 43% (200 mg); mp 81–83 °C. FC: ethyl acetate/petroleum ether (10:90). ¹H NMR (400 MHz, CDCl₃): δ (mixture of rotamers in 50:50 ratio) = 7.58 (dd, J = 18.2, 6.7 Hz, 1 H), 7.38–7.08 (m, 11 H), 7.04 (d, J = 7.8 Hz, 1 H), 6.75 (d, J = 7.8 Hz, 0.5 H), 6.19 (d, J = 21.0 Hz, 0.5 H), 5.97 (d, J = 19.6 Hz, 0.5 H), 4.50–4.34 (m, 0.5 H), 4.22–4.00 (m, 0.5 H), 3.92–3.78 (m, 0.5 H), 3.74–3.60 (m, 0.5 H), 3.12–2.86 (m, 2 H), 1.49 and 1.48 (2 s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ (mixture of rotamers) = 154.7 (d, J = 4.0 Hz), 154.1 (s), 150.9 (s), 150.8 (s), 150.4 (s), 150.3 (s), 150.2 (d, J = 2.7 Hz), 150.1 (s), 135.5 (d, J = 2.4 Hz), 135.5 (d, J = 2.8 Hz), 129.8 (s), 129.7 (s), 129.6 (s), 129.5 (s), 129.2 (d, J = 2.0 Hz), 128.9 (s), 128.4 (d, J = 4.3 Hz), 128.2 (s), 128.1 (s), 128.0 (d, J = 3.5 Hz), 127.9 (d, J = 3.4 Hz), 126.4 (s), 125.3 (s), 125.1 (d, J = 4.6 Hz), 124.9 (s), 120.8 (d, J = 4.2 Hz), 120.7 (d, J = 4.3 Hz), 120.4 (s), 120.3 (s), 120.2 (s), 81.3 (s), 80.8 (s), 54.4 (d, J = 150.8 Hz), 53.3 (d, J = 156.8 Hz), 40.4 (s), 38.6 (s), 28.4 (s), 28.3 (s), 28.2 (s), 28.0 (s). ³¹P NMR (162 MHz, CDCl₃): δ (mixture of rotamers) = 14.35, 13.88. HRMS (ESI⁺): m/z calcd for C₂₆H₂₉NO₅P [M + H]⁺: 466.1778; found: 466.1776.
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