Catalyst-Free Synthesis of Aminals from Indole-Derived α,α-Di­cyanoolefins

Abstract

We have developed an efficient synthesis of indole fused aminals with nucleophilic imines and indole-derived α,α-dicyanoolefins via N-sulfonyl group transfer. The combination of two privileged frameworks, tetrahydroisoquinoline or tetrahydro-β-carboline and indole, can be realized by this approach to the construction of aminals. The synthetic application of this method was further demonstrated by the straightforward transformations into highly functionalized aminals possessing carbonyl groups through oxidative cleavage of the nitrile moiety.

Key words

aminal - tetrahydroisoquinoline - tetrahydro-β-carboline - indole - α,α-dicyanoolefin

• References and Notes

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• 12 CCDC 1871844 for compound 3e. See the Supporting Information for details.
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• 14 Synthesis of Compound 3; General Procedure: A mixture of 3,4-dihydro-isoquinoline imine 1 (0.3 mmol), 2-((1-sulfonyl-1H-indol-3-yl)methylene)malononitrile 2 (0.1 mmol), 4 Å molecular sieves (100 mg) and DMF (0.5 mL) was stirred at 50 °C. Upon the consumption of 2 (monitored by TLC), the reaction was diluted with CH₂Cl₂ (3 mL) and washed with water (3 mL) and brine (3 mL). The organic layer was concentrated and purified by a silica gel flash chromatography (PE/EtOAc) to afford compound 3. Spectral Data for Selected Compounds Compound 3a: Purified by flash column chromatography (PE/EtOAc, 4:1); Yield: 43.3 mg (77%); yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.03 (d, J = 8.3 Hz, 1 H), 7.97 (s, 1 H), 7.93 (s, 1 H), 7.69 (d, J = 7.8 Hz, 1 H), 7.50–7.44 (m, 2 H), 7.41 (t, J = 7.2 Hz, 1 H), 7.34 (d, J = 8.3 Hz, 2 H), 7.02 (d, J = 8.0 Hz, 2 H), 6.60 (s, 1 H), 6.40 (s, 1 H), 3.99 (dd, J = 14.3, 5.1 Hz, 1 H), 3.87 (s, 3 H), 3.67 (s, 3 H), 3.36 (ddd, J = 14.4, 11.8, 5.1 Hz, 1 H), 2.84–2.68 (m, 2 H), 2.32 (s, 3 H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 150.3, 149.8, 148.8, 144.0, 136.6, 136.3, 132.6, 129.5, 127.3, 127.0, 126.7, 125.2, 123.8, 120.9, 118.1, 114.9, 112.4, 111.3, 111.2, 109.5, 77.4, 65.5, 56.1, 56.0, 39.4, 26.4, 21.5; HRMS (ESI): m/z [M+H]⁺ calcd. for C₃₀H₂₇N₄O₄S⁺: 539.1748; found: 539.1743. Compound 3b: Purified by flash column chromatography (PE/EtOAc, 4:1); Yield: 28.1 mg (50%); yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.93 (s, 1 H), 7.90 (s, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.47 (s, 1 H), 7.41 (s, 1 H), 7.34 (d, J = 8.2 Hz, 2 H), 7.29 (s, 1 H), 7.03 (d, J = 8.1 Hz, 2 H), 6.59 (s, 1 H), 6.40 (s, 1 H), 3.98 (dd, J = 14.2, 5.1 Hz, 1 H), 3.87 (s, 3 H), 3.67 (s, 3 H), 3.35 (ddd, J = 14.4, 11.8, 5.0 Hz, 1 H), 2.85–2.67 (m, 2 H), 2.53 (s, 3 H), 2.33 (s, 3 H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 150.2, 149.9, 148.7, 143.9, 136.3, 135.0, 133.7, 132.5, 129.5, 127.6, 127.0, 126.9, 126.8, 126.7, 121.0, 117.8, 115.0, 112.1, 111.2, 110.9, 109.5, 73.4, 65.5, 56.1, 56.0, 39.4, 26.5, 21.6, 21.5; HRMS (ESI): m/z [M+H]⁺ calcd. for C₃₁H₂₉N₄O₄S⁺: 553.1904; found: 553.1899. Compound 3c: Purified by flash column chromatography (PE/EtOAc, 4:1); Yield: 35.7 mg (63%); yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.90–7.87 (m, 3 H), 7.38–7.35 (m, 3 H), 7.11–7.04 (m, 4 H), 6.59 (s, 1 H), 6.41 (s, 1 H), 3.97 (dd, J = 14.5, 5.0 Hz, 1 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.69 (s, 3 H), 3.33 (ddd, J = 14.4, 11.8, 5.0 Hz, 1 H), 2.78–2.33 (m, 2 H), 2.33 (s, 3 H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 157.1, 150.3, 149.8, 148.8, 144.0, 136.4, 132.9, 131.5, 129.5, 128.4, 127.0, 126.8, 120.9, 115.1, 115.0, 114.8, 113.4, 111.3, 111.0, 109.6, 100.2, 73.1, 65.7, 56.1, 56.0, 55.9, 39.4, 26.4, 21.5; HRMS (ESI): m/z [M+Na]⁺ calcd. for C₃₁H₂₈N₄NaO₅S⁺: 591.1673; found: 591.1669. Compound 3e: Purified by flash column chromatography (PE/EtOAc, 4:1); Yield: 34.6 mg (63%); yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.88 (d, J = 4.8 Hz, 2 H), 7.82 (s, 1 H), 7.56 (d, J = 8.2 Hz, 1 H), 7.41 (s, 1 H), 7.34 (d, J = 8.2 Hz, 2 H), 7.23 (d, J = 8.2 Hz, 1 H), 7.02 (d, J = 8.1 Hz, 2 H), 6.60 (s, 1 H), 6.39 (s, 1 H), 4.01 (dd, J = 14.4, 5.7 Hz, 1 H), 3.87 (s, 3 H), 3.67 (s, 3 H), 3.39–3.36 (m, 1 H), 2.90–2.65 (m, 2 H), 2.56 (s, 3 H), 2.32 (s, 3 H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 150.2, 150.0, 148.7, 148.7, 143.9, 137.1, 136.4, 136.4, 135.4, 132.1, 129.5, 126.7, 125.5, 125.0, 121.1, 117.7, 115.0, 112.2, 111.2, 109.5, 73.6, 65.3, 56.1, 56.0, 39.5, 26.5, 22.7, 21.5; HRMS (ESI): m/z [M+Na]⁺ calcd. for C₃₁H₂₈N₄NaO₄S⁺: 575.1724; found: 575.1723. Compound 3f: Purified by flash column chromatography (PE/EtOAc, 4:1); Yield: 27.5 mg (48%); yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.01–7.95 (m, 2 H), 7.87 (s, 1 H), 7.59 (d, J = 8.5 Hz, 1 H), 7.40 (d, J = 8.3 Hz, 2 H), 7.38–7.33 (m, 2 H), 7.06 (d, J = 8.1 Hz, 2 H), 6.60 (s, 1 H), 6.38 (s, 1 H), 4.01 (dd, J = 14.4, 5.3 Hz, 1 H), 3.87 (s, 3 H), 3.69 (s, 3 H), 3.40–3.29 (m, 1 H), 2.85–2.67 (m, 2 H), 2.32 (s, 3 H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 150.4, 149.5, 148.8, 144.1, 136.9, 136.3, 133.0, 131.2, 129.6, 127.1, 126.7, 125.7, 124.4, 120.5, 119.0, 114.6, 112.6, 111.3, 110.9, 109.5, 100.0, 75.2, 65.7, 56.2, 56.0, 39.5, 26.4, 21.5; HRMS (ESI): m/z [M+H₂O+H]⁺ calcd. for C₃₀H₂₈ClN₄O₅S⁺: 591.1463; found: 591.1467. Compound 3g: Purified by flash column chromatography (PE/EtOAc, 4:1); Yield: 30.7 mg (61%); yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.97 (d, J = 8.4 Hz, 1 H), 7.94 (s, 1 H), 7.90 (s, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.48–7.44 (m, 2 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 2 H), 6.99 (d, J = 8.0 Hz, 2 H), 6.89 (d, J = 8.4 Hz, 1 H), 6.74 (dd, J = 8.8, 2.4 Hz, 1 H), 6.68 (d, J = 2.0 Hz, 1 H), 4.06 (dd, J = 14.1, 4.6 Hz, 1 H), 3.79 (s, 3 H), 3.39 (ddd, J = 14.1, 11.8, 4.7 Hz, 1 H), 2.97–2.78 (m, 2 H), 2.31 (s, 3 H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 160.2, 149.7, 143.9, 136.7, 136.3, 135.7, 132.4, 129.5, 128.9, 127.2, 126.6, 125.1, 123.7, 121.8, 118.0, 114.9, 114.4, 113.5, 112.3, 111.2, 73.8, 65.4, 55.4, 39.7, 27.7, 21.4; HRMS (ESI): m/z [M+Na]⁺ calcd. for C₂₉H₂₄N₄NaO₃S⁺: 531.1461; found: 531.1458. Compound 3i: Purified by flash column chromatography (PE/EtOAc, 4:1); Yield: 28.0 mg (53%); yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.03 (d, J = 8.0 Hz, 1 H), 7.98 (s, 1 H), 7.92 (s, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.47–7.40 (m, 4 H), 7.42–7.40 (m, 2 H), 7.22 (t, J = 7.6 Hz, 2 H), 6.59 (s, 1 H), 6.40 (s, 1 H), 4.08–3.98 (m, 1 H), 3.87 (s, 3 H), 3.67 (s, 3 H), 3.43–3.33 (m, 1 H), 2.79–2.78 (m, 2 H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 150.3, 149.9, 148.8, 139.3, 136.6, 132.9, 132.5, 128.9, 127.3, 126.9, 126.6, 125.2, 123.8, 120.9, 118.1, 114.9, 114.8, 112.4, 111.3, 111.2, 109.5, 74.2, 65.5, 56.1, 56.0, 39.5, 26.5; HRMS (ESI): m/z [M+Na]⁺ calcd. for C₂₉H₂₄N₄NaO₄S⁺: 547.1410; found: 547.1411. Compound 3j: Purified by flash column chromatography (PE/EtOAc, 4:1); Yield: 32.9 mg (59%); yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.02 (d, J = 8.4 Hz, 1 H), 7.85 (s, 1 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.71 (d, J = 8.8 Hz, 1 H), 7.66–7.61 (m, 2 H), 7.57–7.43 (m, 7 H), 7.40 (t, J = 7.2 Hz, 1 H), 6.58 (s, 1 H), 6.36 (s, 1 H), 4.25 (dd, J = 13.7, 4.8 Hz, 1 H), 3.83 (s, 3 H), 3.62 (s, 3 H), 3.46 (td, J = 13.6, 4.2 Hz, 1 H), 2.98–2.77 (m, 2 H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 150.2, 149.1, 148.8, 136.8, 135.9, 134.6, 131.7, 131.7, 129.3, 129.2, 129.1, 127.9, 127.7, 127.4, 127.0, 126.9, 125.3, 123.7, 121.4, 121.4, 118.1, 114.8, 114.7, 112.0, 111.2, 109.3, 73.8, 65.3, 56.1, 56.0, 40.4, 27.5; HRMS (ESI): m/z [M+Na]⁺ calcd. for C₃₃H₂₆N₄NaO₄S⁺: 597.1567; found: 597.1561. Compound 3k: Purified by flash column chromatography (PE/EtOAc, 4:1); Yield: 35.4 mg (64%); yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.99–7.97 (m, 2 H), 7.93 (s, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.48 (t, J = 7.6 Hz, 1 H), 7.43–7.40 (m, 2 H), 7.34 (d, J = 8.4 Hz, 2 H), 7.16 (d, J = 8.4 Hz, 2 H), 6.62 (s, 1 H), 6.39 (s, 1 H), 4.05 (dd, J = 13.2, 5.2 Hz, 1 H), 3.89 (s, 3 H), 3.66 (s, 3 H), 3.44–3.36 (m, 1 H), 2.85–2.80 (m, 2 H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 150.4, 149.7, 148.9, 139.6, 137.7, 136.6, 132.1, 129.1, 128.0, 127.2, 126.7, 125.3, 123.9, 120.8, 118.2, 114.9, 114.7, 112.1, 111.3, 111.2, 109.5, 65.4, 56.1, 56.0, 39.8, 29.7, 26.7; HRMS (ESI): m/z [M+Na]⁺ calcd. for C₂₉H₂₃ClN₄NaO₄S⁺: 581.1021; found: 581.1023. Compound 3l: Purified by flash column chromatography (PE/EtOAc, 4:1); Yield: 14.6 mg (25%); yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.12 (s, 1 H), 8.01–7.99 (m, 2 H), 7.75 (d, J = 7.6 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 1 H), 7.42 (t, J = 7.6 Hz, 1 H), 7.36 (s, 1 H), 6.77 (s, 1 H), 6.42 (s, 1 H), 3.99 (dd, J = 14.0, 6.0 Hz, 1 H), 3.93 (s, 3 H), 3.69 (s, 3 H), 3.40 (td, J = 12.4, 4.4 Hz, 1 H), 3.25–3.16 (m, 1 H), 2.93 (dd, J = 12.8, 3.6 Hz, 1 H), 2.62 (s, 3 H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 150.5, 150.0, 148.9, 136.4, 132.8, 127.5, 127.0, 125.3, 124.0, 120.6, 118.4, 114.9, 114.7, 112.3, 111.5, 111.2, 109.8, 74.9, 65.3, 56.1, 56.1, 40.2, 38.9, 27.1; HRMS (ESI): m/z [M+Na]⁺ calcd. for C₂₄H₂₂N₄NaO₄S⁺: 485.1254; found: 485.1249. Compound 3m: Purified by flash column chromatography (PE/EtOAc, 4:1); Yield: 20.0 mg (42%); yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 8.17 (s, 1 H), 8.02 (s, 1 H), 7.96 (d, J = 8.4 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 1 H), 7.41 (t, J = 7.6 Hz, 1 H), 7.37 (s, 1 H), 6.76 (s, 1 H), 6.39 (s, 1 H), 3.98 (dd, J = 14.0, 6.0 Hz, 1 H), 3.93 (s, 3 H), 3.68 (s, 3 H), 3.47–3.40 (m, 1 H), 3.23–3.14 (m, 1 H), 2.92 (dd, J = 16.4, 2.8 Hz, 1 H), 2.72–2.55 (m, 2 H), 1.75–1.56 (m, 2 H), 0.82 (t, J = 7.2 Hz, 3 H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 150.4, 150.0, 148.9, 136.4, 132.8, 127.4, 127.1, 125.1, 123.9, 120.9, 118.4, 114.9, 114.8, 112.3, 111.4, 111.2, 109.7, 74.8, 65.1, 56.1, 56.0, 55.2, 39.4, 27.5, 16.9, 12.9; HRMS (ESI): m/z [M+Na]⁺ calcd. for C₂₆H₂₆N₄NaO₄S⁺: 513.1567; found: 513.1563. Compound 3n: Purified by flash column chromatography (PE/EtOAc, 4:1); Yield: 32.0 mg (66%); yellow solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.95 (s, 1 H), 7.85 (s, 1 H), 7.72 (s, 1 H), 7.58 (d, J = 4.8 Hz, 1 H), 7.56 (d, J = 4.4 Hz, 1 H), 7.50–7.42 (m, 2 H), 7.41–7.29 (m, 3 H), 7.24 (s, 1 H), 7.23–7.18 (m, 2 H), 7.13 (t, J = 7.6 Hz, 1 H), 7.04 (t, J = 7.6 Hz, 2 H), 6.96 (d, J = 8.4 Hz, 2 H), 6.51 (d, J = 7.6 Hz, 2 H), 5.03 (d, J = 17.0 Hz, 1 H), 4.79 (d, J = 17.0 Hz, 1 H), 4.12 (dd, J = 14.7, 5.8 Hz, 1 H), 3.53–3.39 (m, 1 H), 2.91 (dd, J = 16.2, 4.1 Hz, 1 H), 2.73 (dd, J = 11.9, 5.6 Hz, 1 H), 2.26 (s, 3 H); ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 149.8, 144.0, 138.2, 136.4, 136.0, 135.8, 129.5, 128.6, 127.7, 126.7, 126.0, 125.7, 125.3, 125.2, 124.2, 123.8, 120.4, 119.6, 118.1, 113.1, 112.1, 111.3, 109.7, 74.4, 61.6, 46.9, 39.9, 21.4, 20.2; HRMS (ESI): m/z [M+Na]⁺ calcd. for C₃₇H₂₉N₅NaO₂S⁺: 630.1934; found: 630.1943.