Gold(I)-Catalyzed Hydroamination as a General Approach toward the Synthesis of Substituted Hydroisoquinolines: Remarkable Acceleration by Ethanol

Abstract

Construction of 1,2-dihydroisoquinolines and 1-alkylidenyl-1,2,3,4-tetrahydroisoquinolines through cationic gold(I) complex catalyzed hydroamination of the corresponding alkynyl carbamates has been demonstrated. In the presence of EtOH, the reaction proceeded smoothly at room temperature with low catalyst loading (1-3 mol%).

Key words

hydroamination - isoquinolines - catalysis - hetero­cycles - cyclizations

References and Notes

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4

For examples of 1,2-dihydroisoquinoline syntheses, see references cited in ref 2.

10

The corresponding 5-exo cyclized products, namely isoindoles, were not detected in this work, presumably due to their instability.

11

Structure of 2a was fully confirmed by spectroscopy and by its conversion into known 3-phenylisoquinoline; from 1a,
3-phenylisoquinoline was obtained in 70% yield after cleavage of Boc group (TFA, CH₂Cl₂, r.t., 30 min) followed by oxidation (I₂, KOAc, EtOH, reflux, 1 h).

19

Typical Procedure for the Gold(I)-Catalyzed Hydroamination: To a solution of 1a (309 mg, 1.00 mmol) in DCE (2 mL) were added EtOH (231 mg, 293 µL, 5.02 mmol) and a suspension of AuCl(PPh₃) (4.9 mg, 0.0099 mmol) and AgNTf₂ (3.8 mg, 0.0098 mmol) in DCE (1 mL) at r.t. After stirring for 2 h, sat. aq NaHCO₃ was added and the product was extracted with CHCl₃ (3 × 10 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane-EtOAc, 25:1) to afford 2a (256 mg, 83%) as colorless crystals: R _f 0.70 (hexane-EtOAc, 3:1); mp 105-106 °C. ¹H NMR (500 MHz, CDCl₃, TMS): δ = 7.48 (d, J = 7.3 Hz, 2 H), 7.36 (dd, J ₁ = 7.1 Hz, J ₂ = 7.3 Hz, 2 H), 7.30 (t, J = 7.1 Hz, 1 H), 7.18-7.27 (m, 4 H), 6.42 (s, 1 H), 4.89 (s, 2 H), 1.05 (s, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 153.0, 140.6, 139.0, 132.7, 132.0, 128.1, 127.7, 127.5, 127.2, 126.3, 125.1, 125.0, 115.2, 81.0, 47.5, 27.6. IR (CHCl₃): 1693
cm^-1. MS (FAB): m/z = 307 [M⁺]. Anal. Calcd for C₂₀H₂₁NO₂: C, 78.15; H, 6.89; 4.56. Found: C, 78.23; H, 7.07; N, 4.48.
Compound 2e: colorless crystals; R _f 0.55 (hexane-EtOAc, 6:1); mp 168-169 °C. ¹H NMR (500 MHz, CDCl₃, TMS): δ = 7.16-7.26 (m, 4 H), 7.09 (s, 2 H), 6.94 (s, 1 H), 6.41 (s, 1 H), 4.87 (s, 2 H), 2.33 (s, 6 H), 1.06 (s, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 153.0, 140.8, 138.7, 137.5, 132.7, 131.9, 129.3, 127.5, 127.0, 125.0, 124.9, 124.1, 114.6, 80.8, 47.5, 27.6, 21.2. IR (CHCl₃): 1691 cm^-1. MS (FAB): m/z = 335 [M⁺]. Anal. Calcd for C₂₂H₂₅NO₂: C, 78.77; H, 7.51; N, 4.18. Found: C, 78.66; H, 7.50; N, 4.23.
Compound 2h: white powder; R _f 0.50 (hexane-EtOAc, 1:1); mp 115-116 °C. ¹H NMR (500 MHz, CDCl₃, TMS): δ = 7.46 (d, J = 8.2 Hz, 2 H), 7.34 (d, J = 8.2 Hz, 2 H), 7.15-7.26 (m, 4 H), 6.42 (s, 1 H), 4.85 (s, 2 H), 4.68 (s, 2 H), 2.58 (s, 1 H), 1.06 (s, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 152.9, 140.6, 140.2, 137.9, 132.5, 131.8, 127.5, 127.2, 126.6, 126.2, 125.0, 124.9, 115.2, 81.0, 64.7, 47.4, 27.6.
IR (CHCl₃): 3606, 1693 cm^-1. MS (FAB): m/z = 337 [M⁺]. Anal. Calcd for C₂₁H₂₃NO₃: C, 74.75; H, 6.87; N, 4.15. Found: C, 74.47; H, 6.87; N, 3.88.
Compound 4a: colorless needles: R _f 0.38 (hexane-EtOAc, 2:1); mp 164-165 °C. ¹H NMR (500 MHz, CDCl₃, TMS): δ = 7.47 (d, J = 7.6 Hz, 2 H), 7.32 (dd, J ₁ = J ₂ = 7.6 Hz, 2 H), 7.21 (s, 1 H), 7.19 (t, J = 7.6 Hz, 1 H), 6.74 (s, 1 H), 6.61 (s, 1 H), 4.60 (br, 1 H), 3.97 (s, 3 H), 3.89 (s, 3 H), 3.27 (br, 1 H), 3.13 (br, 1 H), 2.66 (br, 1 H), 1.02 (s, 9 H). ¹³C NMR (126 MHz, CDCl₃): δ = 153.3, 149.3, 147.7, 137.2, 134.0, 128.4, 128.3, 128.0, 126.8, 125.4, 117.6, 111.7, 106.4, 80.3, 56.2, 55.9, 43.0, 28.5, 27.7. IR (CHCl₃): 1682 cm^-1.
MS (FAB): m/z = 381 [M⁺]. Anal. Calcd for C₂₃H₂₇NO₄: C, 72.42; H, 7.13; N, 3.67. Found: C, 72.38; H, 7.08; N, 3.47.
Compound 4c: colorless crystals; R _f 0.38 (hexane-EtOAc, 2:1); mp 146-147 °C. ¹H NMR (500 MHz, CDCl₃, TMS):
δ = 7.46 (s, 1 H), 7.36 (d, J = 7.8 Hz, 1 H), 7.24 (dd, J ₁ = J ₂ = 7.8 Hz, 1 H), 7.18 (s, 1 H), 7.17 (d, J = 7.8 Hz, 1 H), 6.68 (s, 1 H), 6.61 (s, 1 H), 4.59 (br, 1 H), 3.96 (s, 3 H), 3.89 (s, 3 H), 3.26 (br, 1 H), 3.12 (br, 1 H), 2.66 (br, 1 H), 1.07 (s, 9 H). ¹³C NMR (126 MHz, CDCl₃): d = 153.0, 149.5, 147.7, 139.1, 135.3, 134.2, 129.5, 128.3, 128.2, 126.7, 126.3, 125.0, 116.0, 111.7, 106.4, 80.6, 56.2, 55.9, 43.1, 28.3, 27.8.
IR (CHCl₃): 1685 cm^-1. MS (FAB): m/z = 415 [M⁺]. Anal. Calcd for C₂₃H₂₆ClNO₄: C, 66.42; H, 6.30; N, 3.37. Found: C, 66.38; H, 6.32; N, 3.35.