A Concise Synthesis of Isocryptolepine by C–C Cross-Coupling Followed by a Tandem C–H Activation and C–N Bond Formation

Abstract

Isocryptolepine (1), a potent antimalarial natural product, was prepared in three steps from 3-bromoquinoline and 2-aminophenylboronic acid hydrochloride. The key transformations were a Suzuki–Miyaura cross-coupling reaction followed by a palladium-initiated intramolecular C–H activation/C–N bond formation between an unprotected amine and an aromatic C–H group. The two key reactions can also be performed in one pot.

Key words

C–H activation - C–N bond formation - isocryptolepine - one-pot reaction - Suzuki–Miyaura cross-coupling

• References and Notes

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• 18 (Quinolin-3-yl)aniline (6): 3-Bromoquinoline (4; 0.39 mL, 2.9 mmol), 2-aminophenylboronic acid hydrochloride (5; 500 mg, 2.9 mmol) and potassium carbonate (1.195 g, 8.6 mmol) were dissolved in EtOH–H₂O (5:1, 1.2 mL) under a nitrogen atmosphere. PdCl₂(dppf) (105 mg, 0.14 mmol) was added and the reaction mixture was stirred at 60 °C overnight. The reaction mixture was then allowed to cool to ambient temperature and the volatiles were removed under reduced pressure. Purification of the concentrate by silica gel column chromatography (PE–EtOAc, 1:1 v/v) gave compound 6 (R _f = 0.16 (PE–EtOAc 75:25 v/v)) as a pale-yellow solid (507 mg, 80%); mp 130–132 °C (lit. ref. 25 119–120 °C). IR (NaCl): 3438, 3331, 3208, 3061, 1619, 1575, 1497, 1452 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.04 (d, J = 2.2 Hz, 1 H,), 8.27 (d, J = 2.1 Hz, 1 H), 8.16 (d, J = 8.5 Hz, 1 H), 7.86 (d, J = 8.1 Hz, 1 H), 7.75 (ddd, J = 1.4, 6.9, 8.4 Hz, 1 H), 7.61–7.57 (m, 1 H), 7.26–7.22 (m, 2 H), 6.91 (dt, J = 1.0, 7.5 Hz, 1 H), 6.84 (d, J = 7.9 Hz, 1 H), 3.79 (br s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 151.4, 147.1, 143.9, 135.3, 132.3, 130.7, 129.4, 129.3, 129.2, 127.8, 127.7, 126.9.123.6, 119.0, 115.8 (in agreement with NMR data reported in ref. 26). HRMS (ESI): m/z [M + H⁺] calcd. for C₁₅H₁₃N₂ ⁺: 221.1079; found: 221.1073.
• 19 H-Indolo[3,2-c]quinolone (7): 2-(Quinolin-3-yl)aniline (6; 60 mg, 0.27 mmol) was dissolved in acetic acid (1 mL) and added to a premixed solution of PdCl₂(dppf) (40 mg, 0.054 mmol), IMes (4.1 mg, 0.013 mmol), H₂O₂ (35 wt%, 0.065 mL, 0.08 mmol) and acetic acid (2 mL). The reaction mixture was introduced into a sealed reactor tube, which was placed in the cavity of a microwave oven for 10 min at 118 °C. The reaction mixture was then transferred to a 25 mL round-bottom flask with the aid of EtOAc and the volatiles were removed under reduced pressure. The resulting crude product was then purified by silica gel column chromatography (CH₂Cl₂–EtOAc, 8:2 → 6:4 v/v) to give compound 7 [R _f = 0.25 (CH₂Cl₂–EtOAc, 1:1 v/v)] as an off-white solid (37 mg, 62% ) along with recovered starting material 6 (9 mg, 15%).
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• 24 H-Indolo[3,2-c]quinolone (7) one-pot reaction:3-Bromoquinoline (4; 0.04 mL, 0.28 mmol), 2-aminophenylboronic acid hydrochloride (5; 50 mg, 0.28 mmol), potassium carbonate (119 mg, 0.86 mmol) and PdCl₂(dppf) (20.4 mg, 0.028 mmol) were dissolved in EtOH–H₂O (5:1, 1.2 mL). The reaction mixture was introduced into in a sealed reactor tube, which was placed in the cavity of a microwave oven for 4 h at 60 °C. Formation of 2-(quinolin-3-yl)aniline (6) was monitored by TLC. This was then followed by addition of acetic acid (4 mL), PdCl₂(dppf) (20.4 mg, 0.028 mmol), IMes (4.3 mg, 0.014 mmol), and H₂O₂ (35 wt%, 0.065 mL, 0.08 mmol). The reaction mixture was introduced into a sealed reactor tube, which was placed in the cavity of a microwave oven for 18 min at 118 °C. The crude reaction mixture was then transferred to a 25 mL round-bottom flask with the aid of EtOAc and the volatiles were removed under reduced pressure. The resulting crude mixture was purified by silica gel column chromatography (CH₂Cl₂–EtOAc 8:2 → 6:4 v/v) to give compound 7 [R _f = 0.25 (CH₂Cl₂–EtOAc, 1:1 v/v)] as an off-white solid (19 mg, 32% ) along with compound 6 (30 mg, 48%). Mp 340–341 °C (lit. ref. 20 333–334 °C). IR (NaCl): 3060, 2958, 2854, 1682, 1582, 1515, 1493 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.71 (br s, 1 H), 9.59 (s, 1 H), 8.52 (dd, J = 1.1, 7.9 Hz, 1 H), 8.32 (d, J = 7.9 Hz, 1 H), 8.13 (dd, J = 1.1, 8.0 Hz, 1 H), 7.77–7.67 (m, 3 H), 7.52–7.48 (m, 1 H), 7.36–7.33 (m, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 145.4, 144.8, 139.7, 138.7, 129.4, 128.0, 125.7, 125.5, 122.1, 121.8, 120.6, 120.1, 117.1, 114.3, 111.8 (in agreement with NMR data reported in ref. 10a). HRMS (ESI); m/z [M + H⁺] calcd. for C₁₅H₁₁N₂ ⁺: 219.0922; found: 219.0925.
• 25 Isocryptolepine (1): Compound 7 (70 mg, 0.32 mmol) was treated with methyl iodide (4.0 mL, 0.064 mol) in refluxing toluene (8 mL) for 3 h (see ref. 20). The volatiles were then removed under reduced pressure and the concentrate was purified by silica column chromatography (CHCl₃–MeOH, 19:1 → 18:2 v/v) to give the hydroiodide salt of isocryptolepine. To obtain isocryptolepine as the free base, its hydroiodide salt was dissolved in CH₂Cl₂ (30 mL), aqueous ammonia (25%, 20 mL) was added, and the reaction mixture was stirred at ambient temperature for 10 min. The organic layer was separated and the aqueous layer was extracted with CH₂Cl₂ (2 × 10 mL). The combined organic layers were washed with brine, dried (MgSO₄), filtered and concentrated in vacuo to give isocryptolepine (1) [R _f = 0.23 (CH₂Cl₂–MeOH, 90:10 v/v)] as a yellow solid (56 mg, 76%); mp 185–187 °C (lit. ref. 18 191–193 °C). IR (NaCl): 3047, 2922, 2852, 1637, 1596, 1486, 1451 cm^–1. ¹H NMR (400 MHz, DMSO-d₆): δ = 9.40 (s, 1 H), 8.77 (dd, J = 1.4, 8.1 Hz, 1 H), 8.13–8.11 (m, 1 H), 8.04 (d, J= 8.5 Hz, 1 H), 7.83 (ddd, J = 1.6, 7.1, 8.7 Hz, 1 H), 7.80–7.78 (m, 1 H), 7.72–7.68 (m, 1 H), 7.42 (ddd, J = 1.2, 7.1, 8.2 Hz, 1 H), 7.25–7.21 (m, 1 H), 4.26 (s, 3 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 155.1, 153.1, 138.7, 136.0, 129.7, 126.2, 125.9, 125.6, 124.4, 121.6, 120.2, 120.0, 118.9, 118.0, 116.7, 42.6 (in agreement with NMR data reported in ref. 18). HRMS (ESI): m/z [M + H⁺] calcd. for C₁₆H₁₃N₂ ⁺: 233.1079; found: 233.1080.
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