CC BY ND NC 4.0 · SynOpen 2017; 01(01): 0041-0044
DOI: 10.1055/s-0036-1590807
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A Concise Synthesis of Isocryptolepine by C–C Cross-Coupling Followed by a Tandem C–H Activation and C–N Bond Formation

Ida T. Urdal Helgeland, Magne O. Sydnes*
  • Faculty of Science and Technology, Department of Mathematics and Natural Science, University of Stavanger, 4036 Stavanger, Norway   Email: magne.o.sydnes@uis.no
The University of Stavanger Toppforsk program and the research program Bioactive is acknowledged for financial support of the study.
Further Information

Publication History

Received: 02 June 2017

Accepted: 06 June 2017

Publication Date:
27 June 2017 (online)

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.

Supporting Information

 
  • 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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