Efficient Synthesis of Isoquinoline Derivatives through Sequential Cyclization–Deoxygenation Reaction of 2-Alkynylbenzaldoximes

Dedicated to Professor Issa Yavari for his outstanding contributions to Chemistry in Iran

Abstract

We describe a novel, simple, robust, and efficient cyclization/deoxygenation approach for the synthesis of functionalized isoquinoline derivatives. Over the course of continued studies on o-alkynylbenzaldoxime cyclization reactions, the formation of cyclic nitrones through 6-endo-dig cyclization was achieved using silver triflate or bromine as an electrophile, and subsequently, the deoxygenation process was carried out in the presence of CS₂ in good to high yields.

Key words

2-alkynylbenzaldoxime - cyclization/deoxygenation - isoquinoline - silver triflate - bromine - carbon disulfide

Publication History

Received: 14 November 2021

Accepted after revision: 30 November 2021

Article published online:
13 January 2022

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• 16 General Procedure for the Synthesis of 2-Alkynylbenzaldoximes 1a–i2-Alkynylbenzaldehyde (2.0 mmol) (synthesized following previously reported procedures¹⁴), hydroxylamine hydrochloride (3 mmol, 1.5 equiv), sodium acetate (4.0 mmol, 2.0 equiv), and CH₃CN (10 mL) were added sequentially into a 25 mL flask and the mixture stirred at room temperature for 12 h (monitored by TLC). After completion of reaction, the solvent was evaporated to afford the crude product. Finally, the pure corresponding 2-alkynylbenzaldoximes 1a–i were obtained by flash chromatography (silica gel, eluent: n-hexane/EtOAc, 4:1).
• 17 General Procedure for the Synthesis of Isoquinolines 2a–i in the Presence of AgOTf and CS₂ To a solution of 2-alkynylbenzaldoximes (0.2 mmol) in DMF (2 mL) was added AgOTf (10 mol%), and the mixture was stirred at 60 ℃ in an oil bath for 30 min, leading to the isoquinolines N-oxide (monitored by TLC). Then CS₂ (1.2 equiv) was added, and the reaction mixture was stirred at 60 ℃ for 6 h. Upon completion of the reaction (as indicated by TLC), the reaction mixture was extracted with H₂O (10 mL) and EtOAc (3 × 10 mL). The combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified using column chromatography (silica gel, eluent: n-hexane/EtOAc, 5:1) to afford the corresponding isoquinolines 2a–i (70–95%). 3-Phenylisoquinoline (2a) Yellow solid (39 mg, yield 95%, mp 48–49 °C), R_f = 0.35 (n-hexane/EtOAc, 5:1). ¹H NMR (300 MHz, CDCl₃): δ = 9.35 (s, 1 H, H-1 isoquinoline), 8.15 (d, J = 7.2 Hz, 2 H, HAr), 8.06 (s, 1 H, HAr), 7.98 (d, J = 8.0 Hz, 1 H, HAr), 7.86 (d, J = 8.0 Hz, 1 H, HAr), 7.68 (t, J = 7.2 Hz, 1 H, HAr), 7.57 (t, J = 7.3 Hz, 1 H, HAr), 7.53 (t, J = 7.3 Hz, 2 H, HAr), 7.43 (t, J = 7.3 Hz, 1 H, HAr). ¹³C {¹H} NMR (75 MHz, CDCl₃): δ = 152.4, 151.2, 139.6, 136.6, 130.5, 128.8, 128.5, 127.7, 127.5, 127.1, 127.0, 126.9, 116.5. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₅H₁₂N: 206.0957; found: 206.0961.
• 18 General Procedure for the Synthesis of 4-Bromo-3-aryl(alkyl)isoquinolines 3a–g Using Br₂and CS₂ A mixture of 2-alkynylbenzaldoxime (0.2 mmol), NaHCO₃ (1.2 equiv), and Br₂ (1.2 equiv) in DMF (2 mL) was stirred at room temperature for 30 min. After preparation of the 4-bromo-3- aryl(alkyl)isoquinoline N-oxide (monitored by TLC), CS₂ (1.2 equiv) was added, and the reaction mixture was allowed to stir at 60 ℃ until the reaction was complete (TLC monitoring, about 3.5 h). The crude mixture was extracted with H₂O (10 mL) and EtOAc (3 × 10 mL), and the combined organic extracts were dried over anhydrous Na₂SO₄, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, eluent: n-hexane/EtOAc, 5:1) to give the corresponding 4-bromo-3-aryl(alkyl)isoquinoline 3a–g (65–89%). 4-Bromo-3-phenylisoquinoline (3a) Brown solid (50 mg, yield 89%, mp 47 °C); R_f = 0.30 (n-hexane/EtOAc, 5:1). 1H NMR (300 MHz, CDCl₃): δ = 9.25 (s, 1 H, H-1 isoquinoline), 8.35 (d, J = 8.6 Hz, 1 H, HAr), 8.02 (d, J = 8.1 Hz, 1 H, HAr), 7.75 (d, J = 6.4 Hz, 1 H, HAr), 7.56–7.48 (m, 3 H, HAr), 7.39–7.32 (m, 3 H, HAr). ¹³C{¹H}NMR (75 MHz, CDCl₃): δ = 151.1, 148.8, 132.5, 132.0, 131.6, 129.9, 129.5, 128.7, 128.4, 128.0, 127.0, 125.2, 118.4. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₅H₁₁ ⁷⁹BrN: 284.0738; found: 284.0741.