CC BY-NC-ND 4.0 · SynOpen 2022; 06(01): 11-15
DOI: 10.1055/s-0040-1719870
letter
Virtual Collection in Honor of Prof. Issa Yavari

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

Mojtaba Ayoubi
a   Peptide Chemistry Research Institute , K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran
,
Ali Nikbakht
a   Peptide Chemistry Research Institute , K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran
,
Kamran Amiri
a   Peptide Chemistry Research Institute , K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran
,
a   Peptide Chemistry Research Institute , K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran
,
a   Peptide Chemistry Research Institute , K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran
,
a   Peptide Chemistry Research Institute , K. N. Toosi University of Technology, P. O. Box 15875-4416, Tehran, Iran
b   Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
› Author Affiliations
We thank the Alexander von Humboldt Foundation for the Linkage Research Group Program and K. N. Toosi University of Technology Research Affairs for support.


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.

Supporting Information



Publication History

Received: 14 November 2021

Accepted after revision: 30 November 2021

Article published online:
13 January 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • References and Notes

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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 1ai 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 2ai (70–95%). 3-Phenylisoquinoline (2a) Yellow solid (39 mg, yield 95%, mp 48–49 °C), Rf = 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 3ag (65–89%). 4-Bromo-3-phenylisoquinoline (3a) Brown solid (50 mg, yield 89%, mp 47 °C); Rf = 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.