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

• References and Notes

• 1a Nicolaou KC, Koumbis AE, Snyder SA, Simonsen KB. Angew. Chem. Int. Ed. 2000; 39: 2529
• 1b Bliznets IV, Shorshnev SV, Aleksandrov GG, Stepanov AE, Lukyanov SM. Tetrahedron Lett. 2004; 45: 9127
• 1c Katritzky AR, Lagowski JM. Chemistry of the Heterocyclic N-Oxides . Academic Press; New York: 1971
• 2 Chung JY. L, Cvetovich RJ, McLaughlin M, Amato J, Tsay F.-R, Jensen M, Weissman S, Zewge DJ. J. Org. Chem. 2006; 71: 8602
• 3 Bernard H, Bülow G, Lange UE. W, Mack H, Pfeiffer T, Schafer B, Seitz W, Zierke T. Synthesis 2004; 2367
• 4 Campeau LC, Stuar DR, Leclerc JP, Bertrand-Laperle M, Villemure E, Sun HY, Lasserre S, Guimond N, Lecavallier M, Fagnou K. J. Am. Chem. Soc. 2009; 131: 3291
• 5a Kim KD, Lee JH. Org. Lett. 2018; 20: 7712
• 5b Fukui M, Tanaka A, Kominami H. Ind. Eng. Chem. Res. 2020; 59: 11412
• 6 Xu P, Xu HC. Synlett 2019; 30: 1219
• 7a Daniher FA, Hackley BE. J. Org. Chem. 1966; 31: 4267
• 7b Olah GA, Arvanaghi M, Vankar YD. Synthesis 1980; 660
• 7c Hayashi E, Ijima C. J. Pharm. Soc. Jpn. 1962; 82: 1093
• 8a Howard JE, Olszewski WF. J. Am. Chem. Soc. 1959; 81: 1483
• 8b Shirinian VZ, Lonshakov IA, Zakharov AV, Lvov AG, Krayushkin MM. Synthesis 2019; 414
• 8c Kaneko C, Yamamori M, Yamamoto A, Hayashi R. Tetrahedron Lett. 1978; 19: 2799
• 9a Kokatla HP, Thomson PF, Bae S, Doddi VR, Lakshman MK. J. Org. Chem. 2011; 76: 7842
• 9b Gowda NB, Rao GK, Ramakrishna RA. Tetrahedron Lett. 2010; 51: 5690
• 9c Ram SR, Chary KP, Iyengar DS. Synth. Commun. 2000; 30: 3511
• 10a Kim J, Kim S, Kim D, Chang S. J. Org. Chem. 2019; 84: 13150
• 10b Jeong J, Lee D, Chang S. Chem. Commun. 2015; 51: 7035
• 10c Donck S, Gravel E, Shah N, Jawale DV, Doris E, Namboothiri IN. RSC Adv. 2015; 5: 50865
• 10d Park ES, Lee SH, Lee JH, Rhee HJ, Yoon CM. Synthesis 2005; 3499
• 10e Saini A, Kumar S, Sandhu JS. Synlett 2006; 395
• 10f Fuentes JA, Clarke ML. Synlett 2008; 2579
• 11a Gupta S, Sureshbabu P, Singh AK, Sabiah SJ. Tetrahedron Lett. 2017; 58: 909
• 11b Yadav JS, Subba Reddy BV, Muralidhar Reddy M. Tetrahedron Lett. 2000; 41: 2663
• 11c Bjørsvik H.-R, Gambarotti C, Jensen VR, Rodríguez González R. J. Org. Chem. 2005; 70: 3218
• 11d Vorbrüggen H, Krolikiewicz K. Tetrahedron Lett. 1983; 24: 5337
• 11e Subbarao KP. V, Reddy GR, Muralikrishna A, Reddy KV. J. Heterocycl. Chem. 2014; 51: 1045
• 11f Zhao X, Fan W, Miao Z, Chen R. Synth. Commun. 2013; 43: 1714
• 12 Movassaghi M, Hill MD. Org. Lett. 2008; 10: 3485
• 13a Deng C, Lam WH, Lin Z. Organometallics 2017; 36: 650
• 13b Hughes G, Bryce MR. J. Mater. Chem. 2005; 15: 94
• 13c Solomon VR, Lee H. Curr. Med. Chem. 2011; 18: 1488
• 13d Kimyonok A, Wang XY, Weck M. J. Macromol. Sci., Polym. Rev. 2006; 46: 47
• 13e Thurston D, Rotella D, Martinez A. Privileged Scaffolds in Medicinal Chemistry. Design, Synthesis, Evaluation . Bräse S. Royal Society of Chemistry; London: 2016
• 13f Araujo DR, Goulart HA, Barcellos AM, Cargnelutti R, Lenardão EJ, Perin G. J. Org. Chem. 2021; 86: 1721
• 13g Gujjarappa R, Vodnala N, Malakar CC. Adv. Synth. Catal. 2020; 362: 4896
• 14a Nikbakht A, Balalaie S, Breit B. Org. Lett. 2019; 21: 7645
• 14b Hayatgheybi S, Khosravi H, Zahedian Tejeneki H, Rominger F, Bijanzadeh HR, Balalaie S. Org. Lett. 2021; 23: 3524
• 15a McKee ML, Wine PH. J. Am. Chem. Soc. 2001; 123: 2344
• 15b Murrells TP, Lovejoy ER, Ravishankara AR. J. Phys. Chem. 1990; 94: 2381
• 15c Zeng Z, Altarawneh M, Dlugogorski BZ. Chem. Phys. Lett. 2017; 669: 43
• 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.