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DOI: 10.1055/s-0040-1719870
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.
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Key words
2-alkynylbenzaldoxime - cyclization/deoxygenation - isoquinoline - silver triflate - bromine - carbon disulfideIn recent years, oxygen-atom-transfer reactions of heteroaromatic N-oxides have received much attention in modern chemistry due to their great potential in the synthesis of natural products, bioactive molecules, and applications in industrial processes.[1] As illustrated in Figure [1], deoxygenation of heteroaromatic N-oxides is the key step for the synthesis of a number of bioactive molecules such as p38 MAP kinase,[2] thrombin,[3] tyrosine kinase, and sodium channel[4] inhibitors.
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Various procedures and conditions have been reported for the reduction of N-heteroarene N-oxides such as photocatalytic reactions,[5] electrochemical reactions,[6] sulfur sources,[7] trivalent phosphorus compounds,[8] hydride reagents,[9] and metal-catalyzed[10] reactions. Nevertheless, some of these processes have serious disadvantages such as utilizing expensive and complex metal catalysts and reagents, high reaction temperature, low yields, harsh reaction conditions, extended reaction times, and difficult workup.[11]
Due to the importance and broad application of the isoquinoline moiety in medicinal chemistry and materials science, numerous approaches such as the Bischler–Napieralski reaction[12] for the synthesis of substituted isoquinolones have been described and deoxygenation of isoquinoline N-oxides is an efficient way to achieve this core.[11e] On the other hand, the intramolecular annulation reaction of 2-alkynylbenzaldoximes with two active sites, which can be obtained by simple condensation of o-alkynylbenzaldehydes with hydroxylamine, is one of the most common methods among various strategies to access isoquinoline N-oxides (Scheme [1]).[13]
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As part of our ongoing studies on the synthesis of functionalized 2-alkynylbenzaldoximes and their applications in a variety of tandem reactions,[14] we wish to report a novel and efficient method for the synthesis of isoquinolines via deoxygenation of in situ generated isoquinoline N-oxide using carbon disulfide as a reductant under mild reaction conditions (Scheme [2]).
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Initially, we investigated the cyclization–deoxygenation reactions of o-(phenylethynyl)benzaldoxime (1a) as a model substrate in the presence of a catalytic amount of AgNO3 and CS2 in DMF at 40 °C, which afforded the desired product 2a in 33% isolated yield (Table [1], entry 1). Subsequently, the influence of the various transition-metal catalysts on the cyclization reaction such as AgOTf, PPh3AuCl, In(OTf)3, and CuBr was screened, in which AgOTf (10 mol%) indicated the best catalytic activity (Table [1], entries 1–5). Then, solvent screening showed DMF to be the best choice (Table [1], entries 5–7). Next, several reaction temperatures were examied and showed that temperature had a significant effect on reaction yield (Table [1], entries 5 and 8–11) with a temperature of 60 °C giving the best results. Increasing the temperature up to 100 °C led to a slight decrease in the yield of the desired product. Screening of different amounts of carbon disulfide revealed that the 1.2 equivalents of CS2 gave the best result (Table [1], entries 9 and 12–14).
a Reaction conditions: 1a (0.2 mmol), CS2 (1.2 equiv), AgOTf (10 mol%), solvent (2 mL) for 6 h.
b Isolated yields.
With optimal reaction conditions in hand, the scope of the reaction was surveyed. To expand the diversity of the starting materials, a wide range of o-alkynylbenzaldoxime derivatives containing electron-withdrawing, electron-donating, and halogen groups substituted on the phenyl ring, as well as aliphatic and aromatic alkynes was synthesized in excellent yields. Subsequently, under optimized reaction conditions, the annulation–deoxygenation reaction of various substituted o-alkynylbenzaldoximes was examined and afforded the corresponding substituted isoquinolines in good to high yields. The observed results are shown in Scheme [3], and all structures were confirmed by 1H and 13C NMR and HRMS spectral analysis (see the Supporting Information).
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In the second part of the work, activation of the alkyne moiety in the 2-alkynylbenzaldoxime skeleton was investigated employing Br2 instead of a transition-metal catalyst, and subsequent deoxygenation of isoquinoline N-oxides was carried out in the presence of the carbon disulfide. After some screening and trials, the best results were obtained using Br2 (1.2 equiv) and NaHCO3 (1.2 equiv) in DMF at room temperature and carbon disulfide (1.2 equiv) in DMF at 60 °C.
The generality of the approach to produce the 4-bromo-3-alkylisoquinoline derivatives was studied under these optimum reaction conditions. As illustrated in Scheme [4, a] wide range of substituted 4-bromo-3-alkylisoquinolines bearing electron-donating and electron-withdrawing groups was synthesized in good to high yields.
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According to the literature,[15] the proposed reaction mechanism is as depicted in Scheme [5]. In the presence of an electrophile, 6-endo-dig cyclization of the 2-alkynylbenzaldoxime by π-activation of alkyne moiety leads to the formation of the isoquinoline-N-oxides I. Then, [3+2] dipolar cycloaddition of the isoquinoline N-oxide with CS2 results in intermediate II. By homolytic cleavage of N–O and C–S bonds, the desired isoquinoline is obtained with COS and S as byproducts, according to the literature.
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To confirm the radical pathway, the deoxygenation reaction was examined by adding the TEMPO as a radical scavenger and neither of the products was obtained. These results demonstrate the reaction does proceed through radical deoxygenation (Scheme [6]).
![](https://www.thieme-connect.de/media/10.1055-s-00032269/202201/thumbnails/i_d0057_s6_10-1055_s-0040-1719870.gif)
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In conclusion, we have opened a novel class of cyclization–deoxygenation reactions through the introduction of a CS2 as an efficient reagent for the synthesis of isoquinoline derivatives using 2-alkynylbenzaldoximes.[16] [17] [18] Furthermore, in comparison to existing approaches in the literature, the use of cheap, commercially available carbon disulfide under mild reaction conditions are some advantages of this reported work.
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Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0040-1719870.
- Supporting Information
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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), 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 3a–g (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.
Corresponding Author
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
- 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), 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 3a–g (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.
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