Synlett, Inhaltsverzeichnis Synlett 2025; 36(08): 1079-1085DOI: 10.1055/a-2460-8054 letter TfOH-Catalyzed Synthesis of Bis(pyrrolo[2,1-a]isoquinolinyl) methanes Jing Zhou , Xue Sheng , Yu-Yi Pan , Hai-Lei Cui ∗ Artikel empfehlen Abstract Artikel einzeln kaufen Alle Artikel dieser Rubrik Abstract The synthesis of bis(pyrrolo[2,1-a]isoquinolinyl)methanes was achieved through TfOH-catalyzed sequential Friedel–Crafts alkylation of pyrrolo[2,1-a]isoquinoline and aldehyde. A series of highly functionalized bis(pyrrolo[2,1-a]isoquinolinyl)methane derivatives can be obtained in acceptable to excellent yields (11 examples, up to 96% yield). Interestingly, deformylation was observed when treating pyrrolo[2,1-a]isoquinoline-derived aldehyde and indole under the current reaction conditions. Furthermore, the replacement of aldehyde with isatin resulted in the formation of methylene-bridged dimeric pyrrolo[2,1-a]isoquinoline. Key word Key wordaldehyde - bis(pyrrolo[2,1-a]isoquinolinyl)methane - deformylation - pyrrolo[2,1-a]isoquinoline - TfOH Volltext Referenzen References and Notes 1 Present address: Guangdong Sanvochemical Industry Technology Co., Ltd., Zhongshan, Guangdong 528429, P. R. of China. 2a Song S, Li X, Wei J, Wang W, Zhang Y, Ai L, Zhu Y, Shi X, Zhang X, Jiao N. Nat. Catal. 2020; 3: 107 2b Mondal H, Patra S, Saha S, Nayak T, Sengupta U, Maji MS. Angew. Chem. Int. Ed. 2023; 62: e202312597 2c Cui H.-L. Recent Progress in the Modification of Heterocycles Based on the Transformation of DMSO. In Targets in Heterocyclic Systems – Chemistry and Properties, Vol. 26. Attanasi OA, Gabriele B, Spinelli D. Societa Chimica Italiana; Roma: 2022: 222-248 3a Pindur U, Lemster T. Curr. Med. Chem. 2001; 8: 1681 3b Kochanowska-Karamyan AJ, Hamann MT. Chem. Rev. 2010; 110: 4489 4 Shiri M, Zolfigol MA, Kruger HG, Tanbakouchian Z. Chem. Rev. 2010; 110: 2250 5a Veluri V, Oka I, Wagner-Döbler I, Laatsch H. J. Nat. 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Chem. 2006; 71: 5482 23 General Procedure for the Synthesis of Compounds 3 To a stirring solution of pyrrolo[2,1-a]isoquinoline 1 (0.2 mmol, 1.0 equiv) and aldehyde 2 (0.5 mmol, 2.5 equiv) in DMF (0.2 M, 0.5 mL), TfOH (4.4 μL, 0.05 mmol, 25 mol%) was added. The resulting reaction mixture was stirred at 150 °C (oil bath) under an air atmosphere for the indicated times shown in Schemes 2 and 3 (monitored by thin-layer chromatography). Then, the mixture was cooled to rt, diluted with DCM (2 mL), washed with water (2 × 2 mL). The organic phase was concentrated, and the residue was purified directly by the silica gel flash chromatography (hexane/EtOAc) to afford compound 3. Analytical Data for Typical CompoundsCompound 3a White solid, 66.3 mg, 96% (using 50 mol% of TfOH); purified by a silica gel flash chromatography (hexane/EtOAc, 97:3). 1H NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 7.7 Hz, 2 H), 7.68 (s, 1 H), 7.56–7.38 (m, 14 H), 7.32–7.21 (m, 5 H), 7.19–7.13 (m, 2 H), 7.10 (ddd, J = 8.4, 7.1, 1.4 Hz, 2 H), 6.72 (d, J = 7.7 Hz, 2 H), 3.26 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.7, 138.1, 136.6, 130.8, 130.4, 128.6, 128.6, 128.4, 127.4, 127.2, 127.1, 126.8, 126.5, 126.0, 125.6, 125.1, 122.9, 122.7, 118.9, 118.4, 112.9, 51.3, 39.9. HRMS (ESI): m/z [M + Na]+ calcd for C47H34N2NaO4 +: 713.2411; found: 713.2419. Compound 3b White solid, 19.9 mg, 28%; purified by a silica gel flash chromatography (hexane/EtOAc, 97:3). 1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 7.6 Hz, 2 H), 7.63 (s, 1 H), 7.46 (ddd, J = 24.7, 10.3, 6.2 Hz, 14 H), 7.30–7.21 (m, 2 H), 7.13–7.02 (m, 6 H), 6.72 (d, J = 7.7 Hz, 2 H), 3.27 (s, 6 H), 2.32 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 166.7, 136.7, 135.0, 130.8, 130.4, 129.3, 128.5, 128.4, 127.4, 127.2, 127.1, 126.8, 126.6, 125.9, 125.5, 125.3, 122.9, 122.7, 118.9, 118.4, 112.8, 51.3, 39.5, 21.0. HRMS (ESI): m/z [M + Na]+ calcd for C48H36N2NaO4 +: 727.2567; found: 727.2560. Compound 3c Pale yellow solid, 40.6 mg, 56%; purified by a silica gel flash chromatography (hexane/EtOAc, 17:3). 1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 7.6 Hz, 2 H), 7.58 (s, 1 H), 7.52–7.37 (m, 14 H), 7.26–7.22 (m, 2 H), 7.13–7.04 (m, 4 H), 6.85–6.79 (m, 2 H), 6.72 (d, J = 7.7 Hz, 2 H), 3.78 (s, 3 H), 3.28 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.7, 158.6, 136.7, 130.7, 130.4, 130.1, 129.8, 128.4, 127.4, 127.2, 127.1, 126.8, 126.5, 125.9, 125.5, 125.4, 122.9, 122.6, 118.9, 118.4, 114.0, 112.9, 55.3, 51.3, 39.2. HRMS (ESI): m/z [M + Na]+ calcd for C48H36N2NaO5 +: 743.2516; found: 743.2524. Compound 3d White solid, 49.2 mg, 68%; purified by a silica gel flash chromatography (hexane/EtOAc, 97:3). 1H NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 7.7 Hz, 2 H), 7.65 (s, 1 H), 7.50–7.39 (m, 14 H), 7.29–7.21 (m, 4 H), 7.15–7.06 (m, 4 H), 6.75 (d, J = 7.7 Hz, 2 H), 3.30 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.7, 136.8, 136.5, 132.9, 130.7, 130.4, 130.0, 128.6, 128.4, 127.33, 127.26, 127.2, 126.8, 126.5, 126.1, 125.8, 124.5, 122.9, 122.4, 118.9, 118.3, 113.2, 51.4, 39.3. HRMS (ESI): m/z [M + Na]+ calcd for C47H33ClN2NaO4 +: 747.2021; found: 747.2018. Compound 3e White solid, 15.8 mg, 21%; purified by a silica gel flash chromatography (hexane/EtOAc, 17:3). 1H NMR (400 MHz, CDCl3): δ = 8.27 (d, J = 7.7 Hz, 2 H), 7.68 (s, 1 H), 7.53–7.39 (m, 16 H), 7.29–7.21 (m, 2 H), 7.19–7.07 (m, 2 H), 7.00 (d, J = 7.7 Hz, 1 H), 6.75 (d, J = 7.6 Hz, 2 H), 3.34 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.8, 140.5, 136.5, 131.7, 130.8, 130.4, 130.3, 130.2, 128.4, 127.4, 127.3, 127.2, 126.8, 126.5, 126.1, 125.8, 124.2, 123.0, 122.6, 122.4, 119.0, 118.4, 113.2, 51.4, 39.5. HRMS (ESI): m/z [M + Na]+ calcd for C47H33BrN2NaO4 +: 791.1516; found: 791.1525. Compound 3h Yellow solid, 33.8 mg, 47%; purified by a silica gel flash chromatography (hexane/EtOAc, 17:3). 1H NMR (400 MHz, CDCl3): δ = 8.20 (d, J = 7.6 Hz, 2 H), 7.64 (s, 1 H), 7.51–7.35 (m, 4 H), 7.33–7.20 (m, 13 H), 7.18–7.05 (m, 4 H), 6.71 (d, J = 7.7 Hz, 2 H), 3.28 (s, 6 H), 2.47 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.7, 136.7, 133.4, 130.5, 130.2, 129.2, 128.7, 128.6, 127.3, 127.1, 127.0, 126.7, 125.9, 125.6, 124.9, 122.9, 122.6, 119.0, 118.5, 112.8, 51.3, 40.0, 21.4. HRMS (ESI): m/z [M + Na]+ calcd for C49H38N2NaO4 +: 741.2724; found: 741.2733. Compound 3i Pale yellow solid, 34.9 mg, 46%; purified by a silica gel flash chromatography (hexane/EtOAc, 17:3). 1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 7.6 Hz, 2 H), 7.64 (s, 1 H), 7.49–7.39 (m, 6 H), 7.36–7.20 (m, 7 H), 7.17–7.09 (m, 4 H), 7.05–6.97 (m, 4 H), 6.70 (d, J = 7.7 Hz, 2 H), 3.91 (s, 6 H), 3.28 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.7, 158.8, 138.2, 131.8, 131.5, 128.6, 128.6, 127.3, 127.08, 127.06, 126.74, 126.65, 125.9, 125.8, 124.9, 122.9, 122.6, 118.6, 113.9, 112.8, 55.2, 51.4, 39.9. HRMS (ESI): m/z [M + Na]+ calcd for C49H38N2NaO6 +: 773.2622; found: 773.2625. Compound 3j White solid, 44.9 mg, 55%; purified by a silica gel flash chromatography (hexane/EtOAc, 9:1). 1H NMR (400 MHz, CDCl3): δ = 8.21 (d, J = 7.6 Hz, 2 H), 7.65 (s, 1 H), 7.56 (d, J = 8.2 Hz, 2 H), 7.48–7.43 (m, 2 H), 7.33–7.22 (m, 5 H), 7.18–7.14 (m, 4 H), 6.72 (d, J = 7.6 Hz, 2 H), 6.66 (d, J = 2.1 Hz, 2 H), 6.59–6.51 (m, 4 H), 3.83–3.80 (m, 12 H), 3.31 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.7, 160.74, 160.69, 138.5, 138.0, 128.7, 128.6, 128.4, 127.3, 127.2, 127.1, 126.7, 126.3, 126.0, 125.5, 124.9, 123.2, 122.6, 118.6, 118.3, 112.9, 108.6, 108.3, 99.8, 55.4, 51.4, 39.8. HRMS (ESI): m/z [M + Na]+ calcd for C51H42N2NaO8 +: 833.2833; found: 833.2843. Compound 3k Yellow solid, 36.4 mg, 48%; purified by a silica gel flash chromatography (hexane/EtOAc, 17:3). 1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 7.7 Hz, 2 H), 7.67 (s, 1 H), 7.52–7.33 (m, 11 H), 7.33–7.23 (m, 6 H), 7.19–7.10 (m, 4 H), 6.73 (d, J = 7.7 Hz, 2 H), 3.28 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.4, 137.9, 135.2, 133.2, 132.2, 131.9, 128.7, 128.6, 127.4, 127.3, 127.2, 126.9, 126.3, 126.2, 125.8, 125.3, 122.8, 122.5, 118.3, 117.4, 113.1, 51.4, 39.8. HRMS (ESI): m/z [M + Na]+ calcd for C47H32Cl2N2NaO4 +: 781.1631; found: 781.1622. Compound 3l White solid, 37.4 mg, 44%; purified by a silica gel flash chromatography (hexane/EtOAc, 17:3). 1H NMR (400 MHz, CDCl3): δ = 8.34 (d, J = 7.9 Hz, 2 H), 7.69 (s, 1 H), 7.52–7.35 (m, 15 H), 7.34–7.27 (m, 2 H), 7.18 (d, J = 7.9 Hz, 2 H), 7.16–7.11 (m, 2 H), 6.92 (t, J = 8.1 Hz, 2 H), 3.27 (s, 6 H). 13C NMR (100 MHz, CDCl3): δ = 166.5, 137.6, 136.2, 130.6, 130.3, 129.9, 128.7, 128.6, 128.5, 128.2, 127.7, 127.4, 127.3, 126.5, 125.0, 124.9, 123.9, 122.4, 121.8, 119.7, 119.1, 111.4, 51.4, 39.7. HRMS (ESI): m/z [M + Na]+ calcd for C47H32Br2N2NaO4 +: 869.0621; found: 869.0630. Compound 3m Pale yellow solid, 22.3 mg, 26%; purified by a silica gel flash chromatography (hexane/EtOAc, 4:1). 1H NMR (400 MHz, CDCl3): δ = 7.38–7.35 (m, 8 H), 7.29–7.25 (m, 1 H), 7.17 (s, 1 H), 7.15 (d, J = 8.7 Hz, 2 H), 6.88–6.81 (m, 2 H), 6.61 (s, 2 H), 6.39 (s, 2 H), 4.02 (d, J = 2.8 Hz, 2 H), 3.92 (q, J = 7.0, 6.6 Hz, 2 H), 3.81 (s, 6 H), 3.79 (s, 3 H), 3.29 (s, 6 H), 3.26 (s, 6 H), 2.96–2.86 (m, 4 H). 13C NMR (100 MHz, CDCl3): δ = 166.6, 158.4, 147.3, 147.1, 136.7, 133.7, 131.3, 130.5, 129.5, 128.1, 126.6, 126.0, 124.5, 121.4, 120.7, 114.0, 113.8, 110.6, 107.9, 55.9, 55.3, 55.0, 51.0, 42.1, 39.7, 29.1. HRMS (ESI): m/z [M + Na]+ calcd for C52H48N2NaO9 +: 867.3252; found: 867.3260. Zusatzmaterial Zusatzmaterial Supporting Information
