Photocatalytic Carbamoyl Radical Transfer to Alkenyl Azaarenes

Abstract

1-Phenyl-3-azaarenyl-propan-1-amine structural moieties have been widely incorporated in pharmaceuticals and biologically active compounds; however, current synthetic methods to access these compounds need multiple steps and proceed with low efficiency. Herein, we reported an efficient photocatalytic carbamoyl radical transfer approach that allows the preparation of these compounds in high yields (up to 88%). The reaction easily runs on a gram-scale and was applied for the preparation of pheniramine in two steps with 72% total yield.

Key words

azaarene - photocatalysis - carbamoyl radical - 1,4-dihydropyridine

Publication History

Received: 07 December 2023

Accepted after revision: 29 January 2024

Accepted Manuscript online:
29 January 2024

Article published online:
15 February 2024

• References and Notes

• 1a Guglielmetti L, Chiesi S, Eimer J, Dominguez J, Masini T, Varaine F, Veziris N, Ader F, Robert J. Future Microbiol. 2020; 15: 779
• 1b Raphoko LA, Lekgau K, Lebepe CM, Leboho TC, Matsebatlela TM, Nxumalo W. Bioorg. Med. Chem. Lett. 2021; 35: 127784
• 1c Tseng C.-H, Chen Y.-R, Tzeng C.-C, Liu W, Chou C.-K, Chiu C.-C, Chen Y.-L. Eur. J. Med. Chem. 2016; 108: 258
• 1d Jaso A, Zarranz B, Aldana I, Monge A. J. Med. Chem. 2005; 48: 2019
• 2a Aslanian R, Mutahi M. w, Shih N.-Y, Piwinski JJ, West R, Williams SM, She S, Wu R.-L, Hey JA. Bioorg. Med. Chem. Lett. 2003; 13: 1959
• 2b Ghorai P, Kraus A, Keller M, Götte C, Igel P, Schneider E, Schnell D, Bernhardt G, Dove S, Zabel M, Elz S, Seifert R, Buschauer A. J. Med. Chem. 2008; 51: 7193
• 3a Xu C, Muir CW, Leach AG, Kennedy AR, Watson AJ. B. Angew. Chem. Int. Ed. 2018; 57: 11374
• 3b Yin Y, Dai Y, Jia H, Li J, Bu L, Qiao B, Zhao X, Jiang Z. J. Am. Chem. Soc. 2018; 140: 6083
• 3c Zeng Y.-L, Chen B, Wang Y.-T, He C.-Y, Mu Z.-Y, Du J.-Y, He L, Chu W.-D, Liu Q.-Z. Chem. Commun. 2020; 56: 1693
• 3d Mao W, Xue W, Irran E, Oestreich M. Angew. Chem. Int. Ed. 2019; 58: 10723
• 3e Wen L, Yue Z, Zhang H, Chong Q, Meng F. Org. Lett. 2017; 19: 6610
• 3f Pattison G, Piraux G, Lam HW. J. Am. Chem. Soc. 2010; 132: 14373
• 3g Roy ID, Burns AR, Pattison G, Michel B, Parker AJ, Lam HW. Chem. Commun. 2014; 50: 2865
• 3h Deng X, Zhang S, Huang H, Cui X, Tang Z, Li G. Chin. Chem. Lett. 2023; 34: 108145
• 4a Liu L, Zheng G, Fan G, Du H, Tan J. Acta Chim. Sin. 2023; 81: 657
• 4b Capaldo L, Fagnoni M, Ravelli D. Chem. Eur. J. 2017; 23: 6527
• 5a Wang P.-Z, Chen J.-R, Xiao W.-J. Org. Biomol. Chem. 2019; 17: 6936
• 5b Gu F, Huang W, Liu X, Chen W, Cheng X. Adv. Synth. Catal. 2018; 360: 925
• 6a Goti G, Bieszczad B, Vega-Peñaloza A, Melchiorre P. Angew. Chem. Int. Ed. 2019; 58: 1213
• 6b Bieszczad B, Perego LA, Melchiorre P. Angew. Chem. Int. Ed. 2019; 58: 16878
• 6c Zhao X, Li B, Xia W. Org. Lett. 2020; 22: 1056
• 6d Liu L, Jiang P, Liu Y, Du H, Tan J. Org. Chem. Front. 2020; 7: 2278
• 6e Jiang P, Liu L, Tan J, Du H. Org. Biomol. Chem. 2021; 19: 4487
• 6f Liu L, Deng Z, Xu K, Jiang P, Du H, Tan J. Org. Lett. 2021; 23: 5299
• 6g Byun Y, Moon J, An W, Mishra NK, Kim HS, Ghosh P, Kim IS. J. Org. Chem. 2021; 86: 12247
• 6h Zeng F.-L, Xie K.-C, Liu Y.-T, Wang H, Yin P.-C, Qu L.-B, Chen X.-L, Yu B. Green Chem. 2022; 24: 1732
• 6i Pálvölgyi ÁM, Ehrschwendtner F, Schnürch M, Bica-Schröder K. Org. Biomol. Chem. 2022; 20: 7245
• 6j Lipp A, Badir SO, Dykstra R, Gutierrez O, Molander GA. Adv. Synth. Catal. 2021; 363: 3507
• 6k Yamanomoto K, Matsudaira T, Akiyama T. Synlett 2023; 34: 1391
• 7a Alandini N, Buzzetti L, Favi G, Schulte T, Candish L, Collins KD, Melchiorre P. Angew. Chem. Int. Ed. 2020; 59: 5248
• 7b Kim I, Park S, Hong S. Org. Lett. 2020; 22: 8730
• 7c Cardinale L, Konev MO, Jacobi von Wangelin A. Chem. Eur. J. 2020; 26: 8239
• 7d Cardinale L, Schmotz M.-OW. S, Konev MO, Jacobi von Wangelin A. Org. Lett. 2022; 24: 506
• 7e Matsuo BT, Oliveira PH. R, Correia JT. M, Paixão MW. Org. Lett. 2021; 23: 6775
• 7f Wang S, Zhou Q, Zhang X, Wang P. Angew. Chem. Int. Ed. 2022; 61: e202111388
• 8a Zhang K, Lu L.-Q, Jia Y, Wang Y, Lu F.-D, Pan F, Xiao W.-J. Angew. Chem. Int. Ed. 2019; 58: 13375
• 8b Zhang H.-H, Zhao J.-J, Yu S. J. Am. Chem. Soc. 2018; 140: 16914
• 9a Dai Z.-Y, Nong Z.-S, Wang P.-S. ACS Catal. 2020; 10: 4786
• 9b Dai Z.-Y, Nong Z.-S, Song S, Wang P.-S. Org. Lett. 2021; 23: 3157
• 10 Carbamoyl Transfer Reaction; General Procedure: A test tube equipped with a magnetic stirrer was charged with 4-carbamoyl-1,4-dihydropyridine 1 (0.1 mmol, 1 equiv) and α-branched 2-vinylquinoline 2 (0.1 mmol, 1 equiv) followed by addition of [Ir(dtbbpy)(ppy)₂][PF₆] (0.002 mmol, 0.01 equiv) and dichloromethane (1.5 mL) under air. The tube was sealed and three vacuum/argon cycles were made, then the mixture was then irradiated with a 60 W, 390 nm Kessil lamp and stirred at room temperature for 12 hours. Upon completion, the reaction mixture was concentrated under vacuum and the residue was purified by column chromatography (petrol ether/EtOAc = 5:1–3:1) to give the desired product. N-Isopropyl-3-phenyl-3-(quinolin-2-yl)propanamide (3a): Yield: 85%; white solid; mp 131–133 ℃. ¹H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 8.4 Hz, 1 H), 7.97 (d, J = 8.5 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 7.73–7.67 (m, 1 H), 7.50 (t, J = 7.5 Hz, 1 H), 7.30 (d, J = 7.1 Hz, 2 H), 7.25 (t, J = 7.4 Hz, 2 H), 7.19 (dd, J = 15.8, 7.8 Hz, 2 H), 6.06 (d, J = 6.4 Hz, 1 H), 4.80 (dd, J = 9.4, 5.5 Hz, 1 H), 3.90 (m, J = 13.2, 6.6 Hz, 1 H), 3.46 (dd, J = 13.7, 9.5 Hz, 1 H), 2.83 (dd, J = 13.7, 5.5 Hz, 1 H), 0.96 (d, J = 6.5 Hz, 3 H), 0.82 (d, J = 6.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.1, 162.1, 147.2, 143.1, 136.3, 129.3, 128.8, 128.6, 128.2, 127.6, 126.9, 126.8, 126.1, 122.6, 50.3, 42.4, 40.9, 22.6, 22.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₃N₂O⁺: 319.1804; found: 319.1782. N-Isopropyl-3-(2-methoxyphenyl)-3-(quinolin-2-yl)propanamide (3b): Yield: 61%; yellow solid; mp 142–146 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.09 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.5 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 1 H), 7.73 (t, J = 7.7 Hz, 1 H), 7.52 (t, J = 7.5 Hz, 1 H), 7.25 (d, J = 8.5 Hz, 1 H), 7.20 (t, J = 7.8 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 6.91 (d, J = 8.2 Hz, 1 H), 6.84 (t, J = 7.4 Hz, 1 H), 6.46 (d, J = 6.6 Hz, 1 H), 5.30 (dd, J = 9.8, 4.5 Hz, 1 H), 3.99–3.90 (m, 1 H), 3.90 (d, J = 7.0 Hz, 3 H), 3.46 (dd, J = 13.6, 10.1 Hz, 1 H), 2.84 (dd, J = 13.8, 4.5 Hz, 1 H), 1.03 (d, J = 6.5 Hz, 3 H), 0.86 (d, J = 6.5 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 171.5, 162.7, 156.5, 147.0, 136.2, 131.3, 129.2, 129.0, 128.6, 127.9, 127.6, 126.9, 125.9, 122.6, 120.6, 110.7, 55.5, 42.6, 40.9, 40.6, 22.7, 22.5. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₅N₂O₂ ⁺: 349.1910; found: 349.1910. 3-(2-Isopropoxyphenyl)-N-isopropyl-3-(quinolin-2-yl)propanamide (3c): Yield: 85%; yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.05 (d, J = 8.4 Hz, 1 H), 7.95 (d, J = 8.5 Hz, 1 H), 7.74 (d, J = 8.1 Hz, 1 H), 7.69 (t, J = 7.6 Hz, 1 H), 7.49 (t, J = 7.5 Hz, 1 H), 7.22 (d, J = 8.5 Hz, 1 H), 7.14 (t, J = 7.8 Hz, 1 H), 7.10 (d, J = 7.6 Hz, 1 H), 6.86 (d, J = 8.2 Hz, 1 H), 6.80 (t, J = 7.4 Hz, 1 H), 6.46 (d, J = 7.0 Hz, 1 H), 5.20 (dd, J = 9.7, 4.5 Hz, 1 H), 4.57 (m, J = 12.0, 6.0 Hz, 1 H), 3.91 (m, J = 13.3, 6.6 Hz, 1 H), 3.47 (dd, J = 13.6, 9.9 Hz, 1 H), 2.81 (dd, J = 13.7, 4.5 Hz, 1 H), 1.32 (d, J = 6.0 Hz, 3 H), 1.25 (d, J = 6.0 Hz, 3 H), 1.01 (d, J = 6.5 Hz, 3 H), 0.84 (d, J = 6.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.6, 162.9, 154.8, 147.0, 135.9, 132.2, 129.4, 129.1, 128.7, 127.7, 127.5, 126.9, 125.8, 122.6, 120.3, 112.9, 69.9, 43.5, 40.8, 40.5, 22.7, 22.5, 22.2, 21.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₉N₂O₂ ⁺: 377.2223; found: 377.2228. N-Isopropyl-3-(quinolin-2-yl)-3-(o-tolyl)propanamide (3d): Yield: 62%; white solid; mp 121–130 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.10 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.5 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 1 H), 7.74 (t, J = 7.7 Hz, 1 H), 7.54 (t, J = 7.5 Hz, 1 H), 7.21 (d, J = 7.4 Hz, 1 H), 7.12 (dd, J = 9.8, 5.9 Hz, 2 H), 7.07 (d, J = 3.0 Hz, 2 H), 6.23 (d, J = 7.1 Hz, 1 H), 5.08 (dd, J = 9.5, 4.9 Hz, 1 H), 3.95 (m, J = 13.4, 6.6 Hz, 1 H), 3.46 (dd, J = 13.8, 9.6 Hz, 1 H), 2.76 (dd, J = 13.8, 4.9 Hz, 1 H), 2.56 (s, 3 H), 1.03 (d, J = 6.5 Hz, 3 H), 0.90 (d, J = 6.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.3, 162.4, 147.1, 141.5, 136.3, 135.9, 130.7, 129.3, 128.8, 128.1, 127.6, 126.9, 126.6, 126.2, 126.1, 122.5, 46.0, 41.6, 41.0, 22.6, 22.5, 19.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₅N₂O⁺: 333.1961; found: 333.1964. N-Isopropyl-3-(3-methoxyphenyl)-3-(quinolin-2-yl)propanamide (3e): Yield: 71%; colorless oil; mp 121–130 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.5 Hz, 1 H), 7.76 (d, J = 8.1 Hz, 1 H), 7.71 (t, J = 7.7 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.23 (d, J = 8.5 Hz, 1 H), 7.18 (t, J = 7.9 Hz, 1 H), 6.88 (d, J = 8.3 Hz, 2 H), 6.74 (d, J = 8.4 Hz, 1 H), 6.05 (d, J = 7.1 Hz, 1 H), 4.77 (dd, J = 9.6, 5.3 Hz, 1 H), 3.90 (dd, J = 13.2, 6.6 Hz, 1 H), 3.74 (s, 3 H), 3.46 (dd, J = 13.7, 9.7 Hz, 1 H), 2.81 (dd, J = 13.7, 5.3 Hz, 1 H), 0.99 (d, J = 6.5 Hz, 3 H), 0.81 (d, J = 6.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.1, 161.9, 159.7, 147.1, 144.6, 136.4, 129.6, 129.4, 128.8, 127.6, 127.0, 126.1, 122.6, 120.5, 114.0, 112.0, 55.1, 50.3, 42.3, 40.9, 22.6, 22.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₅N₂O₂ ⁺: 349.1910; found: 349.1912. N-Isopropyl-3-(4-methoxyphenyl)-3-(quinolin-2-yl)propanamide (3f): Yield: 82%; yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.10 (d, J = 8.4 Hz, 1 H), 8.02 (d, J = 8.5 Hz, 1 H), 7.78 (d, J = 8.1 Hz, 1 H), 7.74 (t, J = 7.6 Hz, 1 H), 7.53 (t, J = 7.4 Hz, 1 H), 7.24 (d, J = 8.5 Hz, 3 H), 6.82 (d, J = 8.6 Hz, 2 H), 6.10 (d, J = 7.2 Hz, 1 H), 4.77 (dd, J = 9.4, 5.5 Hz, 1 H), 3.92 (m, J = 13.3, 6.6 Hz, 1 H), 3.77 (s, 3 H), 3.45 (dd, J = 13.7, 9.5 Hz, 1 H), 2.82 (dd, J = 13.7, 5.5 Hz, 1 H), 1.00 (d, J = 6.5 Hz, 3 H), 0.84 (d, J = 6.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.2, 162.4, 158.4, 136.4, 135.1, 129.4, 129.1, 128.7, 127.6, 126.9, 126.1, 122.6, 114.0, 55.2, 49.5, 42.5, 40.9, 22.6, 22.4. HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₂H₂₄N₂O₂Na⁺: 371.1730; found: 371.1737. 3-(4-Fluorophenyl)-N-isopropyl-3-(quinolin-2-yl)propanamide (3g): Yield: 72%; white solid; mp 108–113 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8.5 Hz, 1 H), 7.76 (d, J = 8.1 Hz, 1 H), 7.71 (t, J = 7.6 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.29 (t, J = 6.7 Hz, 3 H), 7.21 (dd, J = 15.1, 6.4 Hz, 2 H), 6.02 (d, J = 6.6 Hz, 1 H), 4.79 (dd, J = 9.3, 5.5 Hz, 1 H), 3.90 (m, J = 13.5, 6.7 Hz, 1 H), 3.46 (dd, J = 13.6, 9.6 Hz, 1 H), 2.82 (dd, J = 13.7, 5.4 Hz, 1 H), 0.97 (d, J = 6.5 Hz, 3 H), 0.82 (d, J = 6.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.14, 167.2, 162.1, 157.0, 147.2, 143.0, 136.3, 129.3, 128.8, 128.6, 128.2, 127.6, 126.9, 126.8, 126.1, 122.6, 50.3, 42.4, 40.9, 22.6, 22.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₂FN₂O⁺: 337.1710; found: 337.1758. 3-(4-Chlorophenyl)-N-isopropyl-3-(quinolin-2-yl)propanamide (3h): Yield: 81%; white solid; mp 134–136 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.07 (d, J = 8.1 Hz, 1 H), 8.01 (d, J = 8.3 Hz, 1 H), 7.77 (d, J = 7.9 Hz, 1 H), 7.72 (t, J = 7.9 Hz, 1 H), 7.52 (t, J = 7.1 Hz, 1 H), 7.25–7.16 (m, 4 H), 5.95 (d, J = 3.7 Hz, 1 H), 4.84–4.74 (m, 1 H), 3.97–3.85 (m, 1 H), 3.42 (dd, J = 12.6, 10.3 Hz, 1 H), 2.79 (dd, J = 13.0, 3.1 Hz, 1 H), 0.99 (d, J = 3.5 Hz, 3 H), 0.83 (d, J = 3.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 170.7, 161.6, 161.5, 147.2, 141.5, 136.5, 132.6, 129.5, 129.5, 128.9, 128.7, 127.6, 127.0, 126.2, 122.4, 49.6, 42.3, 41.0, 22.6, 22.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₂₂ClN₂O⁺: 353.1415; found: 353.1429. N-Isopropyl-3-(quinolin-2-yl)-3-(p-tolyl)propanamide (3i): Yield: 82%; yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 8.4 Hz, 1 H), 7.97 (d, J = 8.5 Hz, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 7.71 (t, J = 7.7 Hz, 1 H), 7.50 (t, J = 7.5 Hz, 1 H), 7.21 (d, J = 8.6 Hz, 1 H), 7.18 (d, J = 8.0 Hz, 2 H), 7.06 (d, J = 7.9 Hz, 2 H), 6.10 (d, J = 7.4 Hz, 1 H), 4.76 (dd, J = 9.6, 5.3 Hz, 1 H), 3.95–3.84 (m, 1 H), 3.44 (dd, J = 13.7, 9.7 Hz, 1 H), 2.80 (dd, J = 13.7, 5.3 Hz, 1 H), 2.28 (s, 3 H), 0.98 (d, J = 6.5 Hz, 3 H), 0.81 (d, J = 6.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 171.2, 167.1, 164.6, 162.3, 157.0, 147.2, 140.1, 136.3, 136.3, 129.3, 128.8, 128.0, 127.6, 126.9, 126.0, 122.6, 49.9, 42.4, 40.9, 22.6, 22.4, 21.0. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₅N₂O⁺: 333.1961; found: 333.1968.