Synthesis of Cytogenin Analogues by C(sp²)–H Functionalization under Ruthenium(II) Catalysis, and DFT Analysis

This work is dedicated to Professor Deevi Basavaiah, School of Chemistry, University of Hyderabad for his immense contribution to the Baylis–Hillman reaction.

Abstract

The first concise and convenient synthesis of natural products, antibiotics, and anticancer agents resembling cytogenin and other isocoumarins has been achieved by using three components (an N-aroyl β-amino ester, an MBH acetate, and N-bromosuccinimide) under ruthenium(II) catalysis. This method provides intermediate isochroman-1-imines through C(sp²)–H allylation with halocyclization in a single operation. Substrate scope studies, a scale-up, and density functional theory calculations to establish the mechanism of the C–H allylation were carried out.

Key words

ruthenium catalysis - allylation - isochromanimines - isocoumarins - cytogenin analogues

Publication History

Received: 16 February 2025

Accepted after revision: 21 March 2025

Accepted Manuscript online:
21 March 2025

Article published online:
24 April 2025

• References and Notes

• 1a Roush WR. J. Am. Chem. Soc. 2008; 130: 6654
• 1b Li L, Chen Z, Zhang X, Jia Y. Chem. Rev. 2018; 118: 3752
• 1c Nicolaou KC, Rigol S. Nat. Prod. Rep. 2020; 37: 1404
• 1d Atanasov AG, Zotchev SB, Dirsch VM. The International Natural Product Sciences Taskforce. Supuran CT. Nat. Rev. Drug Discovery 2021; 20: 200
• 2a Saeed A. Eur. J. Med. Chem. 2016; 116: 290
• 2b Engelmeier D, Hadacek F, Hofer O, Lutz-Kutschera G, Nagle M, Wurz G, Greger H. J. Nat. Prod. 2004; 67: 19
• 2c Simić MR, Erić S, Borić I, Lubelska A, Latacz G, Kieć-Kononowicz K, Vojnović S, Nikodinović-Runić J, Savić V. J. Serb. Chem. Soc. 2021; 86: 639
• 2d Noor AO, Almasri DM, Bagalagel AA, Abdallah HM, Mohamed SG. A, Mohamed GA, Ibrahim SR. M. Molecules 2020; 25: 395
• 3a Kumagai H, Masuda T, Ohsono M, Hattori S, Naganawa H, Sawa T, Hamada M, Ishizuka M, Takeuchi T. J. Antibiot. 1990; 43: 1505
• 3b Oikawa T, Sasaki M, Inose M, Shimamura M, Kuboki H, Hirano S, Kumagai H, Ishizuka M, Takeuchi T. Anticancer Res. 1997; 17: 1881
• 3c Nakashima T, Hirano S, Agata N, Kumagai H, Isshiki T, Yoshioka T, Ishizuka M, Maeda K, Takeuchi T. J. Antibiot. 1999; 52: 426
• 3d Matsumoto N, Nakashima T, Isshiki K, Kuboki H, Hirano S.-I, Kumagai H, Yoshioka T, Ishizuka M, Takeuchi T. J. Antibiot. 2001; 54: 285
• 3e Kumagai H, Wakazono K, Agata N, Isshiki K, Ishizuka M, Ikeda D. J. Antibiot. 2005; 58: 202
• 4a Dias DA, Urban S, Roessner U. Metabolites 2012; 2: 303
• 4b Babbar P, Das P, Manickam Y, Mankad Y, Yadav S, Parvez S, Sharma A, Reddy DS. ACS Infect. Dis. 2021; 7: 1777
• 5a Liao H.-Y, Cheng C.-H. J. Org. Chem. 1995; 60: 3711
• 5b Wang L, Zhang X, Jiang Y, Ma D. Sci. China, Ser. B: Chem. 2009; 52: 1616
• 6 Mallampudi NA, Reddy GS, Maity S, Mohapatra DK. Org. Lett. 2017; 19: 2074
• 7 Pati BV, Banjare SK, Adhikari GK. D, Nanda T, Ravikumar PC. Org. Lett. 2022; 24: 5651
• 8a Abrams DJ, Provencher PA, Sorensen EJ. Chem. Soc. Rev. 2018; 47: 8925
• 8b Guillemard L, Kaplaneris N, Ackermann L, Johansson MJ. Nat. Rev. Chem. 2021; 5: 522
• 8c Gramage-Doria R, Bruneau C. Coord. Chem. Rev. 2021; 428: 213602
• 8d Murali K, Machado LA, Carvalho RL, Pedrosa LF, Mukherjee R, Da Silva E NJr, Maity D. Chem. Eur. J. 2021; 27: 12453
• 8e de Jesus R, Hiesinger K, van Gemmeren M. Angew. Chem. Int. Ed. 2023; e202306659
• 9a Joshi A, Murthy S, Chavada LR, Singh SK, Pandey AK. Chem. Commun. 2023; 59: 9497
• 9b Chavada LR, Mishra P, Pandey AK. J. Org. Chem. 2024; 89: 9233
• 10a Mondal S, Chowdhury S. Adv. Synth. Catal. 2018; 360: 1884
• 10b Rej S, Ano Y, Chatani N. Chem. Rev. 2020; 120: 1788
• 11a Pandey AK, Han SH, Mishra NK, Kang D, Lee SH, Chun R, Hong S, Park JS. Kim I. S. ACS Catal. 2018; 8: 742
• 11b Pandey AK, Kang D, Han SH, Lee H, Mishra NK, Kim HS, Jung YH, Hong S, Kim IS. Org. Lett. 2018; 20: 4632
• 11c Han SH, Pandey AK, Lee H, Kim S, Kang D, Jung YH, Kim HS, Hong S, Kim IS. Org. Chem. Front. 2018; 5: 3210
• 12a Wang L, Ackermann L. Chem. Commun. 2014; 50: 1083
• 12b Das R, Kapur M. Asian J. Org. Chem. 2018; 7: 1524
• 13a Saeed A, Rama NH, Arfan M. J. Heterocycl. Chem. 2003; 40: 519
• 13b Saeed A. J. Heterocycl. Chem. 2004; 41: 975
• 14a Arockiam PB, Bruneau C, Dixneuf PH. Chem. Rev. 2012; 112: 5879
• 14b de Carvalho RL, Diogo EB. T, Homölle SL, Dana S, da Silva EN. Jr, Ackermann L. Chem. Soc. Rev. 2023; 52: 6359
• 15 CCDC 2423928 contains the supplementary crystallographic data for compound 5g. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
• 16 Krapcho AP. ARKIVOC 2007; (ii): 1
• 17 Saikia P, Gogoi S. Adv. Synth. Catal. 2018; 360: 2063
• 18 Gogoi N, Parhi R, Tripathi RK. P, Pachuau L, Kaishap PP. Tetrahedron 2024; 150: 133740
• 19 Zhao Y, Truhlar DG. J. Chem. Phys. 2006; 125: 194101
• 20a Doig M, Stoll H, Preuss H, Pitzer RM. J. Phys. Chem. 1993; 97: 5852
• 20b Andrae D, Häußermann U, Dolg M, Stoll H, Preuß H. Theor. Chim. Acta 1990; 77: 123
• 21 Hehre WJ, Ditchfield R, Pople JA. J. Chem. Phys. 1972; 56: 2257
• 22 Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Petersson GA, Nakatsuji H, Li X, Caricato M, Marenich AV, Bloino J, Janesko BG, Gomperts R, Mennucci B, Hratchian HP, Ortiz JV, Izmaylov AF, Sonnenberg JL, Williams-Young D, Ding F, Lipparini F, Egidi F, Goings J, Peng B, Petrone A, Henderson T, Ranasinghe D, Zakrzewski VG, Gao J, Rega N, Zheng G, Liang W, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Throssell K, Montgomery JA. Jr, Peralta JE, Ogliaro F, Bearpark MJ, Heyd JJ, Brothers EN, Kudin KN, Staroverov VN, Keith TA, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Millam JM, Klene M, Adamo C, Cammi R, Ochterski JW, Martin RL, Morokuma K, Farkas O, Foresman JB, Fox DJ. Gaussian 16 . Gaussian, Inc; Wallingford: 2016
• 23a Sarki N, Kumawat S, Choudhary M, Narani A, Singh SK, Natte K. J. Catal. 2024; 429: 115248
• 23b Leitch JA, Wilson PB, McMullin CL, Mahon MF, Bhonoah Y, Williams IH, Frost CG. ACS Catal. 2016; 6: 5520
• 24 Marenich AV, Cramer CJ, Truhlar DG. J. Phys. Chem. B 2009; 113: 6378
• 25 Weigend F, Ahlrichs R. Phys. Chem. Chem. Phys. 2005; 7: 3297
• 26a Sivasakthikumaran R, Jambu S, Jeganmohan M. J. Org. Chem. 2019; 84: 3977
• 26b Gupta SS, Gupta S, Manisha, Gupta P, Sharma U. Chem. Eur. J. 2023; 29: e202301360
• 27 Isochroman-1-imines 5a–n; General Procedure An oven-dried screwcap tube was charged with the appropriate amino ester 1 (0.2 mmol, 100 mol%), [Ru(p-cymene)Cl₂]₂ (3.05 mg, 0.005 mmol, 2.5 mol%), AgSbF₆ (6.8 mg, 0.02 mmol, 10 mol%), Cu(OAc)₂·H₂O (19.96 mg, 0.10 mmol, 50 mol%), TCE (1 mL, 0.2 M), and methyl 2-(acetoxymethyl)acrylate (2) (0.4 mmol, 200 mol%) under air at r.t. The mixture was stirred at 120 °C for 4 h then cooled to r.t., and filtered through a small pad of Celite with additional TCE (0.5 mL). The filtrate was collected in another screwcap tube and NBS (0.4 mmol, 200 mol%) was added under the open atmosphere at r.t. The mixture was then stirred at r.t. for 4 h. The resulting mixture was diluted with CH₂Cl₂ (2 mL), then concentrated under reduced pressure. The residue was purified by flash column chromatography [silica gel, EtOAc–hexane (1:9)]. Methyl (1Z)-3-(Bromomethyl)-1-[(3-methoxy-3-oxopropyl)imino]-8-methyl-3,4-dihydro-1H-isochromene-3-carboxylate (5a) Sticky liquid; yield: 64 mg, (80%). IR (KBr): 3019, 1736, 1439, 1214, 1056, 742, 667 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.19 (t, J = 7.5 Hz, 1 H), 7.13 (d, J = 7.3 Hz, 1 H), 6.94 (d, J = 7.1 Hz, 1 H), 3.96 (dt, J = 13.8, 6.8 Hz, 1 H), 3.86–3.80 (m, 1 H), 3.78 (d, J = 10.8 Hz, 1 H), 3.69 (s, 4 H), 3.59 (s, 3 H), 3.24 (s, 2 H), 2.71 (t, J = 6.9 Hz, 2 H), 2.58 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 173.6, 169.8, 150.5, 140.0, 133.0, 131.6, 130.0, 126, 125.4, 80.7, 53.1, 51.6, 42.6, 36.5, 35.8, 35.3, 23.1. HRMS (ESI); m/z [M + H]⁺ calcd for C₁₇H₂₁BrNO₅: 398.0603; found: 398.0602.