Potassium tert-Butoxide Promoted Intramolecular Mizoroki–Heck-Type Radical Cyclization: Photoluminescence Properties and Application in Live Cancer-Cell Imaging

Abstract

Privileged indole-fused phenanthridinones were synthesized by an inexpensive potassium tert-butoxide-promoted intramolecular Mizoroki–Heck-type radical cyclization. This method offers high atom- and step-economic C–C bond formation. An array of the synthesized compounds showed good photoluminescence properties, and could be successfully applied as fluorescent bioprobes for imaging of living cancer cells.

Key words

transition-metal-free reaction - C–H bond functionalization - potassium tert-butoxide - Mizoroki–Heck reaction - phenanthridinones - indoles

Publication History

Received: 18 January 2022

Accepted after revision: 25 February 2022

Accepted Manuscript online:
25 February 2022

Article published online:
25 April 2022

• References and Notes

• 1a Yamaguchi J, Muto K, Itami K. Eur. J. Org. Chem. 2013; 19
• 1b Ball CJ, Willis MC. Eur. J. Org. Chem. 2013; 425
• 1c Vlaar T, Ruijter E, Orru RV. A. Adv. Synth. Catal. 2011; 353: 809
• 1d Johansson C. C. C., Colacot T. J.; Angew. Chem. Int. Ed.; 2010, 49, 676.
• 1e Cahiez G, Moyeux A. Chem. Rev. 2010; 110: 1435
• 1f Yin L, Liebscher J. Chem. Rev. 2007; 107: 133
• 1g Corbet J.-P, Mignani G. Chem. Rev. 2006; 106: 2651
• 1h Bellina F, Rossi R. Chem. Rev. 2010; 110: 1082
• 1i Yang Y, Lan J, You J. Chem. Rev. 2017; 117: 8787

For ligand drawbacks, see:
• 2a Fleckenstein CA, Plenio H. Organometallics 2008; 27: 3924
• 2b Snelders DJ. M, van Koten G, Gebbink RJ. M. K. J. Am. Chem. Soc. 2009; 131: 11407
• 2c Wang D, Weinstein AB, White PB, Stahl SS. Chem. Rev. 2018; 118: 2636
• 2d Zhao T, Ghosh P, Martinez Z, Liu X, Meng X, Darensbourg MY. Organometallics 2017; 36: 1822
• 2e Würtz S, Glorius F. Acc. Chem. Res. 2008; 41: 1523 For the prices of various transition metals, see
• 2f www.metalprices.com (accessed Mar 16, 2022).
• 3a Garrett CE, Prasad K. Adv. Synth. Catal. 2004; 346: 889
• 3b Chatterjee S, Sarkar S, Bhattacharya S. Chem. Res. Toxicol. 2014; 27: 1887
• 3c Egorova KS, Ananikov VP. Organometallics 2017; 36: 4071
• 3d Banik A, Paira R, Shaw BK, Vijaykumar G, Mandal SK. J. Org. Chem. 2018; 83: 3236
• 3e Bera K, Sarkar S, Jalal S, Jana U. J. Org. Chem. 2012; 77: 8780
• 3f Duval JF. L, Paquet N, Lavoie M, Fortin C. Environ. Sci. Technol. 2015; 49: 6625
• 4 Sun C.-L, Shi Z.-J. Chem. Rev. 2014; 114: 9219
• 5a Rueping M, Leiendecker M, Das A, Poisson T, Bui L. Chem. Commun. 2011; 47: 10629
• 5b Kumar S, Rathore V, Verma A, Prasad CD, Kumar A, Yadav A, Jana S, Sattar M, Meenakshi Meenakshi, Kumar S. Org. Lett. 2015; (17) 82
• 5c Bhakuni BS, Kumar A, Balkrishna SJ, Sheikh JA, Konar S, Kumar S. Org. Lett. 2012; 14: 2838
• 5d Cuthbertson J, Gray VJ, Wilden JD. Chem. Commun. 2014; 50: 2575
• 5e Liu Y, Xu J, Zhang J, Xu X, Jin Z. Org. Lett. 2017; 19: 5709
• 5f Nocera G, Young A, Palumbo F, Emery KJ, Coulthard G, McGuire TM, Tuttle T, Murphy JA. J. Am. Chem. Soc. 2018; 140: 9751
• 5g Chan TL, Wu Y, Choy PY, Kwong FY. Chem. Eur. J. 2013; 19: 15802
• 5h De S, Mishra S, Kakde BN, Dey D, Bisai A. J. Org. Chem. 2013; 78: 7823
• 5i Patil M. J. Org. Chem. 2016; 81: 632
• 5j Mehta VP, Punji B. RSC Adv. 2013; 3: 11957
• 5k Rowlands GJ. Annu. Rep. Prog. Chem., Sect. B: Org. Chem. 2012; 108: 15
• 5l Zhang L, Yang H, Jiao L. J. Am. Chem. Soc. 2016; 138: 7151
• 6 Yanagisawa S, Ueda K, Taniguchi T, Itami K. Org. Lett. 2008; 10: 4673
• 7a Sun C.-L, Li H, Yu D.-G, Yu M, Zhou X, Lu X.-Y, Huang K, Zheng S.-F, Li B.-J, Shi Z.-J. Nat. Chem. 2010; 2: 1044
• 7b Shirakawa E, Itoh K.-i, Higashino T, Hayashi T. J. Am. Chem. Soc. 2010; 132: 15537
• 7c Sun C.-L, Gu Y.-F, Wang B, Shi Z.-J. Chem. Eur. J. 2011; 17: 10844
• 7d Chen W.-C, Hsu Y.-C, Shih W.-C, Lee C.-Y, Chuang W.-H, Tsai Y.-F, Chen PP.-Y, Ong T.-G. Chem. Commun. 2012; 48: 6702
• 7e Roman DS, Takahashi Y, Charette AB. Org. Lett. 2011; 13: 3242
• 7f Shirakawa E, Zhang X, Hayashi T. Angew. Chem. Int. Ed. 2011; 50: 4671
• 8a Studer A, Curran DP. Angew. Chem. Int. Ed. 2011; 50: 5018
• 8b Zhou S, Anderson GM, Mondal B, Doni E, Ironmonger V, Kranz M, Tuttle T, Murphy JA. Chem. Sci. 2014; 5: 476
• 8c Barham JP, Coulthard G, Emery KJ, Doni E, Cumine F, Nocera G, John MP, Berlouis LE. A, McGuire T, Tuttle T, Murphy JA. J. Am. Chem. Soc. 2016; 138: 7402
• 8d Drapeau MP, Fabre I, Grimaud L, Ciofini I, Ollevier T, Taillefer M. Angew. Chem. Int. Ed. 2015; 54: 10587
• 9a Ning X.-S, Liang X, Hu K.-F, Yao C.-Z, Qu J.-P, Kang Y.-B. Adv. Synth. Catal. 2018; 360: 1590
• 9b Li S.-S, Xia Y.-Q, Hu F.-Z, Liu C.-F, Su F, Dong L. Chem. Asian J. 2016; 11: 3165
• 9c Ning X.-S, Wang M.-M, Qu J.-P, Kang Y.-B. J. Org. Chem. 2018; 83: 13523
• 9d Shan X.-H, Zheng H.-X, Yang B, Tie L, Fu J.-L, Qu J.-P, Kang Y.-B. Nat. Commun. 2019; 10: 908
• 9e Shan X.-H, Yang B, Zheng H.-X, Qu J.-P, Kang Y.-B. Org. Lett. 2018; 20: 7898
• 9f Zhang Z, Liu K, Chen X, Su S.-J, Deng Y, Zeng W. RSC Adv. 2017; 7: 30554
• 9g Lee HK, Dao PD. Q, Kim Y.-s, Cho CS. Synthesis 2018; 50: 3243
• 9h Guo X, Han Q, Tang Z, Su L, Zhang X, Zhang X, Lin S, Huang Q. Tetrahedron Lett. 2018; 59: 1568
• 10a Park GY, Wilson JJ, Song Y, Lippard SJ. Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 11987
• 10b Rajagopalan R, Lin T.-S, Karwa AS, Poreddy AR, Asmelash B, Dorshow RB. ACS Med. Chem. Lett. 2012; 3: 284
• 10c Abdel-Halim OB, Morikawa T, Ando S, Matsuda H, Yoshikawa M. J. Nat. Prod. 2004; 67: 1119
• 10d Berkov S, Cuadrado M, Osorio E, Viladomat F, Codina C, Bastida J. Planta Med. 2009; 75: 1351
• 10e Suna Q, Shen Y.-H, Tiana J.-M, Tanga J, Sua J, Liua R.-H, Lia H.-L, Xua X.-K, Zhang W.-D. Chem. Biodiversity 2009; 6: 1751
• 10f Miao F, Yang X.-J, Ma Y.-N, Zheng F, Song X.-P, Zhou L. Chem. Pharm. Bull. 2012; 60: 1508
• 10g Alawode OE, Naganaboina V, Liyanage T, Desper J, Rayat S. Org. Lett. 2014; 16: 1494
• 10h Dubost E, Dumas N, Fossey C, Magnelli R, Butt-Gueulle S, Ballandonne C, Caignard DH, Dulin F, de-Oliveira Santos JS, Millet P, Charnay Y, Rault S, Cailly T, Fabis F. J. Med. Chem. 2012; 55: 9693
• 11a Chen C, Shang G, Zhou J, Yu Y, Li B, Peng J. Org. Lett. 2014; 16: 1872
• 11b Yan L, Zhao D, Lan J, Cheng Y, Guo Q, Li X, Wu N, You J. Org. Biomol. Chem. 2013; 11: 7966
• 12a Sivaraman M, Muralidharan D, Perumal PT. Tetrahedron Lett. 2012; 53: 6039
• 12b Sivaraman M, Perumal PT. Org. Biomol. Chem. 2014; 12: 1318
• 12c Sivaraman M, Perumal PT. RSC Adv. 2014; 4: 52060
• 13 CCDC: 1519207 contains the supplementary crystallographic data for compound 3a. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
• 14a Mayakrishnan S, Arun Y, Balachandran C, Awale S, Maheswari NU, Perumal PT. ACS Omega 2017; 2: 2694
• 14b Mayakrishnan S, Arun Y, Balachandran C, Emi N, Muralidharan D, Perumal PT. Org. Biomol. Chem. 2016; 14: 1958
• 14c Nandakumar A, Perumal PT. Org. Lett. 2013; 15: 382
• 14d Mayakrishnan S, Arun Y, Maheswari NU, Perumal PT. Chem. Commun. 2018; 54: 11889
• 15a Wang W, Chen C, Li X, Wang S, Luo X. Chem. Commun. 2015; 51: 9109
• 15b Miao J, Cui H, Jin J, Lai F, Wen H, Zhang X, Ruda GF, Chen X, Yin D. Chem. Commun. 2015; 51: 881
• 15c Abeywickrama CS, Baumann HJ, Alexander N, Shriver LP, Konopka M, Pang Y. Org. Biomol. Chem. 2018; 16: 3382
• 15d Cheng Y, Li G, Liu Y, Shi Y, Gao G, Wu D, Lan J, You J. J. Am. Chem. Soc. 2016; 138: 4730
• 16a Lu Y.-J, Deng Q, Hu D.-P, Wang Z.-Y, Huang B.-H, Du Z.-Y, Fang Y.-X, Wong W.-L, Zhang K, Chow C.-F. Chem. Commun. 2015; 51: 15241
• 16b Shaikh AC, Shalini S, Vaidhyanathan R, Mane MV, Barui AK, Patra CR, Venkatesh Y, Bangal PR, Patil NT. Eur. J. Org. Chem. 2015; 4860
• 16c Hyun JY, Park S.-H, Park CW, Kim HB, Cho JW, Shin I. Org. Lett. 2019; 21: 4439
• 17 3-(2-(2-Bromophenyl)-1H-indol-1-yl)-5,5-dimethylcyclohex-2-en-1-ones 2a–n; General ProcedureA suspension of the appropriate cyclohexanone 1 (1.0 equiv), CuI (0.2 equiv), l-proline (0.4 equiv), and K₂CO₃ (2.0 equiv) in DMSO under N₂ was stirred at 100 °C for 3 h. The mixture was then diluted with H₂O and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, PE–EtOAc (7:3)].3-[2-(2-Bromophenyl)-1H-indol-1-yl]-5,5-dimethylcyclohex-2-en-1-one (2a)Yellow viscous liquid; yield: 276 mg (92%). ¹H NMR (400 MHz, CDCl₃): δ = 7.67 (t, J = 7.7 Hz, 2 H), 7.50 (d, J = 8.2 Hz, 1 H), 7.37 (d, J = 6.3 Hz, 2 H), 7.31–7.22 (m, 3 H), 6.76 (s, 1 H), 6.26 (s, 1 H), 2.28 (s, 2 H), 2.21 (s, 2 H), 0.87 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 199.21, 155.61, 137.65, 136.61, 134.22, 133.30, 132.47, 130.31, 128.64, 127.39, 124.43, 124.35, 123.46, 121.70, 121.25, 111.25, 108.42, 50.96, 44.14, 33.22, 27.94.7,7-Dimethyl-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-ones 3a–m; General ProcedureA solution of the appropriate cyclohexanone 2 (1.0 equiv), t-BuOK (2.0 equiv), and 1,10-phen (0.5 equiv) in DMF was stirred at 120 °C under N₂ until the reaction was complete (TLC). The mixture was then diluted with H₂O and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, PE–EtOAc (8:2)].7,7,12-Trimethyl-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-one (3d)Yellow solid; yield: 50 mg (63%); mp 159–161 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.24 (d, J = 8.3 Hz, 1 H), 7.97 (d, J = 7.8 Hz, 1 H), 7.84 (d, J = 8.7 Hz, 1 H), 7.53–7.39 (m, 3 H), 7.08 (d, J = 8.7 Hz, 1 H), 7.04 (s, 1 H), 3.29 (s, 2 H), 2.53 (s, 2 H), 2.51 (s, 3 H), 1.16 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 197.82, 149.09, 136.48, 133.08, 131.88, 131.85, 128.29, 127.12, 126.77, 125.80, 124.46, 123.25, 123.00, 120.79, 116.15, 112.00, 96.62, 52.32, 44.00, 32.29, 28.62, 21.49. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₂NO: 328.1701; found: 328.1700.