Reaction under Ball-Milling: Solvent- and Metal-Free One-Pot Diastereoselective Synthesis of Tetrahydroquinoline Derivatives as Potential Antibacterial and Anticancer Agents

This paper is dedicated to Professor Brindaban C. Ranu on the occasion of his 75^th birthday.

Abstract

A mild and efficient one-pot, three-component ball-mill-assisted reaction of aldehydes, anilines, and dihydrofuran (or dihydropyran and cyclohexenone) has been described for the first time in the presence of the catalytic amount of aqueous perchloric acid (8 mol%) at room temperature under organic solvent- and metal-free conditions. The reactions are fast (1 h), providing the products with excellent yields and high diastereoselectivity. This procedure endows a simple, efficient, and cost-effective method for the diastereoselective synthesis of furano- and pyrano-tetrahydroquinolines and phenanthridinone derivatives, which are important biological compounds. The diastereomers with cis configuration were isolated as major products. The H–H COSY, NOESY experiments and X-ray crystallographic analysis of selected compounds were performed to confirm the cis isomer. The synthesized tetrahydroquinolines have been evaluated in vitro for their antibacterial and anticancer activities, and it was found that both the prepared compounds showed significant antibacterial and anticancer properties.

Key words

ball-milling - solvent-free - diastereoselective synthesis - tetrahydroquinoline derivatives - antibacterial agent - anticancer agent

Publication History

Received: 24 June 2024

Accepted after revision: 01 August 2024

Accepted Manuscript online:
01 August 2024

Article published online:
23 August 2024

• References and Notes

• 1a Wang G.-W. Chem. Soc. Rev. 2013; 42: 7668
• 1b Zhu S.-E, Li F, Wang G.-W. Chem. Soc. Rev. 2013; 42: 7535
• 1c Stolle A, Szuppa T, Leonhardt SE. S, Ondruschka B. Chem. Soc. Rev. 2011; 40: 2317
• 1d James SL, Adams CJ, Bolm C, Braga D, Collier P, Friščić T, Grepioni F, Harris KD. M, Hyett G, Jones W, Krebs A, Mack J, Maini L, Orpen AG, Parkin IP, Shearouse WC, Steed JW, Waddell DC. Chem. Soc. Rev. 2012; 41: 413
• 1e Friščić T, Mottillo C, Titi HM. Angew. Chem. Int. Ed. 2020; 59: 1018
• 1f Achar TK, Bose A, Mal P. Beilstein J. Org. Chem. 2017; 13: 1907
• 1g Joy J, Krishnamoorthy A, Tanna A, Kamathe V, Nagar R, Srinivasan S. Appl. Sci. 2022; 12: 9312
• 1h Bento O, Luttringer F, Dine TM. E, Pétry N, Bantreil X, Lamaty F. Eur. J. Org. Chem. 2022; e202101516
• 1i Krusenbaum A, Grätz S, Tigineh GT, Borchardt L, Kim JG. Chem. Soc. Rev. 2022; 51: 2873
• 2a Green Chemistry Series. Ball Milling Towards Green Synthesis: Applications, Projects, Challenges. Ranu BC, Stolle A. The Royal Society of Chemistry; Cambridge: 2015. Vol. 31
• 2b Avila-Ortiz CG, Juaristi E. Molecules 2020; 25: 3579
• 2c Do J.-L, Friščić T. ACS Cent. Sci. 2017; 3: 13
• 3a Rodríguez B, Bruckmann A, Rantanen T, Bolm C. Adv. Synth. Catal. 2007; 349: 2213
• 3b Cao Q, Stark RT, Fallis IA, Browne DL. ChemSusChem 2019; 12: 2554
• 4a Thorwirth R, Stolle A, Ondruschka B, Wild A, Schubert US. Chem. Commun. 2011; 47: 4370
• 4b Wang Y, Wang H, Jiang YC, Shao ZJ, Xu D. Green Chem. 2017; 19: 1674
• 4c Hernandez JG, Juaristi E. J. Org. Chem. 2010; 75: 7107
• 4d Bonnamour J, Metro T.-X, Martirez J, Lamaty F. Green Chem. 2013; 15: 1116
• 4e Zhang Z, Wu H.-H, Tan Y.-J. RSC Adv. 2013; 3: 16940
• 5a Jones AC, Nicholson WI, Leitch JA, Browne DL. Org. Lett. 2021; 23: 6337
• 5b Seo T, Toyoshima N, Kubota K, Ito H. J. Am. Chem. Soc. 2021; 143: 6165
• 5c Jiang ZJ, Li ZH, Yu JB, Su WK. J. Org. Chem. 2016; 81: 10049
• 5d Brahmachari G, Karmakar I, Karmakar P. Green Chem. 2021; 23: 4762
• 5e Hernández JG, Bolm C. Chem. Commun. 2015; 51: 12582
• 5f Hermann GN, Unruh MT, Jung SH, Krings M, Bolm C. Angew. Chem. Int. Ed. 2018; 57: 10723
• 5g Cheng H, Hernández JG, Bolm C. Adv. Synth. Catal. 2018; 360: 1800
• 5h Liu Z, Xu H, Wang GW. Beilstein J. Org. Chem. 2018; 14: 430
• 5i Weng Y, Lan T, Sun C, Yang T, Su W, Xie Y. Org. Chem. Front. 2018; 5: 2103
• 5j Schneider F, Ondruschka B. ChemSusChem 2008; 1: 622
• 5k Lou S.-J, Mao Y.-J, Xu D.-Q, He J.-Q, Chen Q, Xu Z.-Y. ACS Catal. 2016; 6: 3890
• 5l Schmidt R, Thorwirth R, Szuppa T, Stolle A, Ondruschka B, Hopf H. Chem. Eur. J. 2011; 17: 8129
• 5m Thorwirth R, Stolle A, Ondruschka B. Green Chem. 2010; 12: 985
• 5n Su W, Yu J, Li Z, Jiang Z. J. Org. Chem. 2011; 76: 9144
• 5o Qin J, Zuo H, Ni Y, Yu Q, Zhong F. ACS Sustainable Chem. Eng. 2020; 8: 12342
• 5p Seo T, Ishiyama T, Kubota K, Ito H. Chem. Sci. 2019; 10: 8202
• 5q Laskar R, Pal T, Bhattacharya T, Maiti S, Akita M, Maiti D. Green Chem. 2022; 24: 2296
• 5r Jones AC, Nicholson WI, Smallman HR, Browne DL. Org. Lett. 2020; 22: 7433
• 6a Li L, Vozniuk O, Cao Z, Losch P, Felderhoff M, Schüth F. Nat. Commun. 2023; 14: 5257
• 6b Chen H, Wang C, Zheng M, Liu C, Li W, Yang Q, Zhou S, Feng X. J. Energy Chem. 2023; 84: 210
• 7a Thorwirth R, Bernhardt F, Stolle A, Ondruschka B, Asghari J. Chem. Eur. J. 2010; 16: 13236
• 7b Kiani A, Acocella MR, Granata V, Mazzotta E, Malitesta C, Guerra G. ACS Sustainable Chem. Eng. 2022; 10: 16019
• 8a Akelis L, Rousseau J, Juskenas R, Dodonova J, Rousseau C, Menuel S, Prevost D, Tumkevičius S, Monflier E, Hapiot F. Eur. J. Org. Chem. 2016; 1: 31
• 8b Zeng JC, Xu H, Yu F, Zhang Z. Tetrahedron Lett. 2017; 58: 674
• 8c Sahoo PK, Bose A, Mal P. Eur. J. Org. Chem. 2015; 6994
• 8d Sharifi A, Ansari M, Darabi HR, Abaee MS. Tetrahedron Lett. 2016; 57: 529
• 8e Nagarajaiah H, Mishra AK, Moorthy JN. Org. Biomol. Chem. 2016; 14: 4129
• 8f Howard JL, Nicholson W, Sagatov Y, Browne DL. Beilstein J. Org. Chem. 2017; 13: 1950
• 8g Beillard A, Bantreil X, Métro TX, Martinez J, Lamaty F. Green Chem. 2018; 20: 964
• 8h Rangarajan SS, Kunchur HS, Balakrishna MS. Dalton Trans. 2022; 51: 15750
• 9a Mack J, Fulmer D, Sofel S, Santos N. Green Chem. 2007; 9: 1041
• 9b Szuppa T, Stolle A, Ondruschka B, Hopfe W. Green Chem. 2010; 12: 1288
• 9c Kubota K, Pang Y, Miura A, Ito H. Science 2019; 366: 1500
• 10a Machuca E, Rojas Y, Juaristi E. Asian J. Org. Chem. 2015; 4: 46
• 10b Machuca E, Juaristi E. Tetrahedron Lett. 2015; 56: 1144
• 10c Li Z, Jiang Z, Su W. Green Chem. 2015; 17: 2330
• 10d Veverková E, Modrocká V, Šebesta R. Eur. J. Org. Chem. 2017; 1191
• 10e Wang Y, Wang H, Jiang Y, Zhang C, Shao J, Xu D. Green Chem. 2017; 19: 1674
• 10f Staleva P, Hernández JG, Bolm C. Chemistry 2019; 25: 9202
• 10g Rodrguez B, Rantanen T, Bolm C. Angew. Chem. Int. Ed. 2006; 45: 6924
• 10h Rodríguez B, Bruckmann A, Bolm C. Chem. Eur. J. 2007; 13: 4710
• 10i Egorov IN, Santra S, Kopchuk DS, Kovalev IS, Zyryanov GV, Majee A, Ranu BC, Rusinova VL, Chupakhin ON. Green Chem. 2020; 22: 302
• 11a Chakraborty B. J. Heterocycl. Chem. 2020; 57: 477
• 11b Fanga R.-K, Yina Z.-C, Chena J.-S, Wang G.-W. Green Chem. Lett. Rev. 2022; 15: 519
• 11c Rinaldi L, Martina K, Baricco F, Rotolo L, Cravotto G. Molecules 2015; 20: 2837
• 12a Leonardi M, Villacampa M, Menendéz JC. Chem. Sci. 2018; 9: 2042
• 12b Pérez-Venegas M, Juarist E. ACS Sustainable Chem. Eng. 2020; 8: 8881
• 13 Roy K, Sahoo S, Saha A, Adak L. Curr. Org. Chem. 2023; 27: 153
• 14a Gharpure SJ, Vishwakarma DS. Eur. J. Org. Chem. 2020; 6887
• 14b Kumar A, Srivastava S, Gupta G, Chaturvedi V, Sinha S, Srivastava R. ACS Comb. Sci. 2011; 13: 65
• 14c Kantevari S, Yempala T, Surineni G, Sridhar B, Yogeeswari P, Sriram D. Eur. J. Med. Chem. 2011; 46: 4827
• 14d Muthukrishnan I, Sridharan V, Menendez JC. Chem. Rev. 2019; 119: 5057
• 14e Rangappa SK, Patil SA. Biomed. Pharmacother. 2014; 68: 1161
• 15a Schiemann K, Finsinger D, Zenke F, Amendt C, Knochel T, Bruge D, Buchstaller H, Emde U, Stahle W, Anzali S. Bioorg. Med. Chem. Lett. 2010; 20: 1491
• 15b Kantevari S, Yempala T, Surineni G, Sridhar B, Yogeeswari P, Sriramc D. Eur. J. Med. Chem. 2011; 46: 4827
• 15c Lavanya G, Venkatapathy K, Magesh CJ, Ramanathan M, Jayasudha R. Bioorg. Chem. 2019; 84: 125
• 16a Babu G, Perumal PT. Tetrahedron Lett. 1998; 39: 3225
• 16b Crousse B, Bégué JP, Bonnet-Delpon D. J. Org. Chem. 2000; 65: 5009
• 16c Yadav JS, Subba Reddy BV, Srinivas R, Madhuri C, Ramalingam T. Synlett 2001; 240
• 16d Yadav JS, Subba Reddy BV, Madhuri C, Sabitha G. Synthesis 2001; 1065
• 16e Makioka Y, Shindo T, Taniguchi Y, Takaki K, Fujiwara Y. Synthesis 1995; 801
• 16f Yu J, Jiang H.-J, Zhou Y, Luo S.-W, Gong L.-Z. Angew. Chem. Int. Ed. 2015; 54: 11209
• 16g Sundararajan G, Prabagaran N, Varghese B. Org. Lett. 2001; 3: 1973
• 16h Mahesh M, Reddy CV, Reddy KS, Raju PV. K, Reddy VV. N. Synth. Commun. 2004; 34: 4089
• 16i Nagarajan R, Chitra S, Perumal PT. Tetrahedron 2001; 57: 3419
• 16j Masaki Y, Yamada T, Kawai H, Itoh A, Arai Y, Furukawa H. Synlett 2006; 288
• 16k Bonilla CA. M, Galvis CE. P, Méndez LY. V, Kouznetsov VV. RSC Adv. 2016; 6: 37478
• 16l Dong T, Wei P, Li M, Gao F, Qin Y. Front. Chem. 2021; 9: 764866
• 17a Ma Y, Qian C, Xie M, Sun J. J. Org. Chem. 1999; 64: 6462
• 17b Srinivas KV. N. S, Das B. Synlett 2004; 1715
• 17c Ansari MI, Hussain MK, Hajela K. ChemistrySelect 2018; 3: 3318
• 18a More SV, Sastry MN. V, Yao C.-F. Synlett 2006; 1399
• 18b Xia M, Lu Y.-D. Synlett 2005; 2357
• 19a Mahajan D, Ganai BA, Sharma RL, Kapoor KK. Tetrahedron Lett. 2006; 47: 7919
• 19b Maiti G, Kundu P. Tetrahedron Lett. 2006; 47: 5733
• 19c Sabitha G, Reddy MS. K, Arundhathi K, Yadav JS. ARKIVOC 2006; (vi): 153
• 20 Nagaiah K, Sreenu D, Rao RS, Vashishta G, Yadav JS. Tetrahedron Lett. 2006; 47: 4409
• 21 Zhou Z, Xu F, Han X, Zhou J, Shen Q. Eur. J. Org. Chem. 2007; 5265
• 22a Palaniappan S, Rajender B, Umashankar M. J. Mol. Catal. A: Chem. 2012; 352: 70
• 22b Puligoundla RG, Vulupala HR, Kommu N, Kondra SB. Synth. Commun. 2015; 45: 494
• 23 Rechac VL, Cirujano FG, Corma A, Xamena FX. L. Eur. J. Inorg. Chem. 2016; 4512
• 24 Yadav JS, Reddy BV. S, Sunitha V, Reddy KS. Adv. Synth. Catal. 2003; 345: 1203
• 25a Yadav JS, Reddy BV. S, Reddy JS. S, Rao RS. Tetrahedron 2003; 59: 1599
• 25b Sahiba N, Sethiya A, Teli P, Agarwal S. ACS Omega 2023; 8: 5877
• 26 Yu Y, Zhou J, Yao Z, Xu F, Shen Q. Heteroat. Chem. 2010; 21: 351
• 27 Narsaiah AV, Reddy AR, Reddy BV. S, Yadav JS. Synth. Commun. 2010; 40: 1750
• 28 See the Supporting Information for details. CCDC numbers of two new molecules are 2357887 (4a) and 2357885 (4i) and contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
• 29 See the Supporting Information for H-H COSY spectra (in CDCl₃) of 4a and 4h and NOESY spectra of compound 4a.
• 30a Ngamsurach P, Praipipat P. RSC Adv. 2022; 12: 26435
• 30b Hannaa JN, Ndip RA, Ngemenyac MN, Simons CR, Toze FA. A, Ghogomu SM, Mbah JA. Sci. Afr. 2022; 17: e01302
• 31a Paul S, Goswami S, Mukhopadhyay CD. New J. Chem. 2015; 39: 8940
• 31b Sengupta S, Banerjee S, Nayek SN, Das P, Chakraborty D, Mukherjee A, Mandal T, Majumder A, Saha M, Chatterjee S, Bhattacharya M. Int. J. Herb. Med. 2023; 11: 14
• 32 Representative Experimental Procedure for the Synthesis of (3aS,4S,9bS)-4-Phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4a, cisIsomer) A mixture of aniline (186 mg, 2 mmol), benzaldehyde (212 mg, 2 mmol), 2,3-dihydrofuran (210 mg, 3 mmol), and aqueous perchloric acid (70%, 16.1 mg, 8 mol%) adsorbed on neutral alumina (6 g) was ball-milled in a 50 mL stainless-steel beaker with five balls (d = 10 mm) of the same material at 350 rpm for 1 h. The ball-milling operation was performed using inverted rotation directions, with an interval of 15 min and taking an interval break of 30 s. Extraction of the reaction residue by simple elution with ethyl acetate followed by evaporation of the solvent gave the crude product, which was purified by column chromatography over silica gel (60–120 mesh) using a 5% ethyl acetate/hexane mixed solvent as eluant to give cis 4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline as a white solid (462 mg, 92% yield, diastereoselective ratio cis:trans = 92:8). The identity and purity of products were confirmed by ¹H NMR and ¹³C NMR spectroscopic analysis and HRMS analysis. 3aS,4S,9bS)-4-Phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4a, cisIsomer) White solid; mp 93–95 ℃. IR (neat): ν = 3327, 2976, 2873, 1605, 1480, 1259, 1054, 1025 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.49–1.59 (m, 1 H), 2.16–2.29 (m, 1 H), 2.75–2.85 (m, 1 H), 3.73 (q, J = 11.1 Hz, 1 H), 3.84 (td, J = 11.2, 4.4 Hz, 2 H), 4.70 (d, J = 3.7 Hz, 1 H), 5.29 (d, J = 8.9 Hz, 1 H), 6.61 (d, J = 10.7 Hz, 1 H), 6.83 (t, J = 9.9 Hz, 1 H), 7.11 (t, J = 10.1 Hz, 1 H), 7.30–7.49 (m, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 24.8, 45.9, 57.6, 66.9, 76.1, 115.0, 119.3, 122.8, 126.6 (2 C), 127.8, 128.5, 128.8 (2 C), 130.2, 142.3, 145.1. HRMS (EI⁺): m/z [M]⁺ calcd for C₁₇H₁₇NO: 251.1310; found: 251.1313. (3aS,4S,9bS)-6-Fluoro-4-phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4b, cisIsomer) White solid; mp 106–108 °C. IR (neat): ν = 3376, 2911, 2843, 1618, 1484, 1208, 1044 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.51–1.58 (m, 1 H), 2.14–2.25 (m, 1 H), 2.76–2.83 (m, 1 H), 3.70–3.76 (m, 1 H), 3.82 (td, J = 8.8, 3.2 Hz, 1 H), 4.14 (s, 1 H), 4.71 (d, J = 2.8 Hz, 1 H), 5.28 (d, J = 7.8 Hz, 1 H), 6.69–6.74 (m, 1 H), 6.88–6.93 (m, 1 H), 7.14 (d, J = 7.7 Hz, 1 H), 7.30–7.41 (m, 3 H), 7.44–7.49 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 24.6, 45.7, 57.0, 67.0, 75.6, 113.6 (d, J = 18 Hz, 1 C), 118.1 (d, J = 7.0 Hz, 1 C), 125.0 (d, J = 2.0 Hz, 1 C), 125.1 (d, J = 3.0 Hz, 1 C), 126.6 (2 C), 127.9, 128.9 (2 C), 133.6 (d, J = 12.0 Hz, 1 C), 141.8, 151.0 (d, J = 238.0 Hz, 1 C). HRMS (EI⁺): m/z [M]⁺ calcd for C₁₇H₁₆FNO: 269.1216; found: 269.1216. (3aS,4S,9bS)-4-(p-Tolyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4g,cisIsomer) Orangish yellow solid; mp 106–108 °C. IR (neat): ν = 3314, 2910, 2874, 1598, 1481, 1290, 1048 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.50–1.58 (m, 1 H), 2.16–2.26 (m, 1 H), 2.37 (s, 3 H), 2.75–2.78 (m, 1 H), 3.70–3.83 (m, 3 H), 4.67 (d, J = 2.8 Hz, 1 H), 5.27 (d, J = 7.9 Hz, 1 H), 6.61 (d, J = 7.9 Hz, 1 H), 6.81 (td, J = 7.2, 0.8 Hz, 1 H), 7.09 (t, J = 7.8 Hz, 1 H), 7.20 (d, 7.9 Hz, 2 H), 7.31–7.41 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.2, 24.8, 45.9, 57.4, 67.0, 76.1, 115.0, 119.2, 122.8, 126.5 (2 C), 128.5, 129.4 (2 C), 130.2, 137.5, 139.3, 145.2. HRMS (EI⁺): m/z [M]⁺ calcd for C₁₈H₁₉NO: 265.1467; found: 265.1465. (4aS,5S,10bS)-5-Phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline (4h, cis Isomer) White solid; mp 128–130 °C. IR (neat): ν = 3313, 2939, 2865, 1605, 1487, 1274, 1062 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.30–1.34 (m, 1 H), 1.41–1.46 (m, 1 H), 1.51–1.59 (m, 2 H), 2.15–2.21 (m, 1 H), 3.45 (td, J = 9.1, 2.6 Hz, 1 H), 3.58–3.62 (m, 1 H), 3.88 (br s, 1 H), 4.70 (d, J = 2.4 Hz, 1 H), 5.34 (d, J = 5.6 Hz, 1 H), 6.61 (dd, J = 7.9, 0.6 Hz, 1 H), 6.78–6.81 (td, J = 7.7, 0.7 Hz, 1 H), 7.11 (td, J = 7.9, 0.6 Hz, 1 H), 7.30–7.34 (m, 1 H), 7.37–7.45 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = 18.2, 25.6, 39.1, 59.5, 60.8, 72.9, 114.5, 118.4, 120.0, 126.9 (2 C), 127.6, 127.8, 128.2, 128.5 (2 C), 141.3, 145.3. HRMS (EI⁺): m/z [M]⁺ calcd for C₁₈H₁₉NO: 265.1467; found: 265.1467. (4aS,5S,10bS)-5-(Naphthalen-1-yl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline (4l, cis Isomer) Yellow solid; mp 130–132 °C. IR (neat): ν = 3380, 2903, 2837, 1598, 1481, 1304, 1268,1055 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.17–1.20 (m, 1 H), 1.39–1.66 (m, 3 H), 2.45–2.51 (m, 1 H), 3.46 (td, J = 10.6, 2.8 Hz, 1 H), 3.60 (dd, J = 11.3, 4.3 Hz, 1 H), 3.89 (br s, 1 H), 5.50–5.52 (m, 2 H), 6.69 (d, J = 7.8 Hz, 1 H), 6.85 (t, J = 7.52 Hz, 1 H), 7.15 (t, J = 7.4 Hz, 1 H), 7.50–7.59 (m, 4 H), 7.82 (t, J = 7.7 Hz, 2 H), 7.91–7.94 (m, 1 H), 7.98 (d, J = 8.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 18.7, 25.5, 36.7, 55.1, 60.8, 72.8, 114.8, 118.5, 120.3, 122.4, 123.8, 125.2, 125.8, 126.5, 127.9, 128.1, 128.2, 129.3, 130.5, 134.0, 136.2, 145.7. HRMS (EI⁺): m/z [M]⁺ calcd for C₂₂H₂₁NO: 315.1623; found: 315.1623. (3aS,4S,9bS)-4-(Thiophen-2-yl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (4o, cis Isomer) Brown solid; mp 90–92 °C. IR (neat): ν = 3357, 2910, 2874, 1598, 1466, 1253, 1048 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.91–1.99 (m, 1 H), 2.40–2.50 (m, 1 H), 2.97–3.05 (m, 1 H), 3.65 (q, J = 7.2 Hz, 1 H), 3.91–4.00 (m, 2 H), 5.15 (d, J = 2.9 Hz, 1 H), 5.43 (d, J = 7.8 Hz, 1 H), 6.76 (d, J = 8 Hz, 1 H), 7.00 (td, J = 7.2, 0.4 Hz, 1 H), 7.17–7.19 (m, 1 H), 7.24–7.28 (m, 2 H), 7.42–743 (m, 1 H), 7.52 (d, J = 7.5 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 25.3, 46.1, 53.8, 66.7, 75.8, 115.1, 119.7, 122.9, 124.2, 124.4, 126.8, 128.5, 130.2, 144.5, 145.6. HRMS (EI⁺): m/z [M]⁺ calcd for C₁₅H₁₅NOS: 257.0874; found: 257.0870.> (3aS,4R,9bS)-4-Heptyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (7a, cis Isomer) Yellow solid; mp 58–60 °C. IR (neat): ν = 3335, 2918, 2844, 1598, 1481, 1290, 1055 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 0.89–0.93 (m, 5 H), 1.31–1.35 (m, 9 H), 1.50–1.54 (m, 2 H), 1.81–1.89 (m, 1 H), 1.98–2.08 (m, 1 H), 2.58–2.66 (m, 1 H), 3.40–3.44 (m, 1 H), 3.78–3.82 (m, 2 H), 5.12 (d, J = 7.9 Hz, 1 H), 6.51 (d, J = 7.8 Hz, 1 H), 6.75 (t, J = 6.8 Hz, 1 H), 7.04 (td, J = 7.4, 1.2 Hz, 1 H), 7.30 (d, J = 7.5 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.2, 22.8, 24.1, 26.0, 29.3, 29.8, 31.9, 34.5, 42.6, 52.6, 66.7, 75.9, 114.5, 118.7, 123.0, 128.3, 130.2, 145.2. HRMS (EI⁺): m/z [M]⁺ calcd for C₁₈H₂₇NO: 273.2093; found: 273.2096. (3aS,4S,9bS)-4-(tert-Butyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (7d, cis Isomer) Pale green solid; mp 104–106 °C. IR (neat): ν = 3350, 2947, 2881, 1598, 1473, 1298, 1055 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.05 (s, 9 H), 1.83–1.91 (m, 1 H), 2.03–2.13 (m, 1 H), 2.68–2.75 (m, 1 H), 3.22 (d, J = 1.8 Hz, 1 H), 3.50–3.88 (m, 3 H), 5.18 (d, J = 7.5 Hz, 1 H), 6.55 (d, J = 8.0 Hz, 1 H), 6.75 (d, J = 7.6 Hz, 1 H), 7.04 (td, J = 7.6 Hz, 1 H), 7.31 (d, J = 7.56 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 24.6, 27.4(3C), 33.7, 39.9, 61.4, 67.1, 77.6, 114.6, 118.5, 122.6, 128.2, 129.8, 145.6. HRMS (EI⁺): m/z [M]⁺ calcd for C₁₅H₂₁NO: 231.1623; found: 231.1623. (6S,6aR,10aS)-2-Methyl-6-phenyl-5,6a,7,8,9,10a-hexahydrophenanthridin-10(6H)-one (10c, cis Isomer) Yellow liquid. IR (neat): ν = 3365, 2918, 2844, 1715, 1605, 1510, 1209 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.64–1.72 (m, 1 H), 1.94–2.15 (m, 2 H), 2.19 (s, 3 H), 2.22–2.27 (m, 2 H), 2.42 (dd, J = 18.8, 2.5 Hz, 1 H), 2.69–2.75 (m, 2 H), 4.47 (s, 1 H), 4.58 (d, J = 2.4 Hz, 1 H), 6.54 (d, J = 8.6 Hz, 2 H), 6.95 (d, J = 8.4 Hz, 2 H), 7.17–7.22 (m, 1 H), 7.27–7.34 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 20.3, 22.6, 22.7, 46.0, 48.8, 52.3, 66.0, 113.4 (2 C), 125.7 (2 C), 127.0, 127.5, 129.0 (2 C), 129.9 (2 C), 142.0, 146.0, 212.1. HRMS (FAB⁺): m/z [M + H]⁺ calcd for C₂₀H₂₂NO: 292.1701; found: 292.1701.