Download PDF
Synlett 2024; 35(20): 2487-2495
DOI: 10.1055/a-2378-1847
letter
Special Issue to Celebrate the 75th Birthday of Prof. B. C. Ranu

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

Keya Roy
a   Department of Chemistry, Indian Institute of Engineering Science and Technology, Shibpur, Botanic Garden, Howrah 711103, India
,
Anay Saha
a   Department of Chemistry, Indian Institute of Engineering Science and Technology, Shibpur, Botanic Garden, Howrah 711103, India
,
Suprakash Sahoo
a   Department of Chemistry, Indian Institute of Engineering Science and Technology, Shibpur, Botanic Garden, Howrah 711103, India
,
Subhrajyoti Banerjee
b   Center of Healthcare Science and Technology, Indian Institute of Engineering Science and Technology, Shibpur, Botanic Garden, Howrah 711103, India
,
Chitrangada Das Mukhopadhyay
b   Center of Healthcare Science and Technology, Indian Institute of Engineering Science and Technology, Shibpur, Botanic Garden, Howrah 711103, India
,
Subhash Banerjee 
c   Department of Chemistry, Guru Ghasidas Vishwavidyalaya, Koni, Bilaspur, PIN 495009, Chhattisgarh, India
,
Laksmikanta Adak∗
a   Department of Chemistry, Indian Institute of Engineering Science and Technology, Shibpur, Botanic Garden, Howrah 711103, India
› Author AffiliationsL. Adak gratefully acknowledges the support of the funding agency Science and Engineering Research Board (SERB), the Department of Science and Technology (DST) and Biotechnology, Ministry of Science and Technology, India (Project SRG/2020/001350), and the Department of Science and Technology (DST), Government of West Bengal (Project 1854 (Sanc.)/ST/P/S&T/15G-7/2019). K.R. is grateful to the Department of Science and Technology (DST), Ministry of Science and Technology, India, New Delhi for providing her with Junior Research Fellowship. A.S. and S.S. thank the Indian Institute of Engineering Science and Technology, Shibpur (IIESTS) for fellowship support. Financial assistance from the IIESTS is acknowledged. DST-sponsored Sophisticated Analytical Instrument Facility (SAIF), IIESTS is acknowledged for providing NMR and HRMS facilities.
› Further Information
    Permissions and Reprints All articles of this category


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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2378-1847.
  • Supporting Information


Publication History

Received: 24 June 2024

Accepted after revision: 01 August 2024

Accepted Manuscript online:
01 August 2024

Article published online:
23 August 2024

© 2024. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References and Notes

  • 13 Roy K, Sahoo S, Saha A, Adak L. Curr. Org. Chem. 2023; 27: 153
    CrossrefSearch in Google Scholar
    • 18a More SV, Sastry MN. V, Yao C.-F. Synlett 2006; 1399
    • 18b Xia M, Lu Y.-D. Synlett 2005; 2357
      Thieme Connect
  • 20 Nagaiah K, Sreenu D, Rao RS, Vashishta G, Yadav JS. Tetrahedron Lett. 2006; 47: 4409
    CrossrefSearch in Google Scholar
  • 21 Zhou Z, Xu F, Han X, Zhou J, Shen Q. Eur. J. Org. Chem. 2007; 5265
    Crossref
  • 23 Rechac VL, Cirujano FG, Corma A, Xamena FX. L. Eur. J. Inorg. Chem. 2016; 4512
    Crossref
  • 24 Yadav JS, Reddy BV. S, Sunitha V, Reddy KS. Adv. Synth. Catal. 2003; 345: 1203
    CrossrefSearch in Google Scholar
  • 26 Yu Y, Zhou J, Yao Z, Xu F, Shen Q. Heteroat. Chem. 2010; 21: 351
    CrossrefSearch in Google Scholar
  • 27 Narsaiah AV, Reddy AR, Reddy BV. S, Yadav JS. Synth. Commun. 2010; 40: 1750
    CrossrefSearch in Google Scholar
  • 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.
  • 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.