Next Article in Journal
2-Diphenylphosphinomethyl-3-methylpyrazine
Previous Article in Journal
4-Chlorobenzyl Chloride
Communication

4-Aminoalkyl Quinolin-2-one Derivatives via Knorr Cyclisation of ω-Amino-β-Keto Anilides

Faculty of Chemistry, University of Plovdiv Paisii Hilendarski, 24 Tsar Asen Str., 4000 Plovdiv, Bulgaria
*
Author to whom correspondence should be addressed.
Academic Editor: Raffaella Mancuso
Molbank 2021, 2021(3), M1266; https://doi.org/10.3390/M1266
Received: 14 June 2021 / Revised: 23 June 2021 / Accepted: 2 August 2021 / Published: 5 August 2021
(This article belongs to the Section Organic Synthesis)

Abstract

In a high-yielding and solvent-free procedure N-ethoxycarbonyl protected ω-amino-β-keto anilides undergo Knorr cyclisation in neat polyphosphoric acid to provide straightforward route to 4-aminoalkyl quinolin-2-one derivatives with variable length of the alkyl chain.
Keywords: Knorr; quinolin-2-one; 2-quinolone; carbostyril; solvent-free Knorr; quinolin-2-one; 2-quinolone; carbostyril; solvent-free

1. Introduction

The quinoline ring system is present in a vast number of natural [1,2] and synthetic [3,4] organic compounds with valuable properties. Among this large group, the subclass of quinolin-2-ones (also known as carbostyrils) stands out with many bioactive structures [5]. For example, the quinolin-2-one fragment is found in alkaloids such as Viridicatins [6,7,8,9], Aflaquinolones [10] and Yaequinolones [11], as well as in synthetic drug candidates with anti-inflammatory [12,13] and antibacterial [14] properties. The construction of the quinolin-2-one ring system is most commonly achieved via the classic Knorr cyclisation of β-keto anilides in acidic media [15,16]. The mechanism of this reaction has been studied in detail [17] and also an alternative approach based on N-aryl amides of 3-arylpropynoic acids has been developed [18]. In addition to this classical method, the scope of which is limited in the presence of acid-sensitive functionalities, there have been many recent developments. The modern approaches include Pd-catalysed formation of C-C or C-N bonds in the ring system [19,20,21], Pd-catalyzed synthesis from quinoline N-oxides and azodicarboxylates [22], Co-catalyzed cyclization of α-bromo-N-phenylacetamides [23], Intermolecular addition/cyclization of carbamoyl radicals under photoredox [24] or Ag [25] catalysis, hypervalent iodine(III)-mediated decarboxylative cyclization [26] and chemoenzymatic approaches [27,28].
Quinolin-2-ones with aminoalkyl substituent at position 4 are interesting as building blocks for complex natural products [29,30] and also in their own right as bioactive substances [12,13,14]. To date, all instances of these molecules in the literature are synthesised by either SN2 amination of the corresponding 4-halogenoalkyl derivatives [12,13,31,32] or hydrogenation of the corresponding 4-cyano derivatives [14]–approaches that work mostly for the preparation of 4-aminomethyl derivatives and are not well suited for derivatives with a longer carbon chain between the amino functionality and the quinolin-2-one core. In this communication, we demonstrate that the Knorr reaction can be successfully carried out with N-ethoxycarbonyl protected ω-amino-β-keto anilides, leading directly to the corresponding 4-aminoalkyl quinolin-2-one derivatives with variable length of the alkyl chain.

2. Results

The problematic accessibility of ω-amino-β-keto anilides (1) by known methods is probably the main reason why these compounds have not been used as precursors to quinolin-2-ones until now. However, since a method developed recently in our laboratory provided easy access to these substrates [33], we decided to investigate their behaviour under Knorr-type conditions. After a quick screening of various acids and solvents, we arrived at polyphosphoric acid (PPA) as the optimal medium for the targeted cyclocondensation of 1 to 4-aminoalkylquinolin-2-ones 2. The cyclisation of 1 to 2 (Scheme 1, Table 1) proceeded for 90 min at 80 °C in neat PPA. The products 2 were isolated in 80–90% yield after easy workup, including only the addition of water to the reaction mixture and filtration of the precipitated product or, optionally, extraction in CH2Cl2. Although the extractive workup gave slightly cleaner products in case 2b and 2c, this synthesis could be carried out as a completely solvent-free procedure, depending on the operator preferences.

3. Materials and Methods

The starting N-ethoxycarbonyl ω-amino-β-keto anilides (1) were prepared from the corresponding ω-amino acids and acetoacetanilide, according to our previously published procedure [33]. Polyphosphoric acid (115% H3PO4 basis, CAS No. 8017-16-1) was purchased from (Sigma-Aldrich, Darmstadt, Germany). NMR spectra were run on a Bruker Avance AV600 (600/150 MHz 1H/13C) or Bruker DRX 250 (250/62.5 MHz 1H/13C) spectrometers at BAS-IOCCP—Sofia and chemical shifts (δ, ppm) are downfield from TMS. High resolution mass spectral measurements were performed on a Thermo Scientific Q Exactive hybrid quadrupole-orbitrap mass spectrometer. TLC was conducted on aluminium-backed Silica gel 60 sheets (Merck) with KMnO4 staining; Melting points were measured on Boetius hot stage apparatus and are not corrected.

Synthetic Procedure

4-aminoalkyl quinolin-2-ones (2ac), general procedure: To the corresponding β-keto anilide 1ac (200 mg) in a glass vial was added PPA (5–6 g, 2.5–3 mL). The mixture was heated to 80 °C and was stirred intensely until full homogenization (ca. 15–20 min). The homogenous mixture was left for a further 90 min. at 80 oC, then the vial was cooled to r.t. with tap water and the contents were rinsed and poured into a glass with 50–70 mL of water. The isolation of the products 2ac was conducted by filtration of the resulting suspension (2a) or by extraction with 2 × 30 mL CH2Cl2 (2b, 2c). The yields of 2b and 2c were practically unaffected by the type of workup procedure (filtration or extraction). For product 2a, filtration is recommended because of its poor solubility in CH2Cl2.
(2-Oxo-1,2-dihydro-quinolin-4-ylmethyl)-carbamic acid ethyl ester (2a): m.p. 173–174 °C; 1H NMR (DMSO-d6, δ ppm, J Hz): 1.19 (t, J = 7, 3H), 4.04 (q, J = 7, 2H), 4.42 (d, J = 5.9, 2H), 6.32 (s, 1H), 7.18–7.77 (m, 4H, ArH), 7.76 (br t, 1H, NH), 11.71 (br s, 1H, NH); 13C NMR (DMSO-d6, δ ppm): 15.1, 41.3, 60.6, 116.1, 118.1, 118.7, 122.2, 124.3, 130.9, 139.3, 148.9, 156.9, 162.1; HRMS (ES+): m/z [M + Na]+ calcd for C13H14N2NaO3+: 269.0897, found: 269.0896;
[2-(2-Oxo-1,2-dihydro-quinolin-4-yl)-ethyl]-carbamic acid ethyl ester (2b): m.p. 185–186 °C; 1H NMR (250 MHz, DMSO-d6, δ ppm, J Hz): 1.15 (t, 3H, J = 7), 2.95 (t, 2H, J = 7), 3.29 (m, 2H), 3.98 (q, 2H, J = 7), 6.36 (s, 1H), 7.17–7.84 (m, 5H) ArH +NH, 11.64 (s, 1H) NH; 13C NMR (DMSO-d6, δ ppm): 161.51, 156.31, 148.74, 138.96, 130.16, 124.32, 121.68, 120.99, 118.80, 115.68, 59.60, 39.74, 31.82, 14.62; HRMS (ES+): m/z [M + Na]+ calcd for C14H16N2NaO3+: 283.1053, found: 283.1055;
[3-(2-Oxo-1,2-dihydro-quinolin-4-yl)-propyl]-carbamic acid ethyl ester (2c): m.p. 116–118 °C; 1H NMR (250 MHz, CDCl3, δ ppm, J Hz): 1.27 (t, 3H, J = 7), 1.97 (m, 2H), 2.94 (t, 2H, J = 8), 3.34 (m, 2H), 4.15 (q, 2H, J = 7), 4.98 (br s, 1H) NH, 6.66 (s, 1H), 7.23–7.74 (m, 4H) ArH, 12.67 (br s, 1H) NH; 13C NMR (DMSO-d6, δ ppm): 164.12, 156.85, 152.89, 138.42, 130.69, 124.02, 122.87, 119.78, 119.04, 117.11, 60.90, 40.63, 29.40. 29.20, 14.66; HRMS (ES+): m/z [M + Na]+ calcd for C15H18N2NaO3+: 297.1210, found: 297.1206.

Supplementary Materials

The following are available online, S1.PDF—processed 1H and 13C NMR spectra. S2.zip—Raw NMR data, and mol files structure.

Author Contributions

Conceptualization, chemical synthesis and manuscript writing: P.A.; chemical synthesis: S.V. and P.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Bulgarian National Science Fund, grant number DN09-15/2016.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available in this article and supporting Supplementary Materials.

Acknowledgments

The authors are grateful to the Faculty of Biology, Department of Plant Physiology and Molecular Biology for access to high resolution mass spectrometer, provided under the EC FP7/REGPOT-2009-1/BioSupport project.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Shang, X.-F.; Natschke, S.L.M.; Liu, Y.-Q.; Guo, X.; Xu, X.-S.; Goto, M.; Li, J.-C.; Yang, G.-Z.; Lee, K.-H. Biologically active quinoline and quinazoline alkaloids part I. Med. Res. Rev. 2018, 38, 775–828. [Google Scholar] [CrossRef] [PubMed]
  2. Shang, X.-F.; Natschke, S.L.M.; Yang, G.-Z.; Liu, Y.-Q.; Guo, X.; Xu, X.-S.; Goto, M.; Li, J.-C.; Zhang, J.-Y.; Lee, K.-H. Biologically active quinoline and quinazoline alkaloids part II. Med. Res. Rev. 2018, 38, 1614–1660. [Google Scholar] [CrossRef] [PubMed]
  3. Nainwal, N.M.; Tasneem, S.; Akhtar, W.; Verma, G.; Khan, M.F.; Parvez, S.; Shaquiquzzaman, M.; Akhter, M.; Alam, M.M. Green recipes to quinoline: A review. Eur. J. Med. Chem. 2019, 164, 121–170. [Google Scholar] [CrossRef] [PubMed]
  4. Harry, N.A.; Ujwaldev, S.M.; Anilkumar, G. Recent advances and prospects in the metal-free synthesis of quinolines. Org. Biomol. Chem. 2020, 18, 9775–9790. [Google Scholar] [CrossRef]
  5. Tashima, T. The structural use of carbostyril in physiologically active substances. Bioorg. Med. Chem. Lett. 2015, 25, 3415–3419. [Google Scholar] [CrossRef] [PubMed]
  6. Kobayashi, Y.; Harayama, T. A Concise and Versatile Synthesis of Viridicatin Alkaloids from Cyanoacetanilides. Org. Lett. 2009, 11, 1603–1606. [Google Scholar] [CrossRef]
  7. Tangella, Y.; Manasa, K.L.; Krishna, N.H.; Sridhar, B.; Kamal, A.; Babu, B.N. Regioselective Ring Expansion of Isatins with In Situ Generated α-Aryldiazomethanes: Direct Access to Viridicatin Alkaloids. Org. Lett. 2018, 20, 3639–3642. [Google Scholar] [CrossRef]
  8. Liang, P.; Zhang, Y.Y.; Yang, P.; Grond, S.; Zhang, Y.; Qian, Z.-J. Viridicatol and viridicatin isolated from a shark-gill-derived fungus Penicilliumpolonicum AP2T1 as MMP-2 and MMP-9 inhibitors in HT1080 cells by MAPKs signaling pathway and docking studies. Med. Chem. Res. 2019, 28, 1039–1048. [Google Scholar] [CrossRef]
  9. Einsiedler, M.; Jamieson, C.S.; Maskeri, M.A.; Houk, K.N.; Gulder, T.A.M. Fungal Dioxygenase AsqJ is Promiscuous and Bimodal: Substrate-Directed Formation of Quinolones versus Quinazolinones. Angew. Chem. Int. Ed. 2021, 60, 8297–8302. [Google Scholar] [CrossRef] [PubMed]
  10. Neff, S.A.; Lee, S.U.; Asami, Y.; Ahn, J.S.; Oh, H.; Baltrusaitis, J.; Gloer, J.B.; Wicklow, D.T. Aflaquinolones A−G: Secondary Metabolites from Marine and Fungicolous Isolates of Aspergillus spp. J. Nat. Prod. 2012, 75, 464–472. [Google Scholar] [CrossRef]
  11. Jia, W.-L.; Ces, S.V.; Fernández-Ibánez, M.A. Divergent Total Syntheses of Yaequinolone-Related Natural Products by Late-Stage C−H Olefination. J. Org. Chem. 2021, 86, 6259–6277. [Google Scholar] [CrossRef]
  12. Kalkhambkar, R.G.; Kulkarni, G.M.; Kamanavalli, C.M.; Premkumar, N.; Asdaq, S.M.B.; Sun, C.M. Synthesis and biological activities of some new fluorinated coumarins and 1-aza coumarins. Eur. J. Med. Chem. 2008, 43, 2178–2188. [Google Scholar] [CrossRef] [PubMed]
  13. Bonnefous, C.; Payne, J.E.; Roppe, J.; Zhuang, H.; Chen, X.; Symons, K.T.; Nguyen, P.M.; Sablad, M.; Rozenkrants, N.; Zhang, Y.; et al. Discovery of Inducible Nitric Oxide Synthase (iNOS) Inhibitor Development Candidate KD7332, Part 1: Identification of a Novel, Potent, and Selective Series of Quinolinone iNOS Dimerization Inhibitors that are Orally Active in Rodent Pain Models. J. Med. Chem. 2009, 52, 3047–3062. [Google Scholar] [CrossRef] [PubMed]
  14. Skepper, C.K.; Armstrong, D.; Balibar, C.J.; Bauer, D.; Bellamacina, C.; Benton, B.M.; Bussiere, D.; De Pascale, G.; De Vicente, J.; Dean, C.R.; et al. Topoisomerase Inhibitors Addressing Fluoroquinolone Resistance in Gram-Negative Bacteria. J. Med. Chem. 2020, 63, 7773–7816. [Google Scholar] [CrossRef] [PubMed]
  15. Yuan, Y.; Yang, R.; Zhang-Negrerie, D.; Wang, J.; Du, Y.; Zhao, K. One-Pot Synthesis of 3-Hydroxyquinolin-2(1H)-ones from NPhenylacetoacetamide via PhI(OCOCF3)2-Mediated α-Hydroxylation and H2SO4-Promoted Intramolecular Cyclization. J. Org. Chem. 2013, 78, 5385–5392. [Google Scholar] [CrossRef] [PubMed]
  16. Liu, X.; Zhang, Q.; Zhang, D.; Xin, X.; Zhang, R.; Zhou, F.; Dong, D. PPA-Mediated C-C Bond Formation: A Synthetic Route to Substituted Indeno[2,1-c]quinolin-6(7H)-ones. Org. Lett. 2013, 15, 776–779. [Google Scholar] [CrossRef]
  17. Sai, K.K.S.; Gilbert, T.M.; Klumpp, D.A. Knorr Cyclizations and Distonic Superelectrophiles. J. Org. Chem. 2007, 72, 9761–9764. [Google Scholar] [CrossRef] [PubMed]
  18. Ryabukhin, D.S.; Gurskaya, L.Y.; Fukin, G.K.; Vasilyev, A.V. Superelectrophilic activation of N-aryl amides of 3-arylpropynoic acids: Synthesis of quinolin-2(1H)-one derivatives. Tetrahedron 2014, 70, 6428–6443. [Google Scholar] [CrossRef]
  19. Guan, M.; Pang, Y.; Zhang, J.; Zhao, Y. Pd-Catalyzed sequential β-C(sp3)–H arylation and intramolecular amination of δ-C(sp2)–H bonds for synthesis of quinolinones via an N,O-bidentate directing group. Chem. Commun. 2016, 52, 7043–7046. [Google Scholar] [CrossRef]
  20. Han, J.; Wu, X.; Zhang, Z.; Wang, L. Palladium-catalyzed arylation/cyclization/desulfonation cascades toward 4-aryl quinolin-2(1H)-ones with diaryliodonium salts. Tetrahedron Lett. 2017, 58, 3433–3436. [Google Scholar] [CrossRef]
  21. Silva, V.L.M.; Silva, A.M.S. Palladium-Catalysed Synthesis and Transformation of Quinolones. Molecules 2019, 24, 228. [Google Scholar] [CrossRef]
  22. Peng, J.-B.; Chen, B.; Qi, X.; Ying, J.; Wu, X.-F. Palladium-catalyzed synthesis of quinolin-2(1H)-ones: The unexpected reactivity of azodicarboxylate. Org. Biomol. Chem. 2018, 16, 1632–1635. [Google Scholar] [CrossRef]
  23. Cheng, Y.-C.; Chen, Y.-Y.; Chuang, C.-P. Cobalt salt-catalyzed carbocyclization reactions of α-bromo-N-phenylacetamide derivatives. Org. Biomol. Chem. 2017, 15, 2020–2032. [Google Scholar] [CrossRef]
  24. Petersen, W.F.; Taylor, R.J.K.; Donald, J.R. Photoredox-catalyzed procedure for carbamoyl radical generation: 3,4-dihydroquinolin-2-one and quinolin-2-one synthesis. Org. Biomol. Chem. 2017, 15, 5831–5845. [Google Scholar] [CrossRef] [PubMed]
  25. Jin, C.; He, J.-Y.; Bai, Q.-F.; Feng, G. Silver-Catalyzed Decarboxylative Radical Addition/Cyclization of Oxamic Acids with Alkenes towards quinolin-2-ones. Synlett 2020, 31, 1517–1522. [Google Scholar] [CrossRef]
  26. Fan, H.; Pan, P.; Zhang, Y.; Wang, W. Synthesis of 2-Quinolinones via a Hypervalent Iodine(III)-Mediated Intramolecular Decarboxylative Heck-Type Reaction at Room Temperature. Org. Lett. 2018, 20, 7929–7932. [Google Scholar] [CrossRef] [PubMed]
  27. Kishimoto, S.; Hara, K.; Hashimoto, H.; Hirayama, Y.; Champagne, P.A.; Houk, K.N.; Tang, Y.; Watanabe, K. Enzymatic one-step ring contraction for quinolone biosynthesis. Nat. Commun. 2018, 9, 2826. [Google Scholar] [CrossRef]
  28. Tang, H.; Tang, Y.; Kurnikov, I.V.; Liao, H.-J.; Chan, N.-L.; Kurnikova, M.G.; Guo, Y.; Chang, W.-C. Harnessing the Substrate Promiscuity of Dioxygenase AsqJ and Developing Efficient Chemoenzymatic Synthesis for Quinolones. ACS Catal. 2021, 11, 7186–7192. [Google Scholar] [CrossRef]
  29. Selig, P.; Bach, T. Enantioselective Total Synthesis of the Melodinus Alkaloid (+)-Meloscine. Angew. Chem. Int. Ed. 2008, 47, 5082–5084. [Google Scholar] [CrossRef]
  30. Selig, P.; Herdtweck, E.; Bach, T. Total Synthesis of Meloscine by a [2+2]-Photocycloaddition/Ring-Expansion Route. Chem. Eur. J. 2009, 15, 3509–3525. [Google Scholar] [CrossRef]
  31. Brandes, S.; Selig, P.; Bach, T. Stereoselective Intra-and Intermolecular [2+2] Photocycloaddition Reactions of 4-(2′-Aminoethyl)quinolones. Synlett 2004, 2588–2590. [Google Scholar] [CrossRef]
  32. Selig, P.; Bach, T. Photochemistry of 4-(2¢-Aminoethyl)quinolones: Enantioselective Synthesis of Tetracyclic Tetrahydro-1aH-pyrido[4′,3′:2,3]-cyclobuta[1,2-c] Quinoline-2,11(3H,8H)-diones by Intra-and Intermolecular [2+2]-Photocycloaddition Reactions in Solution. J. Org. Chem. 2006, 71, 5662–5673. [Google Scholar] [CrossRef] [PubMed]
  33. Yanev, P.; Angelov, P. Synthesis of functionalised β-keto amides by aminoacylation/domino fragmentation of β-enamino amides. Beilstein J. Org. Chem. 2018, 14, 2602–2606. [Google Scholar] [CrossRef] [PubMed]
Scheme 1. Knorr cyclisation of ω-amino-β-keto anilides to 4-aminoalkylquinolin-2-ones.
Scheme 1. Knorr cyclisation of ω-amino-β-keto anilides to 4-aminoalkylquinolin-2-ones.
Molbank 2021 m1266 sch001
Table 1. Yields of 4-aminoalkylquinolin-2-ones 2, prepared according to Scheme 1.
Table 1. Yields of 4-aminoalkylquinolin-2-ones 2, prepared according to Scheme 1.
ProductnYield (%)
2a190
2b280
2c385
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Back to TopTop