Reformatsky reactions with N-arylpyrrolidine-2-thiones: synthesis of tricyclic analogues of quinolone antibacterial agents

doi:10.1016/S0040-4020(01)00964-4

Tetrahedron

Volume 57, Issue 47, 19 November 2001, Pages 9635-9648

https://doi.org/10.1016/S0040-4020(01)00964-4 Get rights and content

Abstract

A convenient synthesis of 5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acids, tricyclic analogues of the quinolone antibiotics, is described. Key steps in the route are a novel zinc-mediated Reformatsky reaction between diethyl bromomalonate and N-arylpyrrolidine-2-thiones 18, and cyclisation of the resulting diethyl pyrrolidinylidenemalonate intermediates 19 in polyphosphoric acid. The products proved to be devoid of biological activity.

Two key steps in the synthesis, including an atypical Reformatsky reaction with thiolactams, are shown.

Introduction

Enaminones,¹ the basic structure of which is shown in 1, are versatile intermediates for the synthesis of heterocycles.² A less well recognised property of substructure 1 is its ability to serve as a pharmacophore.3., 4. Examples of biologically active enaminones include the anticonvulsant 2,⁴ the 2-alkylideneindole 3, which has anti-inflammatory potential,⁵ and the fused polycyclic compound 4, a synthetic analogue of the duocarmycin class of antitumour agents.⁶ However, the most important chemotherapeutic agents to contain an embedded enaminone component are without doubt the quinolone antibacterials.7., 8. In particular, the fluorinated quinolones, representative examples of which include ciprofloxacin (5), norfloxacin (6) and pefloxacin (7), are amongst the most effective broad-spectrum oral antibacterial agents developed to date. Ciprofloxacin, for instance, is used worldwide for treating genitourinary, gastrointestinal, respiratory and skin infections, as well as sexually transmitted diseases. The fluoroquinolones are especially effective against Gram-negative bacteria, DNA synthesis in which is inhibited by the drugs' ability to corrupt the activities of DNA gyrase and topoisomerase IV, inducing these essential enzymes to kill cells by generating high levels of double-stranded DNA breaks.9., 10. Furthermore, newer compounds are being developed with promising activity against Gram-positive bacteria, anaerobes and mycobacteria,11., 12., 13. as well as antitumour activity.¹⁴ Even though literally thousands of quinolones have been synthesised for biological evaluation, the search for improved quinolone drugs continues, driven by the need for enhanced performance, broader efficacy, novel interventions and problems with bacterial resistance.

Structure–activity relationships for the quinolone antibacterials, summarised in a classic review by Albrecht,¹⁵ and updated several times since then,11., 16., 17., 18. have highlighted, among other factors, the importance of the carboxylic acid at C-3, as well as a small hydrophobic substituent on nitrogen (N-1), typically an ethyl or cyclopropyl group. Although substituents at C-2 invariably render the compounds inactive, a short bridge of two or three atoms between N-1 and C-2 seldom compromises activity. The bridge may include nitrogen, sulphur or oxygen.¹⁹ The all-carbon bridged pyrrolo[1,2-a]quinolinone 8, a pefloxacin analogue, has a minimal inhibitory concentration (MIC) of 0.78 μg ml⁻¹ against Staphylococcus aureus CMX686B, and 1.56 μg ml⁻¹ against Escherichia coli.²⁰ This compound also includes two structural features that seem to be obligatory for high biological activity: a fluorine substituent at C-6, and a cyclic amine at C-7. A related compound, 9, has also demonstrated activity against a wide range of microorganisms.²¹

As part of our continuing investigations into the use of enaminones (vinylogous amides, vinylogous urethanes and related systems) as precursors for alkaloids and other nitrogen-containing heterocycles,²² we have explored a new synthetic route to tricyclic analogues of the quinolone antibacterials. In this paper we describe a flexible synthesis of several 5-oxo-1,2,3,5-tetrahydropyrrolo[1,2-a]quinoline-4-carboxylic acids that allows for easy variation in the nature, number and position of substituents on the aromatic ring, as well as providing access to the active compound 8 itself. Some preliminary results were reported in a prior communication.²³

Section snippets

Results and discussion

Two principal strategies, both proceeding via enaminone intermediates, have been reported for the construction of the quinolin-4-one nucleus of the quinolone antibacterials (Scheme 1).²⁴ In the route developed by chemists at Bayer AG,25., 26. the quinolone nucleus 10 is formed by base-induced cyclisation of 2-(2-halobenzoyl)-3-aminoacrylates 11. The alternative route employs a thermal or acid-catalysed Gould–Jacobs cyclisation²⁷ of anilinomethylenemalonates 12. This cyclisation is essentially a

General methods

All solvents used for reactions and preparative chromatography were distilled. Chloroform and carbon tetrachloride were dried by passage through a short column of basic alumina. THF and diethyl ether were distilled from Na/benzophenone, dichloromethane, acetonitrile, DMF and triethylamine from CaH₂, and benzene and toluene from Na. Commercially available chemicals were used as received. Melting points, recorded on a Reichert hot-stage microscope apparatus, are uncorrected. TLC was performed on

Acknowledgements

We thank the National Research Foundation, Pretoria, the University of the Witwatersrand, and the UK/RSA Science and Technology Fund for providing the funding for this research. We are grateful to Dr P. R. Boshoff (Cape Technikon) and Mrs S. Heiss (University of the Witwatersrand) for mass spectra and NMR spectra, respectively, and to Professor I. Moodley and his staff (Department of Pharmacy, University of the Witwatersrand) for the antimicrobial testing.

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Reformatsky reactions with N-arylpyrrolidine-2-thiones: synthesis of tricyclic analogues of quinolone antibacterial agents

Abstract

Introduction

Section snippets

Results and discussion

General methods

Acknowledgements

Adv. Heterocycl. Chem.

Adv. Drug Res.

Tetrahedron

Tetrahedron Lett.

Tetrahedron

J. Chem. Soc., Perkin Trans. 1

Aust. J. Chem.

Tetrahedron Lett.

Pharmazie

Acta Crystallogr., Sect. B

S. Afr. J. Chem.

Chem. Soc. Rev.

Curr. Med. Chem.

Curr. Med. Chem.

J. Prakt. Chem.

J. Am. Chem. Soc.

Int. J. Antimicrob. Agents

Drugs

Curr. Pharm. Design

Med. Res. Rev.

Curr. Opin. Invest. Drugs

Recent Res. Dev. Antimicrob. Agents Chemother.