Microwave-assisted preparation of the quorum-sensing molecule 2-heptyl-3-hydroxy-4(1H)-quinolone and structurally related analogs |
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Authors: | Hodgkinson James T Galloway Warren R J D Welch Martin Spring David R |
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Institution: | Department of Chemistry, University of Cambridge, Cambridge, UK. |
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Abstract: | An optimized procedure for the efficient preparation of 2-heptyl-3-hydroxy-4(1H)-quinolone (Pseudomonas quinolone signal or PQS) and a diverse range of structurally related 2-alkyl-4-quinolones with biological activity is presented. The two-step synthesis begins with the formation of α-chloro ketones by the coupling of a Weinreb amide (2-chloro-N-methoxy-N-methylacetamide) and an appropriate Grignard reagent. The resulting α-chloro ketones can be reacted with commercially available anthranilic acids under microwave irradiation conditions to furnish the desired 2-alkyl-4-quinolone products. As a typical example, the synthesis of PQS, a molecule involved in quorum sensing in the pathogenic bacterium Pseudomonas aeruginosa, is described in detail. The first step of this process (α-chloro ketone formation) takes ~10 h in total to complete from commercially available bromoheptane and 2-chloro-N-methoxy-N-methylacetamide. The second step (microwave-assisted reaction with anthranilic acid) takes ~14 h in total to complete (the reaction typically proceeds in ~30 min, with work-up and purification requiring ~13 h). |
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