Divergent synthesis of arylated pyridin-2(1H)-one derivatives via metal-catalysed cross-coupling processes Jamie S. Siddle a , Andrei S. Batsanov a , Stuart T. Caldwell b , Graeme Cooke b , Martin R. Bryce a, * a Department of Chemistry, Durham University, Durham DH1 3LE, UK b Department of Chemistry, WestCHEM, University of Glasgow, Glasgow G12 8QQ, Scotland, UK article info Article history: Received 18 March 2010 Received in revised form 30 April 2010 Accepted 28 May 2010 Available online 8 June 2010 Keywords: Pyridine Pyridone Palladium catalysis Cross-coupling Suzuki-Miyaura reaction Arylation Boronic acid CeN coupling Copper catalysis abstract 1,5-Di(hetero)arylated-pyridin-2(1H)-one derivatives have been readily obtained in good yields starting from 2-fluoro-5-pyridylboronic acid. The sequence comprises three steps: (i) palladium-catalysed Su- zuki-Miyaura reaction; (ii) base-catalysed hydrolysis; (iii) copper-catalysed CeN coupling. X-ray crystal structures are reported for selected pyridin-2(1H)-one derivatives. These compounds are of interest as new scaffolds for drug discovery. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction Functionalised pyridones are of continued interest due to their prevalence in naturally occurring compounds, 1e3 bioactive com- pounds and drugs, 4e14 coordination chemistry 15 and their catalytic acitivity. 16 New routes for their synthesis and functionalisation continue to be developed. 17,18 Metal-catalysed cross-coupling re- actions have revolutionised the modification of pyridones 19 and related heterocycles, with CeC, CeN, CeO bond forming processes now widely utilised. 20,21 Notably, Suzuki-Miyaura, Buchwald- Hartwig and Ullmann type reactions have become ubiquitous in the post-functionalisation of heterocycles. Access to N-arylpyridones was traditionally achieved using harsh Ullmann-Goldberg condi- tions 22 resulting in low yields and poor functional group tolerance. Ligand-accelerated and copper-catalysed approaches have led to much milder coupling conditions. 23e28 Other methods for N-ary- lating pyridones and related heterocycles include: copper- mediated coupling with arylboronic acids, 24,29,30 lead-mediated coupling to aryl halides 31,32 and HATU-mediated coupling of arylamides to 4-hydroxyquinazolines. 33 There is interest in se- quential metal-catalysed routes to functionalised heteroaryl sys- tems. 34e39 The aim of the present work was to develop an efficient divergent route to tri-(hetero)aryl systems based on the pyridin-2 (1H)-one framework starting from the commercially-available 2- fluoro-5-pyridylboronic acid 1 . 40 We also report related reactions of 2,6-difluoro-5-pyridylboronic acid. 2. Results and discussion An overview of our methodology is shown in Scheme 1 . Suzuki- Miyaura cross-coupling of 2-fluoro-5-pyridylboronic acid 1 with (hetero)aryl bromides 2e4 furnished compounds 5e7 under stan- dard conditions 41,42 in high isolated yields (Table 1). Conversion of 5e7 into the 2-pyridone derivatives 8e10 was achieved in high yields by hydrolysis under basic conditions (Table 1). 43 Compounds 6 and 7 reacted faster than 5, presumably due to the electron withdrawing effect of the quinolyl and pyridyl sub- stituents, respectively. It has previously been observed that the copper-catalysed cou- pling of 2-pyridones can lead to both CeN and CeO arylated products. 28,44 To explore this reaction, pyridone derivative 8 was reacted with 11 (Scheme 2). After isolation of the N-heteroarylated product 12a vide infra, a comparison with the crude 1 H NMR * Corresponding author. Tel.: þ44 191 3342018; e-mail address: m.r.bryce@ durham.ac.uk (M.R. Bryce). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2010.05.108 Tetrahedron 66 (2010) 6138e6149