Copper(0) in the Ullmann heterocycle-aryl ether synthesis of 4-phenoxypyridine using multimode microwave heating Faysal Benaskar a,  , Volker Engels b,  , Narendra Patil a , Evgeny V. Rebrov a , Jan Meuldijk a , Volker Hessel a , Lumbertus A. Hulshof c , David A. Jefferson b , Jaap. C. Schouten a, * , Andrew E. H. Wheatley b, * a Laboratory of Chemical Reactor Engineering, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands b Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK c Applied Organic Chemistry, Eindhoven University of Technology, PO Box 513, 5600 MB, Eindhoven, The Netherlands article info Article history: Received 28 September 2009 Revised 19 October 2009 Accepted 28 October 2009 Available online 30 October 2009 Keywords: Ullmann synthesis Copper nanoparticles Microreactors Microwave heating Catalysis abstract The action of nanoparticulate copper catalysts with a mean particle size of 10 nm in the Ullmann ether synthesis is reported using multimode microwave heating and employing stable chloropyridine salts and unactivated phenol, with stabilized copper nanoparticles outperforming other copper catalysts in terms of stability and reusability. Ó 2009 Elsevier Ltd. All rights reserved. The Ullmann ether synthesis has been a topic of intense interest since it was first reported by Ullmann and Goldberg in 1905, 1 with many Ullmann reaction products acting as precursors for fine chemicals and pharmaceuticals. 2 Many refinements have been made, leading to a better understanding of the beneficial ligand ef- fects to be had by tailoring homogeneous copper 3 and palladium 4 catalysts. Moreover, solvent effects in the synthesis have been intensively investigated by Cherng. 5 Recently, the industrial solvents DMF and DMA have attracted particular attention, being successfully used in conjunction with microwave heating. 6 These solvents possess strong polar moments and so rapidly heat up when microwaves are applied suggesting green chemical benefits through enhanced yields and decreased energy consumption by selective heating. Hence, for example, the single mode micro- wave-assisted synthesis of phenoxypyridines using chlorohetero- cycles has resulted in higher yields than those that could be achieved with conventional heating, albeit on a small scale. 7 These heating effects can be amplified, allowing less harsh bulk tempera- tures, when microwave-absorbing materials are used in conjunc- tion with the catalyst, through hotspot formation at the solid surface. 8 While it has been used as a catalyst in organic synthesis at the molecular level for many decades, nanoparticulate copper has only recently been deployed. This represents part of a recent research trend towards the use of nanoparticles in process intensification. In this context, exploitable methods now exist for the fabrication of the copper-based nanomaterials Cu(0), CuO and Cu 2 O. 3a These have been tested in fine chemical syntheses, including C–H (N– H) activation reactions in the quantitative preparation of propar- gylamines, bis-(4-hydroxy-2-oxothiazolyl)methanes in ionic liq- uids and the selective aza-Michael reaction of N-alkyl- and N- arylpiperazines in the presence of aromatic amino or aliphatic hy- droxy groups. 3b Proof-of-concept has been achieved for the use of nanoparticulate Cu, with nano-Cu 2 O-catalyzed Ullmann-type ami- nation using aryl chlorides and very long reaction times, 9 and nano-Cu-catalyzed etherification using expensive aryl iodides 10 described. Although this use of nanocatalysts offers new opportu- nities in terms of economic and sustainable processes where homogeneously catalyzed reactions suffer from major drawbacks such as an inability to easily recover the catalyst, product contam- ination and space-time yield limitations, the sensitivity of nanop- articulate copper towards oxidation has previously limited applications. We report here what is, to the best of our knowledge, the first use of nanoparticulate Cu in a microwave-assisted Ullmann ether synthesis. We varied both the metal oxidation state and particle size in combination with multimode microwave irradiation. The use of microwave methods was shown to result in a near 20-fold 0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.10.126 * Corresponding authors. Tel.: +31 40 247 3088; fax: +31 40 244 6653 (J.C.S), tel.: +44 1223 763122; fax: +44 1223 336362 (A.E.H.W.). E-mail addresses: J.C.Schouten@tue.nl (J.C. Schouten), aehw2@cam.ac.uk (A.E.H. Wheatley).   These authors contributed equivalently. Tetrahedron Letters 51 (2010) 248–251 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet