Facile oxidation of electron-poor benzo[b]thiophenes to the corresponding sulfones with an aqueous solution of H 2 O 2 and P 2 O 5 w Dyeison Antonow, Teresa Marrafa, Irfaan Dawood, Tauheed Ahmed, Mohammad R. Haque, David E. Thurston and Giovanna Zinzalla* Received (in Cambridge, UK) 19th November 2009, Accepted 21st December 2009 First published as an Advance Article on the web 25th January 2010 DOI: 10.1039/b924333j A facile oxidation for the clean conversion of benzo[b]thiophenes to their corresponding sulfones is described employing an aqueous solution of H 2 O 2 and P 2 O 5 ; the solution can be prepared and stored on a multi-gram scale with a shelf-life of up to two weeks. Benzo[b]thiophene 1,1-dioxides are an emerging class of heterocyclic compounds with synthetic and medicinal chemistry applications. These unsaturated sulfones are dipolarophiles that have been shown to undergo a number of synthetically useful cycloaddition reactions 1,2 and to be useful synthons for various chemical transformations. 3–5 Also, this class of cyclic sulfones possesses a variety of biological activities. 6–11 Nevertheless, their potential is under-exploited due to a lack of synthetic methods to prepare derivatives with a wide range of substituents. Benzo[b]thiophene 1,1-dioxides are commonly obtained from benzo[b]thiophenes using synthetic methods based on a small number of reagents capable of oxidizing thiophenes bearing electron-donating groups (EDGs). Fewer reagents are available for the more challenging derivatives bearing electron-withdrawing groups (EWG). 12–15 The sulfur atom of the benzo[b]thiophene ring system is even more difficult to oxidize to 1,1-dioxides and few methods have been explored. 16–18 In particular, no general methods have been reported for the direct synthesis of benzo[b]thiophene 1,1-dioxides possessing EWGs by oxidation of the corresponding benzo[b]thiophenes. Based on studies in the literature for thiophenes and benzo[b]thiophenes, oxidizing systems that could be successfully exploited include the use of hydrogen peroxide (30% aqueous solution) at room temperature with metal-based salts such as MoO 2 Cl 2 , 19 ZrCl 4 18 or binuclear manganese, 16 the use of 98% hydrogen peroxide with trifluoroacetic anhydride, 12 or the use of dimethyl dioxirane (DMD). 15 Metal-free catalysis is desirable from an environmental viewpoint, and 98% hydrogen peroxide is highly explosive, has to be produced ‘‘in loco’’ and then the oxidizing species (i.e., trifluoroperacetic acid) formed in situ by mixing the H 2 O 2 with TFAA. 12 Its instability is also an issue for storage purposes; reactions cannot be carried out at temperatures higher than 35 1C as the trifluoro- peracetic acid degrades. 12 Finally, the use of DMD is problematic in reactions of more than 100 mg scale, as the complex preparation 20 of this reagent limits its scalability. Thus, we focused on developing an oxidation method that would allow the conversion of benzo[b]thiophenes to benzo[b]- thiophene 1,1-dioxides in a facile manner, and on a multi- gram scale for potential industrial applications. We report here the use of an aqueous solution of H 2 O 2 (60%) and P 2 O 5 that involves inexpensive and enviromentally friendly reagents. A further advantage of this oxidizing system is that it does not need to be freshly prepared in situ, but can be prepared on a mutli-gram scale as a single reagent containing the reactive species peroxymonophosphoric acid 21 (0.88 M aq.). The solution has a shelf-life of up to two weeks when stored at 4 1C. 22 To evaluate the versatility of this reagent we investigated the oxidation of benzo[b]thiophenes bearing EWGs, where the sulfur atom is more difficult to oxidize. In particular, we selected the more challenging benzo[b]thiophene carboxamides (Table 1) whose oxidation to 1,1-dioxides has not been reported. For each of these derivatives, the carboxamide group is at the 2-, 3- or 5-positions of the benzo[b]thiophene system, and the phenyl ring of the amide possesses an EDG or EWG. For comparison purposes two other oxidative methods were investigated alongside involving a novel H 2 O 2 /TFAA procedure employing non-explosive 60% aq. H 2 O 2 , and DMD. 20 For these preliminary investigations we used the benzo[b]thiophene 1 (Scheme 1). The reactions were carried out in parallel at room tempera- ture in acetonitrile using 2 equivalents of the oxidizing agent. Clean sulfone formation (i.e., no by-products) allowed efficient isolation of the products in excellent yields. Longer reaction times were required for substrates possessing a nitro group. Only in the case of entry 3 was the desired product not formed and starting material fully recovered. 60% aq. H 2 O 2 and TFAA afforded the desired compounds in lower yields when compared to H 2 O 2 –P 2 O 5 , which was particularly noticeable for the nitro-substituted substrates. The use of DMD afforded the oxidized products in comparable yields to the H 2 O 2 –P 2 O 5 Scheme 1 Oxidation of 1 with aqueous H 2 O 2 –P 2 O 5 . Cancer Research UK Protein-Protein Interactions Drug Discovery Research Group, The School of Pharmacy, University of London, 29-39 Brunswick Square, London, UK. E-mail: giovanna.zinzalla@pharmacy.ac.uk; Fax: +44 (0)207753 5964; Tel: +44 (0)207 7753 5932 w Electronic supplementary information (ESI) available: Experimental details for preparation of the aqueous H 2 O 2 –P 2 O 5 reagent and for all the reactions described here. Full characterisation of all starting materials and products is also included. See DOI: 10.1039/b924333j This journal is  c The Royal Society of Chemistry 2010 Chem. Commun., 2010, 46, 2289–2291 | 2289 COMMUNICATION www.rsc.org/chemcomm | ChemComm