Journal of Catalysis 247 (2007) 223–230 www.elsevier.com/locate/jcat MgO nanoparticle-based multifunctional catalysts in the cascade reaction allows the green synthesis of anti-inflammatory agents Maria Jose Climent, Avelino Corma ∗ , Sara Iborra, Maria Mifsud Instituto de Tecnología Quimica, UPV-CSIC, Universidad Politécnica de Valencia, Avda. de los Naranjos s/n, 46022 Valencia, Spain Received 15 January 2007; revised 1 February 2007; accepted 2 February 2007 Available online 8 March 2007 Abstract Up to now, the anti-inflammatory agent nabumetone has been synthesized by a two-step process involving either a Heck reaction between 6-bromo-2-methoxynaphthalene and methyl vinyl ketone or a condensation between 6-methoxy-2 naphthaldehyde and acetone to give an inter- mediate that is separated, purified, and hydrogenated in a second and separate process to give the final product, while producing a large amount of waste products. Here we report a residue-free catalytic process for the production of nabumetone with 98% yield and 100% selectivity achieved through a cascade reaction system involving a multifunctional base/acid/hydrogenation catalyst based on nanocrystalline (∼3 nm) MgO.  2007 Elsevier Inc. All rights reserved. Keywords: Aldol condensation; Anti-inflammatory; Cascade reaction; MgO; Multifunctional catalyst 1. Introduction Nabumetone, 4-(6-methoxy-2-naphthyl)-2-butanone, like α-aryl propionic acids (e.g., ibuprofen, naproxen, ketoprofen) have nonsteroidal anti-inflammatory activity (NSAI). Besides being an effective anti-inflammatory and analgesic in the treat- ment of various rheumatic and arthritic diseases, nabumetone has fewer side effects and lower toxicity to the gastrointestinal tract than other anti-inflammatory agents [1]. Various industrial processes for the preparation of nabume- tone have been proposed that involve the preparation of an analogue compound with a double bond in the aliphatic chain 4-(6-methoxy-2-naphthyl)-3-buten-2-one (1), followed by hy- drogenation of the double bond. It is interesting that although the unsaturated intermediary presents the same analgesic and/or anti-inflammatory activity as the final hydrogenated compound, it produces a certain degree of estrogenicity; for this reason, the final hydrogenated product is medically recommended. Two main standard methods for carbon–carbon formation have been used for the preparation of intermediate 1: the Heck reaction [2] and aldol condensation. Thus, the Hoechst Celanese process re- * Corresponding author. Fax: +34 (96) 3877809. E-mail address: acorma@itq.upv.es (A. Corma). acts 6-bromo-2-methoxynaphthalene and methyl vinyl ketone (Heck reaction) in dimethylformamide as a solvent, using a ho- mogeneous palladium (II) catalyst at 405 K. The Pd catalyst generally results from a Pd(II) salt and a phosphine ligand, such as triphenylphosphine (PPh 3 ). Hydrogenation of the unsatu- rated product formed during the Heck reaction with a palladium on carbon prewetted (Pd–C) catalyst in a second reaction step yields 87.4% of nabumetone [3] (2) (see Scheme 1) and leaves bromide salts as byproducts. Reaction byproducts formed in this process are generated from the subsequent Heck C–C coupling of 1 to give prod- uct A and the corresponding hydrogenated (C), as well as the formation of 4-(6-methoxy-2-naphthyl)-2-butanol (B) (see Scheme 1). Rhodia Chimie [4] synthesized 1 by reacting in an au- toclave 1,6-dibromo-2-methoxynaphthalene with methyl vinyl ketone (MVK) in toluene anhydrous in the presence of Et 3 N, Pd(OAc) 2 , PPh 3 , and H 2 at 423 K and 40 bar (yield of 1 ∼58%, and only a 5% of 2 was detected). Alternatives to MVK for the synthesis of nabumetone have been sought by industry due to its limited stability (due to competing side reactions, such as oligomerization) and toxicologic concerns associated with its use. An alternative method of obtaining 2 involves 2-bromo-6- methoxynaphthalene, 3-buten-2-ol, palladium acetate, PPh 3 , in 0021-9517/$ – see front matter  2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jcat.2007.02.003