Synthesis of trifluoromethylated 2-benzoyl- and 2-aminoimidazoles from ring rearrangement of 1,2,4-oxadiazole derivatives Antonio Palumbo Piccionello a , Andrea Pace a , Silvestre Buscemi a, * , Nicolo ` Vivona a , Marcella Pani b a Dipartimento di Chimica Organica ‘E. Paterno ` ’, Universita ` degli Studi di Palermo, Viale delle Scienze, Parco d’Orleans II, I-90128 Palermo, Italy b Dipartimento di Chimica e Chimica industriale, Universita ` di Genova, Via Dodecaneso 31, I-16146 Genova, Italy Received 8 November 2007; received in revised form 25 January 2008; accepted 14 February 2008 Available online 6 March 2008 Abstract Fluoroalkylated 2-ylamino-imidazoles have been synthesized by reaction of 3-amino-5-phenyl-1,2,4-oxadiazole with fluorinated b-dicar- bonyl compounds and subsequent base-induced BoultoneKatritzky Rearrangement (BKR) of the isolated b-enaminocarbonyl intermediate. Alternatively, one-pot reactions performed in the presence of Montmorillonite K10 favoured the condensation at the 3-amino moiety of the oxadiazole and, in some cases, allowed the direct synthesis of 2-benzoylamino-imidazoles. Hydrolysis of 2-benzoylamino-imidazoles easily yielded fluorinated 2-amino-imidazoles targets. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: 1,2,4-Oxadiazole; Montmorillonite; Imidazoles; b-Dicarbonyls; b-Enaminoketones; Crystal structure 1. Introduction The imidazole ring plays a critical role in many aspects of biological structure and function. For example, the imidazole ring of the aminoacid histidine is often found in the active cata- lytic site of enzymes. Considering the important function of this heterocycle, it is not surprising that many ring-fluorinated imidazoles possess quite interesting biological properties. 1 Moreover, perfluoroalkylated imidazoles have been used as 19 F NMR spectroscopic probes for biomimetic studies 2 and intracellular pH determinations, 3 ionic liquids 4 and lightfast optical recording media. 5 In turn, 2-amino-imidazole moieties are present in several biologically active marine alkaloids 6 and this prompted research into efficient and general methodol- ogies for the synthesis of these target molecules. 7 Nevertheless, despite their potential interest as bioactive molecules, to the best of our knowledge, no fluoroalkylated 2-aminoimidazole has been ever reported. The only example regards trifluoromethylated imidazo[1,2-a]benzimidazoles [containing a tertiary amino moiety on the C(2) of the fluori- nated imidazole nucleus], which have been recently reported as corticotropin-releasing factor 1 receptor (CRF1R) antago- nists for the treatment of depression, anxiety and stress-related disorders. 8 We therefore decided to synthesize a series of trifluorome- thylated imidazole derivatives by following the Ring-Rear- rangement Approach, which takes advantage of the thermal and photochemical reactivities of suitable heterocyclic syn- thons and is a very versatile approach to fluorinated heterocy- cles. 9 In this context, it is worth remarking that the presence of a fluorinated moiety [either as a fluorine atom, as a per(poly)- fluoroalkyl or as a per(poly)fluoroaryl group] can strongly af- fect such reactivity or the outcome of the reaction with respect to the results obtained with non-fluorinated analogues. 9 In the last decade, we have been revisiting several reactions of the 1,2,4-oxadiazole, a heterocycle, which is very likely to un- dergo ring rearrangement into the more stable heterocycles, with the aim of synthesizing fluorinated heterocyclic targets. 9 An interesting example of the reactivity of 1,2,4-oxadiazoles is afforded by N-(1,2,4-oxadiazol-3-yl)-b-enaminoketones 1. For these systems, two different rearrangements have been shown * Corresponding author. Fax: þ39 091 596825. E-mail address: sbuscemi@unipa.it (S. Buscemi). 0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.02.047 Available online at www.sciencedirect.com Tetrahedron 64 (2008) 4004e4010 www.elsevier.com/locate/tet