Transformations of enaminones. A simple one-pot synthesis of imidazolone derivatives Jure Bezen  sek, Uro  s Gro  selj, Katarina Stare, Jurij Svete, Branko Stanovnik * Faculty of Chemistry, University of Ljubljana, A sker ceva 5, 1000 Ljubljana, Slovenia article info Article history: Received 25 July 2011 Received in revised form 20 October 2011 Accepted 7 November 2011 Available online 13 November 2011 Keywords: Enaminones Michael additions One-pot synthesis Imidazolones abstract Ethyl (5-benzoyl-2-oxo-3-substituted-2,3-dihydro-1H-imidazol-1-yl)carbamates 7 were prepared by the Michael addition of diethyl azodicarboxylate (3) to (E)-3-(dimethylamino)-1-phenylprop-2-en-1- one (2) followed by substitution of the dimethylamino group with primary amines 5aen to afford a mixture of (E) and (Z) diethyl 1-(1-(substituted)amino)-3-oxo-3-phenylprop-1-en-2-yl)hydrazine-1,2- dicarboxylates (6aen), followed by cyclization to give final products 7aen. The intermediate 6i was isolated and characterized and transformed into 7i. All imidazolones 7aen were synthesized in one pot reaction sequences with individual reactions being very clean. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction Nitrogen containing heterocycles 1 are of special interest in or- ganic synthetic chemistry, since they occur in a wide variety of natural products. The imidazolone motif appears in many natural products, 2 which possess interesting biological activities. 3 They are inhibitors of V-RAF murine sarcoma viral oncogene homologue B1. 4 They are antagonists of many receptors including the neurokinin-1 receptor 5 and the dopamine receptor. 6 They were applied as in- termediates in the synthesis of many natural products, such as bi- otin, 7 slagenins, 8 axinohydantoins, 9 oroidin-derived alkaloids, 10 aplysinopsins, 11 Lancetta-derived alkaloid carcaridine A, 12 and others. Due to their importance, many methods have been de- veloped for the construction of the imidazole ring. 13,14 Recently, there has been great progress in copper-catalysed N-arylation. 15,16 4-Aroyl-1,3-dihydro-2H-imidazol-2-ones, have been prepared by acylation of the appropriate 2H-imidazol-2-ones and evaluated as a new class of cardiotonic agents. 17 The most important compound in this series is 4-methyl-5-[4-(methylthio)benzoyl]-1H-imidazol- 2(3H)-one (Perfan Ò or Enoximone Ò )(Fig. 1), a selective phospho- diesterase inhibitor, which has significant inotropic and vaso- dilating properties that have proved useful in the postoperative management of infants and children having cardiac surgery. 18,19 The effects of phosphodiesterase (III/IV)-inhibitors and cytokines on mechanical properties of neutrophilic granulocytes in neonates and adults have been studied. 20 In this communication we report a simple one-pot synthesis of imidazolone derivatives using enaminone methodology recently extensively studied in our laboratory. The wide applicability of 3- (dimethylamino)propenoates and related enaminones as versatile reagents in heterocyclic synthesis, 21 including natural products and their analogues 11,22 and regiospecific microwave-assisted [2þ2] cycloadditions with electron-poor acetylenes and their trans- formations into highly substituted heterocyclic systems has been demonstrated. 23 In this communication we report a simple one-pot synthesis of ethyl (5-benzoyl-2-oxo-3-substituted-2,3-dihydro-1H-imidazol-1- yl)carbamates, which were prepared by the Michael addition of diethyl azodicarboxylate to (E)-3-(dimethylamino)-1-phenylprop- 2-en-1-one followed by substitution of the dimethylamino group with primary amines and cyclization into imidazolone derivatives. 2. Results and discussion First, (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (2) prepared from acetophenone (1) and N,N-dimethylformamide Fig. 1. 4-Methyl-5-[4-(methylthio)benzoyl]-1H-imidazol-2(3H)-one (Perfan Ò or Enoximone Ò ). * Corresponding author. Tel.: þ386 1 2419238; fax: þ386 2419220; e-mail ad- dress: Branko.Stanovnik@fkkt.uni-lj.si (B. Stanovnik). Contents lists available at SciVerse ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2011.11.013 Tetrahedron 68 (2012) 516e522