From targeted aza-Michael addition to linked azaheterocyclic scaffolds Orazio A. Attanasi a , Lucia De Crescentini a , Paolino Filippone a , Gianluca Giorgi b , Simona Nicolini a , Francesca R. Perrulli a , Stefania Santeusanio a, * a Department of Biomolecular Science, Section of Organic Chemistry and Organic Natural Compounds, Universit a degli Studi di Urbino “Carlo Bo”, Via I Maggetti 24, 61029 Urbino, Italy b Department of Chemistry, Universit a degli Studi di Siena, Via Aldo Moro, 53100 Siena, Italy article info Article history: Received 30 April 2014 Received in revised form 30 June 2014 Accepted 9 July 2014 Available online 15 July 2014 Keywords: Aza-Michael addition Multi-component reaction Hydantoin Thiohydantoin Heteroannulation Spiro compounds abstract A straightforward method for the synthesis of spaced, phenyl-linked bis(thiohydantoin) derivatives and (thio)hydantoins spiro-fused to pyrroline ring has been developed. All the synthetic strategies here presented rely on initial aza-Michael addition followed by acylation/regioselective ring-closure step involving DD, primary amine and iso(thio)cyanate in a 3-CR providing 1,3,5-trisubstituted (thio)hydan- toins. The choice of opportune acyclic reagents in the sequential 3-CR followed by 1,4-nucleophilic ad- dition/intramolecular ring closing and 1,3-dipolar cycloaddition permits a number of CeN and CeC formation that realizes different kind of linkage between several pharmacophores. Ó 2014 Elsevier Ltd. All rights reserved. 1. Introduction The structural diversity of natural and synthetic heterocycles has become a key topic in organic, bioorganic and medicinal chemistry. As a result, there is an increasing need to access new areas of chemical space with the aim to discover biologically rele- vant heterocyclic molecules in a rapid and economic fashion. Multi- component reactions (MCRs) 1 have gained much importance in synthetic organic chemistry as they produce the target compounds in a single step avoiding the isolation of intermediates. MCRs can use domino reactions or sequential reactions and have proved to be efficient for the construction of many different types of heterocycles. 2 Specifically hydantoin and 2-thiohydantoin-based scaffolds ex- hibit a wide array of properties ranging from bioscience materials 3 to bioactive compounds; 4 therefore, numerous synthetic strategies both on solid support 5 and in solution phase 6 have been reported in the literature. In this field our research group has recently developed a se- quential 3-CR to afford selectively substituted hydantoins 7a and 2-thiohydantoins 7b from 1,2-diaza-1,3-dienes (DDs) 8 as readily available building blocks. Since MCRs that afford products with reactive functional groups capable of being utilized in a further reaction are powerful methods for generating diverse collections of functionalized heterocyclic templates, 9 we envisioned the extension of our pre- vious results to allow the synthesis of linked azaheterocyclic architectures. In a continuation of recent studies, we herein describe synthetic strategy to spiro-fused as well as spaced azaheterocyclic scaffolds based on initial 3-CR. 2. Results and discussion The aza-Michael reaction can be considered a hydroamination process and it has been largely applied to DDs by our group as a strategic starting point to produce different heterocyclic tem- plates. 10 The a-aminohydrazone A, resulted from the nucleophilic addition of primary amine 2 to DD 1 , is a densely functionalized derivative, which accounts for its chemical versatility through the simultaneous presence of both electrophilic (i.e., ester and hydra- zone functions) and nucleophilic (i.e., secondary amine) centres (Scheme 1). * Corresponding author. Tel.: þ39 (0)722 303442; fax: þ39 (0)722 303441; e-mail address: stefania.santeusanio@uniurb.it (S. Santeusanio). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet http://dx.doi.org/10.1016/j.tet.2014.07.038 0040-4020/Ó 2014 Elsevier Ltd. All rights reserved. Tetrahedron 70 (2014) 7336e7343