A © Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–K L. Le Corre et al. Paper Syn thesis Synthesis of Multifunctionalized 2-Iminothiazolidin-4-ones and Their 2-Arylimino Derivatives Laurent Le Corre Maria Chiara Dasso Lang Christiane Garbay Christine Gravier-Pelletier Patricia Busca Mélanie Ethève-Quelquejeu Emmanuelle Braud* UMR CNRS 8601, Université Paris Descartes, Sorbonne Paris Cité, Centre interdisciplinaire Chimie Biologie – Paris, 45 rue des Saints-Pères, 75006 Paris, France emmanuelle.braud@parisdescartes.fr N S O N N CN O O CH 3 R R 1 = H, Ar N N CN O O CH 3 R NH 2 O Cl Cl N N CN O O CH 3 R NH KSCN or Ar-NCS, DBU N R 1 O Cl 12 examples 45–74% yield Received: 11.05.2016 Accepted after revision: 05.07.2016 Published online: 09.09.2016 DOI: 10.1055/s-0035-1562521; Art ID: ss-2016-z0339-op Abstract Multifunctionalized 2-imino-3-(pyrazol-4-yl)thiazolidin-4- ones and 2-arylimino-3-(pyrazol-4-yl)thiazolidin-4-ones were prepared according to an efficient four-step procedure. The key step of the syn- thetic pathway involved the cyclization of 2-chloro-N-(pyrazol-4-yl)acet- amide intermediate using KSCN or aryl isothiocyanate, respectively. The structure of the title compounds was confirmed on the basis of NMR data and 15 N-labeling. Key words thiazolidin-4-ones, pyrazoles, cyclization, heterocycles, re- gioselectivity Present in natural or synthetic products, five-mem- bered heterocyclic rings are privileged scaffolds for the de- sign of therapeutic agents. Among them, the 1,3-thiazoli- din-4-one core has been widely explored due to its versatile biological properties. 1–3 In particular, 2-iminothiazolidin-4- ones I (Figure 1) display antifungal, 4–6 anti-inflammatory, 7,8 anticonvulsant, 9,10 hypnotic, 11 and antibacterial 6,12 activi- ties. On the other hand, pyrazole scaffolds have also been largely exploited by medicinal chemists, leading to the de- velopment of valuable bioactive compounds. 13,14 Figure 1 General structures of 2-iminothiazolidin-4-ones I and target compounds 5 and 7 In continuation of our ongoing programs dedicated to the synthesis of new pyrazole and thiazolidin-4-one deriva- tives endowed with biological properties, 15,16 we became interested in the design of new hybrid compounds combin- ing these two scaffolds. Such compounds have already demonstrated inhibitory activities toward VHR phospha- tase, histone acetyltransferases, ADAMTS-5, and the TNF-α- TNFRc1 interaction as well as anti-inflammatory and anti- microbial properties. 17 To our knowledge, despite a large diversity of reported 2-iminothiazolidine-4-ones, there is no example of deriva- tives bearing a pyrazole moiety at the position 3 of the thi- azolidinone ring (Figure 1). Yet, the substituent R (Figure 1) has been chosen among the alkyl 7 and heteroaryl groups, the latter mainly including substituted phenyl, 18 thi- azolyl, 4,19 and naphthyl 20 derivatives. Thus, we report here- in the regioselective synthesis of two new series of 2-imi- nothiazolidin-4-ones, including the 2-imino-3-(pyrazol-4- yl)-thiazolidin-4-ones 5 and their 2-arylimino derivatives 7 (Figure 1). To unambiguously confirm the structure of the latter compounds, a 15 N-labeled 2-aryliminothiazolidin-4- one was synthesized. A convenient method for the preparation of 2-iminothi- azolidin-4-ones A1 involves the reaction of 2-haloacet- amides in the presence of potassium thiocyanate 4,5,19,20 or ammonium thiocyanate (Scheme 1). 21,22 It has been report- ed that this cyclization process can lead to the formation of the regioisomer A2 using either NH 4 SCN 23–25 or KSCN. 26 Scheme 1 Synthesis of 2-iminothiazolidin-4-ones A1 and A2 N S O HN N N CN O O CH 3 R 5 7 N 3 2 S 1 5 4 O N R R 1 I N S O N N N CN O O CH 3 R Ar R-NH 2 O N H X R N S O HN R A1 HN S O N A2 or ClCOCH 2 X KSCN X = Br, Cl R NH 4 SCN or SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2016, 48, A–K paper Heruntergeladen von: Universite Laval. Urheberrechtlich geschützt.