Month 2017 One-Step Synthesis of 3,4-Diphenyl-2-pyrrolinones by Solvent-Free and Bi 2 O 3 -Catalyzed Approaches and Cytotoxicity Screening Against Glioma Cells Silvio Cunha, a,b * José Claudio Serafim, a,b Lourenço Luis Botelho de Santana, a,b Fabiano Damasceno, a,b José Tiago Menezes Correia, a,b Airam Oliveira Santos, a,b Mona Oliveira, c,d Janaína Ribeiro, c,d Jéssika Amparo, c,d and Silvia Lima Costa c,d * a Instituto de Química, Universidade Federal da Bahia, Campus de Ondina, 40170-115 Salvador, Bahia, Brazil b INCT em Energia e Ambiente, Instituto Nacional de Ciência e Tecnologia, Universidade Federal da Bahia, Campus de Ondina, Salvador, Bahia 40170-290, Brazil c Instituto de Ciências da Saúde, Departamento de Biofunção/Bioquímica, Laboratório de Neuroquímica e Biologia Celular, Salvador, Bahia 40.110-100, Brazil d INCT em Neurociência Translacional, Instituto Nacional de Ciência e Tecnologia, Universidade Federal da Bahia, Salvador, Bahia 40170-290, Brazil * E-mail: silviodc@ufba.br; costasl@ufba.br Received January 13, 2017 DOI 10.1002/jhet.2921 Published online 00 Month 2017 in Wiley Online Library (wileyonlinelibrary.com). Multifunctionalized 2-pyrrolinones were synthesized from the formal aza-[3 + 2] cycloaddition reaction of acyclic enaminones and diphenylcyclopropenone. For primary enaminones, solventless reaction under microwave heating was developed. On the other hand, catalysis by Bi 2 O 3 under conventional heating was the more suitable strategy when secondary enaminones were employed. These conditions allowed the synthesis of a set of 2-pyrrolinones with two vicinal phenyl substituents, which were evaluated for cytotoxicity against U251 and C6 glioblastoma cells. In general, all tested 2-pyrrolinones with two vicinal phenyl rings were more active than those without this structural moiety, and 1-butyl-5-methyl-5-(2- oxopropyl)-3,4-diphenyl-1,5-dihydro-2H-pyrrol-2-one was the most cytotoxic and appears to be a new possibility as an antitumor scaffold to this aggressive brain tumor. J. Heterocyclic Chem., 00, 00 (2017). INTRODUCTION The 2-pyrrolinone core is present in several compounds that possess interesting biological activities [1–7]. Because of this aspect, the synthesis of densely substituted 2- pyrrolinone is a theme of ongoing interest, and the development of practical synthetic routes to access this heterocycle demands continuous improvements [8–13]. In a subclass of this δ-lactam, the occurrence of two vicinal phenyl substituents is a relevant structural scaffold because it increases the biological effect [1]. Acyclic enaminones are attractive as building blocks to the synthesis of polysubstituted heterocycles, because they can be easily prepared from 1,3-dicarbonyl compounds, among other precursors [14–24]. In this scenario, the formal aza-[3 + 2] cycloaddition of enaminones emerges as a versatile strategy to the preparation of five-membered N-heterocycles because two sigma bonds are formed in a single step, and catalysis by metal salts and metal-free annulations have already been reported [25–32] (Fig. 1). Some characteristic features emerge from Figure 1: the adequate selection of the reaction conditions and electrophile affords the synthesis of pyrrole or pyrrolinone with regiochemical control of the substituents, and the heterocycles are formed by incorporating two carbons of the applied electrophile and two carbons and the nitrogen of the ─N─C═C─ moiety © 2017 Wiley Periodicals, Inc.