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Regioselective addition of pyrrole to methyl 3-aryl-2-cyanoacrylates was achieved, in high yields, with copper(II) triflate as the catalyst in toluene. C-Alkylated pyrroles afforded novel pyrrolizin-3-ones, in good to high yields and high diastereomeric ratio by an intramolecular cyclization reaction under mild reaction conditions.Bridgehead-nitrogen-containing heterocycles constitute a very large family of natural products. Pyrrolizine alkaloids are of interest among heterocyclic compounds since they have a wide range of biological activity. 1 Therefore, the development of efficient and simple synthetic methods for heterocyclic compounds occupy a broad area in organic synthesis.In several previously published works, different synthetic approaches have been used to construct the pyrrolizin-3-one structure (Scheme 1). Cyclization of the condensation product of pyrrole-2-carbaldehyde and malonic acid yielded pyrrolizin-3-one in very low yields. 2 It was reported that the reaction of 2-[(dimethylamino)methyl]pyrrole and diethyl acetamidomalonate in basic medium directly produced the bicyclic pyrrolizin-3-one structure (Scheme 1, eq. 1). 3 McNab was the first to generate 3H-pyrrolizin-3-one by flash vacuum pyrolysis (FVP) of the condensation product of pyrrole-2-carbaldehyde with Meldrum's acid (Scheme 1, eq. 2). 4 Pinho e Melo and co-workers later obtained pyrrolizin-3-ones by FVP of N-vinyl-and Cvinylpyrroles generated by the thermal extrusion of sulfur dioxide from pyrrolo[1,2-c]thiazole 2,2-dioxides (Scheme 1, eqs. 3 and 4). 5 Recently, pyrrolizin-3-one derivatives were synthesized from the alkylation products of pyrrole with a,b-unsaturated 2-acylimidazoles by Evans and Fandrick (Scheme 1, eq. 5) 6 and from the cyclization of the radical reaction product of pyrrole and a-halo esters by Byers and co-workers (Scheme 1, eq. 6). 7Despite the existence of different synthetic approaches for the synthesis of the pyrrolizin-3-one structure with different substituents, there remains a need for efficient and simple synthetic methods that provide substituted pyrrolizine structures under mild reaction conditions. We previously demonstrated that metal triflates are very efficient catalysts for the addition of pyrrole to a,b-unsaturated carbonyl compounds under mild reaction conditions. 8 This methodology allows direct alkylation of pyrroles in high yields. Alkylated products, especially with carbonyl or ester functionalities, have been demonstrated to be convenient precursors for the synthesis of pyrrolizine structures by their intramolecular cyclization. 9,10

The widespread usage of Schiff bases in chemistry, industry, medicine, and pharmacy has increased interest in these compounds. Schiff bases and derivative compounds have important bioactive properties. Heterocyclic compounds containing phenol derivative groups in their structure have the potential to capture free radicals that can cause diseases. In this study, we designed and synthesized eight Schiff bases (10–15) and hydrazineylidene derivatives (16–17), which contain phenol moieties and have the potential to be used as synthetic antioxidants, for the first time using microwave energy. Additionally, the antioxidant effects of Schiff bases (10–15) and hydrazineylidene derivatives (16–17) were studied using by the bioanalytical methods of 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) cation radical (ABTS•+) and 1,1-diphenyl-2-picrylhydrazyl (DPPH•) scavenging activities, and Fe3+, Cu2+, and Fe3+-TPTZ complex reducing capacities. In the context of studies on antioxidants, Schiff bases (10–15) and hydrazineylidene derivatives (16–17) were found to be as powerful DPPH (IC50: 12.15–99.01 μg/mL) and ABTS•+ (IC50: 4.30–34.65 μg/mL). Additionally, the inhibition abilities of Schiff bases (10–15) and hydrazineylidene derivatives (16–17) were determined towards some metabolic enzymes including acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase I and II (hCAs I and II), enzymes that are linked to some global disorders including Alzheimer’s disease (AD), epilepsy, and glaucoma. In the context of studies on enzyme inhibition, it was observed that the synthesized Schiff bases (10–15) and hydrazineylidene derivatives (16–17) inhibited AChE, BChE, hCAs I, and hCA II enzymes with IC50 values in ranges of 16.11–57.75 nM, 19.80–53.31 nM, 26.08 ± 8.53 nM, and 85.79 ± 24.80 nM, respectively. In addition, in light of the results obtained, we hope that this study will be useful and guiding for the evaluation of biological activities in the fields of the food, medical, and pharmaceutical industries in the future.

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