Preliminary studies towards the preparation of reactive 3-pyrrolin-2-ones in conjugate addition reactions for the syntheses of potentially bioactive 2-pyrrolidinones and pyrrolidines

Abstract

Pirrolin-2-onas e 2-pirrolidinonas são subunidades geralmente encontradas na estrutura de vários produtos naturais bioativos e 3-pirrolin-2-onas são valiosos materiais de partida em síntese orgânica devido à habilidade de reagirem como aceptores em reações de adição conjugada. Neste artigo relatamos os resultados iniciais do estudo realizado objetivando as sínteses de 3-pirrolin-2-onas reativas em reações de adição conjugada e a preparação de um precursor potencial para a síntese do nootrópico (+/-)-nebracetam.Pyrrolin-2-ones and 2-pyrrolidinones are moieties often found in the structure of several biologically active natural products and 3-pyrrolin-2-ones are valuable starting materials in organic synthesis due to their ability to react as acceptors in conjugate addition reactions. In this article we report the initial results about the performed study aiming at the syntheses of reactive 3-pyrrolin-2-ones in conjugate addition reactions and the preparation of a potential precursor for the synthesis of the nootropic (+/-)-nebracetam.

2-Pyrrolidinones and 3-Pyrrolin-2-ones: A Study on the Chemical Reactivity of These Structural Moieties

“…The reaction of 8 with S-α-methylbenzylamine generated a complex mixture of substances. After a detailed analysis of 1 H NMR, 13 C NMR, 1 Hx 1 H-Cosy, HETCOR, IR and GC/MS spectra, we propose the structure of the probable isomers 11-13 as products of that reaction, resulting from the speculative mechanism depicted in Scheme 5. The proposition of the substances 11-13 as the probable products from that reaction was reinforced at the GC/MS spectra by the peaks at m/z 281 (T R 2.1, 7.4 and 8.4 min), attributed to the protonated [M + H] + ions of that mixture of isomers.…”

“…Thus, the treatment of 1 with a suspension of NaH in THF followed by reaction with (Boc) 2 O [3] generated a compound characterized by 1 H NMR as the pyrrolidinone 2. The substance 2 was partially converted to a product identified by 1 H NMR as the thiophenoxylactam 3, as result of alpha deprotonation of the carbamate of 2 with LDA solution [4], followed by nucleophilic substitution of the generated lithium enolate with diphenyl disulfide [5]. At the 1 H NMR spectrum of 3, signals were detected relative to two isomers in the proportion (10 : 1) measured by integrals relative to methyls of the groups tert-butoxycarbonyl at δ 1.52 (major isomer) and δ 1.43 (minor isomer).…”

“…After the respective times of reaction described in Table 1, crude products were isolated, filtered over column chromatography of silica gel, and then analysed by 1 H NMR. The signals of hydrogens relative to elimination product 5 were not observed at the spectrum of experiment 1.…”

“…For execution of the reactions described in Scheme 4, we used as substrate N-benzyl-3-pyrrolin-2-one(8), which was previously obtained [1]. Thus, the treatment of 8 with TMSCl followed by reaction with the Grignard reagent PhMgBr and CuBr·SMe 2 [11][12][13] generated a product identified by 1 H NMR, IR, and LRMS as the hemiaminal 9.…”

“…In connection with our studies on the syntheses of potentially bioactive 2-pyrrolidinones and 3-pyrrolin-2-ones [1], we describe in this paper the results of the performed study on the chemical reactivity of these structural moieties in reactions of addition, nucleophilic substitution, elimination, and reduction as well as the protection of the lactamic nitrogen.…”