Abstract
Synthetic approaches towards novel 3-pyrazolidinone derivatives functionalized at positions N(1) and/or C(5) were studied. 5-Aminoalkyl-3-pyrazolidinones were prepared in four steps from N-protected glycines via Masamune-Claisen homologation, reduction, O-mesylation, and cyclisation with a hydrazine derivative. The free amines were prepared by acidolytic deprotection. Title compound was also prepared by 'ring switching' transformation of N-Boc-pyrrolin-2(5H)-one with hydrazine hydrate. Hydrogenolytic deprotection of 5-(N-alkyl-N-Cbz-aminomethyl)pyrazolidine-3-ones followed by cyclisation with 1,1'-carbonyldiimidazole (CDI) gave two novel representatives of perhydroimidazo[1,5-b] pyrazole, which is an almost unexplored heterocyclic system. Amidation of 3-oxopyrazolidine-5-carboxylic acid gave the corresponding carboxamides in moderate yields. Diastereomeric non-racemic carboxamides obtained from (S)-AlaOMe and (S)-ProOMe were separated by MPLC.
Highlights
Synthetic approaches towards novel 3-pyrazolidinone derivatives functionalized at positions N(1) and/or C(5) were studied. 5-Aminoalkyl-3-pyrazolidinones were prepared in four steps from N-protected glycines via Masamune-Claisen homologation, reduction, O-mesylation, and cyclisation with a hydrazine derivative
In the context of our ongoing work on the synthesis of chiral heterocycles with emphasis on pyrazole[33,34] and pyrazolidinone derivatives,[31,32] we reported the synthesis of tetrahydropyrazolo[1,5–c]pyrimidine-2,7-diones as the first representatives of a novel saturated heterocyclic system,[35,36] followed by preparation of closely related tetrahydropyrazolo[1,5–c]pyrimidine-3-carboxamides[37] and tetrahydro-1H-imidazo[1,5–b]pyrazole-2,6-diones.[38]
The 5-substituted pyrazolidinone was obtained by cyclization of the corresponding β-mesyloxy ester, which in turn was obtained in three steps from a suitably functionalized carboxylic acid.[31]
Summary
Hetero(bi)cycles are commonly used building blocks for applications in medicinal chemistry, catalysis, and materials science.[1,2] In this context, 3-pyrazolidinones and their bicyclic analogues are attractive targets due to their easy availability from α,β-unsaturated esters and because of their applicability and biological activity.[3,4,5,6] Pyrazolidinone derivatives have been employed as dyes and photographic developers[3,5] and as inhibitors of cyclooxygenase, lipoxygenase,[7] and γ-aminobutyrate aminotransferase[8] exhibiting analgesic, antipyretic, anti-inflammatory, and anorectic activity. The 5-substituted pyrazolidinone was obtained by cyclization of the corresponding β-mesyloxy ester, which in turn was obtained in three steps from a suitably functionalized carboxylic acid.[31] Pyrazolidinones with 2-hydroxyethyl[36] and 2-aminoethyl[35,37] functional groups at position 5 were used as key intermediates in the synthesis of novel saturated heterocyclic systems, while 5-[(S)-1-aminoalkyl] derivatives prepared from N-protected α-amino acids were used as scaffolds for potential organocatalysts[38] and as key-intermediates in the synthesis of 3-pyrrolinones.[40]. Nomethyl and 5-carboxy substituted 3-pyrazolidinones available from glycine derivatives and from dimethyl maleate, respectively These novel pyrazolidinone derivatives are interesting intermediates in the synthesis of chiral saturated pyrazolidine-based heterocyclic systems
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