Molecules2023_Synthesis of new azetidine and oxetane amino acid derivatives through aza-Michael addition of NH-heterocycles with methyl 2 (azetidin- or oxetan-3-ylidene)acetates

In this paper, a simple and efficient synthetic route for the preparation of new heterocyclic amino acid derivatives containing azetidine and oxetane rings is described. The starting (N Boc azetidin-3-ylidene)acetate was obtained from (N-Boc)azetidin-3-one by the DBU-catalysed Horner–Wadsworth–Emmons reaction, followed by aza-Michael addition with NH-heterocycles to yield the target functionalised 3-substituted 3-(acetoxymethyl)azetidines. Methyl 2 (oxetan-3-ylidene)acetate was obtained in a similar manner, which was further treated with various (N-Boc-cycloaminyl)amines to yield the target 3-substituted 3-(acetoxymethyl)oxetane compounds. The synthesis and diversification of novel heterocyclic amino acid derivatives were achieved through the Suzuki–Miyaura cross-coupling from the corresponding brominated pyrazole–azetidine hybrid with boronic acids. The structures of the novel heterocyclic compounds were confirmed via 1H-, 13C-, 15N-, and 19F-NMR spectroscopy, as well as HRMS investigations.

本文详细阐述了合成新型含氮杂环氨基酸衍生物的简便高效路线，该衍生物包含氮杂环丁烷和氧杂环丁烷环状结构。以（N-苄氧羰基）氮杂环丁烷-3-基甲酰基乙酸酯为起始物，通过DBU催化的霍纳-沃茨-埃蒙斯反应从（N-苄氧羰基）氮杂环丁烷-3-酮中制得，随后与NH杂环化合物进行亚甲基化反应，得到目标功能化的3-取代3-(乙氧甲酰甲基)氮杂环丁烷。类似地，通过相同方法制备了甲基2-(氧杂环丁烷-3-基甲酰基)乙酸酯，进一步与多种（N-苄氧羰基-环氨基）胺反应，得到目标3-取代3-(乙氧甲酰甲基)氧杂环丁烷化合物。新型杂环氨基酸衍生物的合成与多样化是通过相应溴化吡唑-氮杂环丁烷杂化物与硼酸之间的 Suzuoki-Miyaura 交叉偶联反应实现的。新型杂环化合物的结构通过1H、13C、15N和19F核磁共振光谱以及高分辨质谱（HRMS）分析得到确认。