Reactions of Piperazin-2-one, Morpholin-3-one, and Thiomorpholin-3-one with Triethyl Phosphite Prompted by Phosphoryl Chloride: Scope and Limitations

The reaction of the title lactams with triethyl phosphite prompted by phosphoryl chloride provided six-membered ring heterocyclic phosphonates or bisphosphonates. These novel scaffolds might be of interest as building blocks in medicinal chemistry. The course of the reaction was dependent on the structure of the used substrate. Thus, morpholin-3-one and thiomorpholin-3-one readily provided the corresponding 1,1-bisphosphonates (compounds 1, 2, 7, 14 and 16), whereas the protection of their nitrogen atom resulted in the formation of dehydrophosphonates (compounds 5, 6, and 8). Piperazin-2-one reacted differently yielding mixture of cis- and trans- piperazine-2,3-diyl-bisphosphonates (compounds 10 and 11). Since cytosine could be considered as an analogue of piperin-2-one, its ditosyl derivative 18 was used as a substrate affording compound 19 being a product of phosphite addition to double bond. In dependence of their structures, hydrolysis of the obtained diethyl phosphonates resulted either in corresponding cyclic phosphonic acids or in the degradation of carbon-to-phosphorus bond.

本文标题所指的内酰胺（lactams）在三氯氧磷（phosphoryl chloride）的引发下与三乙基亚磷酸酯（triethyl phosphite）发生反应，生成六元环杂环膦酸酯或双膦酸酯（bisphosphonates）。此类新型骨架可作为药物化学领域的关键合成砌块（building blocks），具备潜在的研究价值。该反应的进程取决于所用底物（substrate）的结构：吗啉-3-酮（morpholin-3-one）与硫代吗啉-3-酮（thiomorpholin-3-one）可顺利生成对应的1,1-双膦酸酯（化合物1、2、7、14和16）；而对二者的氮原子进行保护后，则会生成脱氢膦酸酯（dehydrophosphonates，化合物5、6和8）。哌嗪-2-酮（piperazin-2-one）的反应路径则有所不同，会生成顺式（cis-）与反式（trans-）哌嗪-2,3-二基双膦酸酯的混合物（化合物10和11）。由于胞嘧啶（cytosine）可被视为哌嗪-2-酮的类似物，本研究以其二对甲苯磺酰基（ditosyl）衍生物18为底物，得到了亚磷酸酯加成至双键的产物19。根据产物结构的差异，所得二乙基膦酸酯（diethyl phosphonates）的水解反应要么生成对应的环型膦酸（cyclic phosphonic acids），要么发生碳-磷键（carbon-to-phosphorus bond）的断裂降解。