No abstract

A convenient synthesis of phosphonic analogues of pipecolic acid and its heterocyclic analogues is reported. The major step of the elaborated procedure is the introduction of the phosphonate group into the skeleton of the appropriate cyclic amide through N‐acyliminium ions. The former ones were obtained by preparation of the hemiaminals or their methyl ethers from the N‐protected cyclic amides. Finally, the reaction with trimethyl phosphite in the presence of BF3·OEt2 afforded the desired phosphonates, which were converted into phosphonic acids by the hydrolysis of phosphonate moiety with simultaneous cleavage of the nitrogen protecting groups.

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.