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.