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. 2019 May 22;4(5):9056-9064.
doi: 10.1021/acsomega.9b01137. eCollection 2019 May 31.

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

Rubén Oswaldo Argüello-Velasco  1 , Błażej Dziuk  2 , Bartosz Zarychta  2 , Mario Ordóñez  1 , Paweł Kafarski  3
Affiliations

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

Rubén Oswaldo Argüello-Velasco et al. ACS Omega. .

Abstract

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Reaction of Lactams by Vilsmeier–Haack-Like Reaction
Scheme 2
Scheme 2. Reactions of Morpholin-3-one and Thiomorpholin-3-one and Their Derivatives
Scheme 3
Scheme 3. Mechanism of Reaction of Mopholin-3-one and N-benzylmopholin-3-one
Scheme 4
Scheme 4. Reaction of N-benzylvalerolactam
Scheme 5
Scheme 5. Synthesis of tetraethyl N-benzyl-2,3-morpholyl-3,3-bisphosphonate (9) by procedure of Wang et al.
Scheme 6
Scheme 6. Products of the Reaction of Piperazin-2-one as a Substrate
Scheme 7
Scheme 7. Presumable Mechanism of the Formation of gem-bisphosphonates 10 and 11
Figure 1
Figure 1
Crystal structures for compounds 12 (left panel) and 13 (right panel).
Figure 2
Figure 2
Crystal structure of the product of the degradation of C–P bonds upon hydrolysis of compound 14.
Scheme 8
Scheme 8. Reactions of Derivatives of Piperazin-2,3-dione
Scheme 9
Scheme 9. Reaction of 3-methyl-piperazin-3-one
Figure 3
Figure 3
Crystal structure of compound 19.
Scheme 10
Scheme 10. Addition of Phosphite to Double Bond of Ditosyl–Cytosine
See this image and copyright information in PMC

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