1260402-40-1Relevant articles and documents
Heteroaliphatic Dimethylphosphine Oxide Building Blocks: Synthesis and Physico-Chemical Properties
Fedyk, Andrii,Slobodyanyuk, Evgeniy Y.,Stotska, Olha,Vashchenko, Bohdan V.,Volochnyuk, Dmitriy M.,Sibgatulin, Dmitriy A.,Tolmachev, Andrey A.,Grygorenko, Oleksandr O.
, p. 6591 - 6603 (2021)
Scalable synthesis of saturated heterocyclic dimethyl phosphine oxides (derivatives of azetidine, pyrrolidine, piperidine, and morpholine) is disclosed. The key steps of the synthesis relied on the reactions of HP(O)Me2, i. e. the phospha-Mannich (the Kabachnik-Fields-type) condensation with cyclic imines or monoprotected diamines, palladium-catalyzed reactions of alkenyl halides or trifltates (generated from cyclic ketones), as well as base-mediated nucleophilic substitution, Michael addition, or oxirane ring opening. It was shown that introducing the P(O)Me2 group into the saturated heterocyclic core had very strong impact on the compound's basicity: the corresponding α-, β-, and γ-isomeric derivatives were by ca. 4, 2, and 1.6 pKa units less basic, respectively, as compared to the parent saturated heterocycle. Meanwhile, the P(O)Me2-substituted compound was more basic than its SO2i-Pr and SO2NMe2-containing isosteres (by ca. 1.2 and 0.4 pKa units, respectively). It was also demonstrated that the P(O)Me2 group typically increased the compound's hydrophilicity and aqueous solubility. In particular, the LogP values for the corresponding derivatives were by ca. 1.4–1.7 and 0.6 units lower than for the non-substituted counterpart and sulfonamide/sulfone isosteres, respectively. Finally, a potential of the synthesized building blocks to generate lead-like three-dimensional compound libraries was confirmed using the Nelson's LLAMA tool.
