Heteroaliphatic Dimethylphosphine Oxide Building Blocks: Synthesis and Physico‐Chemical Properties

Abstract

Abstract 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)Me 2 , 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)Me 2 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 p K a units less basic, respectively, as compared to the parent saturated heterocycle. Meanwhile, the P(O)Me 2 ‐substituted compound was more basic than its SO 2 i‐ Pr and SO 2 NMe 2 ‐containing isosteres (by ca. 1.2 and 0.4 p K a units, respectively). It was also demonstrated that the P(O)Me 2 group typically increased the compound's hydrophilicity and aqueous solubility. In particular, the Log P 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.