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

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 pK 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 2containing isosteres (by ca. 1.2 and 0.4 pK 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 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.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…Also, some chemotypes that were not covered in the current review but are certainly relevant to its topic can be found in the literature. As it was mentioned in the Introduction, these include, for example, sulfoximines, [39,527,528] sulfonimidamides [529,530] and their analogs, [531] dialkyl phospine oxides [40,145] -unusual isosteres of amides, sulfonamides, sulfones, and related compounds (Figure 13), as well as deuterated analogues, [41] silicon-containing isosteres, [42] or Ntrifluoromethylated azoles. [43] It is interesting to note that nearly all these examples, as well as most of those discussed in this review, originate from organosulfur, -boron, -phosphorus, -silicon, or -fluorine chemistry.…”

“…The SuFEx reactions typically use common sulfonylation conditions (Et 3 N, CH 2 Cl 2 ); [130,[136][137][138][139] also, ammonia [140][141][142][143][144][145] or aliphatic amines [146][147][148][149][150][151] can act both as reagents and as bases (Scheme 15A). One more important modification includes reaction of sulfonyl halides and aliphatic N-silylamines in refluxing in MeCN.…”

Chemoselective Reactions of Functionalized Sulfonyl Halides

“…Typically, these reactions are performed with an excess of amine or in the presence of a base like Et 3 N, pyridine, or iPr 2 NEt (Scheme 34); other notable protocols include the use of Ca(NTf 2 ) 2 catalysis [214] and HOBt -1,1,3,3-tetramethyldisiloxane (TMDS) promotion [177] (also requiring the presence of a base). These SuFEx reactions were compatible with the presence of ester, [143,203,[215][216][217][218] nitrile, [40,88,177,219] aromatic [152,220] and aliphatic [177] ketone, chalcone [207] moieties; other groups included azide, [83] phosphine, [177] phosphite, [69] SF 5 , [218] and unprotected carbox- ylic acid. [22,177,221] Furthermore, free alcohol [146,222,223] and phenol [22,177] groups in the starting sulfonyl fluoride, as well as unprotected aniline (in the case of aliphatic amines as Nnucleophiles) [64,177,222,[224][225][226] could be tolerated.…”

“…Being a strong electron‐withdrawing group, the SO 2 F fragment is considered as one of the best double bond activators for the nucleophilic conjugate (Michael) addition [60] . Indeed, alkenyl sulfonyl fluorides readily react with a huge variety of C ‐, [60–64] N ‐, [43,62,64–67] S ‐, [25,64,67,68] or P ‐nucleophiles [69] (Scheme 4). For example, Michael addition to the simplest vinyl sulfonyl fluoride was used for the preparation of [ 18 F]‐labelled amino acids [70] and modification of s ‐tetrazine building blocks [71] .…”

(Diazomethyl)dimethylphosphine Oxide – A Diazoalkane Reagent for [3+2] Cycloadditions

“…For example, vinyldimethylphosphine oxide (1) was introduced into [3 + 2] cycloaddition with azomethine ylide (Scheme 1, C). [6] Diazoalkanes are versatile reagents in organic synthesis that have become increasingly important in recent years due to the development of safe protocols for their in-situ generation. [8][9][10][11][12][13][14] While dialkyl diazophosphonates are widely recognized re-agents in organic synthesis, [15][16][17][18][19][20] diazoalkanes with a phosphine oxide moiety are much rarer (Scheme 1, E), [21][22][23][24] and their reactivity is studied very scarcely.…”