Chemoselective Activation of Diethyl Phosphonates: Modular Synthesis of Biologically Relevant Phosphonylated Scaffolds

Abstract

Phosphonates have garnered considerable attention for years owing to both their singular biological properties and their synthetic potential. State‐of‐the‐art methods for the preparation of mixed phosphonates, phosphonamidates, phosphonothioates, and phosphinates rely on harsh and poorly selective reaction conditions. We report herein a mild method for the modular preparation of phosphonylated derivatives, several of which exhibit interesting biological activities, that is based on chemoselective activation with triflic anhydride. This procedure enables flexible and even iterative substitution with a broad range of O, S, N, and C nucleophiles.

Triflic Anhydride (Tf2O)-Activated Transformations of Amides, Sulfoxides and Phosphorus Oxides via Nucleophilic Trapping

“…Shortly after the publication of our mixed phosphonate synthesis, 119 the Maulide group reported a Tf2O/TEAC-mediated electrophilic activation strategy of phosphonates 76a, allowing various nucleophile partners to afford mixed phosphonates 76b (Scheme 76). 124 This approach employing Tf2O/2-I-Py/TEAC conditions demonstrated diverse heteroatom nucleophiles (Nu = O, S, N, C) as efficient nucleophile partners to prepare mixed phosphonate derivatives 76c-76n. It is worth mentioning that the use of a chloride reagent (TEAC) and the deprotonated nucleophiles would contribute to extend the scope of available nucleophiles.…”

Denitrative Cross-Couplings of Nitrostyrenes

“…Although each proposal differs in detail, the main three characteristic steps feature in all proposals. Firstly, carbon- or heteroatom-centered radical 4 is generated in situ by various methods from precursors 6 – 33 [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ]. These include a thermal homolytic cleavage of labile bonds, metal-catalyzed and photochemically initiated processes.…”

“…The benefits of the direct preparation of conjugate phosphonates from nitrostyrene we re soon after the discovery appreciated by two research groups. Maulide [ 49 ] and Kang [ 50 ] independently in 2018 repeated the reaction of nitrostyrene and diethyl phosphite and demonstrated its utility in a straightforward synthesis of conjugated phosphonate 3cz ( Scheme 25 ). Albeit, 3cz was obtained in low yield, the simplicity and reliability of the novel approach prevailed over the more traditional preparations of conjugated phosphonates.…”

N-Phosphorylated Pyrrolidines: An Overview of Synthetic Approaches

“…An approach to phosphonylated compounds via chemoselective activation of diethyl phosphonates with triflic anhydride and subsequent interaction with nucleophiles was developed by Maulide et al 60 The reaction of phosphonate 45 with lithium 3,3-difluoropyrrolidin-1-ide as the N-nucleophile allowed the authors to obtain (pyrrolidin-1yl)phosphinate 46 (Scheme 6, B). Notably, a double bond was preserved during the reaction.…”