Controlled chemistry of Moisture Sensitive Reagents in Ionic Liquids

PCl3 and POCl3 are key synthetic precursors in a wide range of chemical processes, required in the synthesis of compounds ranging from bulk chemicals such as pesticides, flame retardants and plasticizers to the advanced synthetic intermediates and reagents, therapeutic precursors and metal catalysts ligands. However, whether neat or in organic solvents, these reagents and their derivatives are highly air and water sensitive and must be used under strictly anhydrous conditions, often in excess at low temperatures to allow for some level of control in order to achieve chemoselectivity and avoid side-product formation. For instance, excess of phosphitylating reagent must be used in aprotic organic solvents at low temperature under anhydrous and dissolution conditions in order to obtain mono-derivatised chlorophosphines and overcome the high chemical reactivity of the trivalent chlorophosphine’s P-Cl bonds. As such, by virtue of their chemical instability in organic media, the use of chlorophosphines in the direct phosphitylation of alcohols and amines has been limited and very difficult to control. In industry, the reagents used and available for phosphitylation reactions have been restricted to compounds such as dibenzyloxychlorophosphine, dichlorodiisopropylaminophosphite, chlorocyanoethyldiisopropyl-aminophosphite and cyanoethyl-bisdiisopropylaminophosphite. Although these reagents are commercially available and used extensively as precursors in the synthesis of many phosphoruscontaining fine chemicals, major variability can be observed in their purity and stability upon storage. As a consequence, yields of phosphitylation reactions are highly variable and thus compromise overall synthetic efficiency in particular that of automated processes such as solid phase synthesis of oligonucleotides, which require highly pure nucleoside phosphoramidites to be effective. We have established that ionic liquids can alleviate many of the issues surrounding the use and preparation of P-X containing compounds as synthetic reagents. Initially, the stability of PCl3/POCl3 in ILs and the controllable reactivity of PCl3 in this medium has been demonstrated. In addition, in the area of PCl3 manipulation, ILs was shown to permit the selective conversion of individual P-Cl bonds (Figure 1) to be performed with control not observed in molecular solvent systems. This has been particularly valuable in the formation of nucleotide phosphoramidites.