Metal-free direct arylation of dialkyl phosphonates for the synthesis of mixed alkyl aryl phosphonates

Inventors

Kang, Jun Yong • Huang, Hai

Abstract

Provided herein are phosphates, thiophosphates, phosphonates, and phosphinates, methods of making same, and methods of using these compounds and methods for the generation of pharmaceutically relevant phosphate, phosphonate, and phosphinate analogs. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Core Innovation

The invention relates to methods of making compounds having structures represented by formulas in which variable positions are defined by Markush ranges. The formulas include variables such as n being 0 or 1, A being selected from O, S, NR20, and CHR21, and Q or Z being selected from O, S, and NR22 or NR23, with defined selections for R20, R21, R22, R23, R1, Ar1, Ar2, and Ar3, and optional covalent bonding of R1 and R20 to form a 3- to 6-membered heterocycloalkyl.

The method comprises reacting a phosphonate derivative or a phosphinate derivative having a structure represented by a formula with a nucleophile having a structure represented by a formula in the presence of an activating agent and a base. The activating agent is selected from triflic anhydride, mesyl chloride, tosyl chloride, oxalyl chloride, thionyl chloride, acetic anhydride, benzoic anhydride, and trifluoroacetic anhydride, and optional salt formation is described for the resulting compounds.

The disclosure further describes broad substituent sets for aryl and heteroaryl groups, including halogen, nitro, cyano, hydroxyl, thiol, amino, alkyl, alkenyl, alkynyl, haloalkyl, cyanoalkyl, hydroxyalkyl, haloalkoxy, alkoxy, thioalkyl, aminoalkyl, alkylamino, dialkylamino, cycloalkyl, aryl, and related linkage groups. Dependent embodiments refine the scope by selecting particular activating agents and bases, including triflic anhydride and pyridine, and by selecting particular depicted compound structures.

Claims Coverage

The consolidated claim coverage identifies four independent method claims directed to making compounds with a defined, highly substituted structural formula. The core inventive framework is the reaction of a phosphonate derivative or phosphinate derivative with a nucleophile in the presence of an activating agent and a base, combined with tightly constrained product-formula variables; dependent refinements include triflic anhydride and pyridine.

Across the independent claims, the inventive coverage is the same transformation concept: making a compound with a highly constrained structural formula by reacting a phosphonate or phosphinate derivative with a nucleophile using an activating agent from the stated list and a base. The dependent refinements narrow the scope with specific reagent choices, including triflic anhydride and pyridine.

Stated Advantages

Documented Applications