Preparation of Arylphosphonates by Palladium(0)‐Catalyzed Cross‐Coupling in the Presence of Acetate Additives: Synthetic and Mechanistic Studies

Abstract

An efficient protocol for the synthesis of arylphosphonate diesters via a palladium-catalyzed cross-coupling of H-phosphonate diesters with aryl electrophiles, promoted by acetate ions, was developed. A significant shortening of the cross-coupling time in the presence of the added acetate ions was achieved for bidentate and monodentate supporting ligands, and for different aryl electrophiles (iodo, bromo and triflate derivatives). The reaction conditions were optimized in terms of amount of the catalyst, supporting ligands, and source of the acetate ion used. Various arylphosphonates, including those of potential biological significance, were synthesized using this newly developed protocol. Some mechanistic aspects of the investigated reactions are also discussed.

Design and Synthesis of Polyoxazole‐based Macrocycles Tethered with a Phosphonate Group

“…A two-step transformation by treatment of 4 with PBr 5 followed by esterification furnished the diethyl 4-bromopyridine-2,6-dicaboxylate (5). Cross-coupling of 5 with diethyl phosphite under Stawinski's conditions [10] afforded the phosphonate 6 in 80% yield. Attempted hydrolysis of 6 was problematic for this particular substrate although hydrolysis of ester is an easily occurring transformation.…”

“…Preparation of phosphonate 6 [10] To a 25 mL Schlenk tube equipped with a magnetic bar was added Pd(OAc) 2 (3.4 mg, 0.015 mmol), dppf (16.6 mg, 0.03 mmol) and KOAc (6.4 mg, 0.065 mmol). The tube was then evacuated (10 min×3) under vacuum and backfilled with Ar.…”

Pd-Catalyzed P-Arylation of Triarylantimony Dicarboxylates with Dialkyl H-Phosphites without a Base: Synthesis of Arylphosphonates

“…They were inferior to Pd(PPh 3 ) 4 in the terms of the reaction time and yield of the cross-coupling product (entries [12][13][14][15][16]. The screening of solvent showed that the reaction proceeded effectively in dioxane (94%), 1,2-dichloroethane (DCE) (78%), 1,2-dimethoxyethane (DME) (75%) and tetrahydrofuran (THF) (71%) whereas toluene, CH 3 CN, N-methylpyrrolidone (NMP) and EtOH gave inferior results (entries [17][18][19][20][21][22][23]. The addition of a base such as triethylamine to facilitate the Hirao reaction decreased the yield of the coupling product (10) (38%).…”

“…The Pd-catalyzed P-arylation of aryl halides with dialkyl H-phosphites is promoted by acetate ions, and ArPdOAc (C) is the key intermediate for reaction mechanism. 12,13,19) The ligand exchange of ArPdOAc (C) with dialkyl H-phosphite (9) gives ArPdP(O)(OR) 2 intermediate D, which undergo reductive elimination to form the coupling product and regenerate the Pd(0) species (A).…”

“…[7][8][9] With regard to the synthesis of arylphosphonates, the Pd-catalyzed cross-coupling reactions of aryl halides with dialkyl H-phosphites (i.e., Hirao P-arylation) have proved to be a powerful method. [10][11][12][13][14][15][16][17][18][19][20][21] The general procedure of these P-arylations involves a Pd-phosphine complex as the catalyst with the use of a stoichiometric or an excess amount of a base. Recently, different aryl substances were investigated for their reactivity with phosphorus agents.…”