Phosphine Oxides (−POMe₂) for Medicinal Chemistry: Synthesis, Properties, and Applications

Abstract

A general practical approach to hetero(aromatic) and aliphatic P(O)Me 2 -substituted derivatives is elaborated. The key synthetic step was a [Pd]-mediated C−P coupling of (hetero)aryl bromides/iodides with HP(O)Me 2 . The P(O)Me 2 substituent was shown to dramatically increase solubility and decrease lipophilicity of organic compounds. This tactic was used to improve the solubility of the antihypertensive drug prazosin without affecting its biological profile.

Fluorinated Aliphatic Diazirines: Preparation, Characterization, and Model Photolabeling Studies

“…Additionally, another P(O)Me 2 -substituted model compound 35 with improved water solubility was synthesized (Scheme ). Its irradiation in methanol under different wavelengths gave mainly alkene 36 .…”

Defluorophosphorylation of fluoroalkyl peroxides for the synthesis of highly substituted furans

“…As shown in Table 1, using Ph 2 P(O)H, polyfluorinated benzylic peroxides 1 bearing a variety of electronically and sterically varied aryl groups reacted smoothly to give the corresponding [P2] and [P1] products in 42-91% yields. Substituents on the aryl ring, including alkyl (5-8), methoxy (9-10), amino (11)(12), halogens (13-23), trifluoromethyl (24)(25), carbalkoxy (26)(27), and cyano (28)(29), were tolerated under the mild reaction conditions. As for substrates with a naphthalene or thiophene motif, products 30-33 were generated in acceptable yields.…”

“…9 These methods rely on air- and moisture-sensitive organometallics and/or toxic phosphorus reagents. During the past decade, Hirao-type 10 or dehydrogenative C(sp 2 )–P bond cross-coupling reactions of (hetero)aryl electrophiles with H-phosphine oxides catalyzed by Pd, 11–15 Cu, 16,17 Ni, 18–20 and others 21 have been well documented (Fig. 1, B, b).…”

Synthesis of Phosphorus(V)-Substituted Six-Membered N-Heterocycles: Recent Progress and Challenges

“…Mykhailiuk and co-workers [ 91 ] expanded the scope of this reaction using the Pd 2 (dba) 3 /Xantphos catalytic system in the reaction of bromo(iodo)pyridines with dimethylphosphine oxide ( Scheme 15 ). The scope of this reaction was found to be quite general and enables facile preparation of 2-, 3-, and 4-dimethylphosphine-oxide-substituted pyridines 72 in up to good yields.…”

“…Since the first work on palladium-catalyzed phosphorylation of pyrimidines published in 2008 by Belabassi et al [ 45 ], transition-metal-catalyzed cross-coupling of halopyrimidines with secondary phosphine oxides and phosphonates proved to be an efficient route to phosphorylpyrimidines. Mykhailiuk and co-workers [ 91 ] published a procedure for Pd(II)-catalyzed coupling of halo(Br/I)pyrimidines 126 with dimethylphosphine oxide, showing remarkable generality ( Scheme 31 ). Synthesis of 2-, 4-, and 6-phosphine-oxide-substituted pyrimidines 127 bearing electron-donating and electron-withdrawing substituents on the heterocyclic moiety was accomplished using Pd 2 (dba) 3 in the presence of the Xantphos ligand.…”