Controlled Reactivity of Phosphonates by Temporary Silicon Connection

Abstract

In this review a summary of the different syntheses of trimethylsilylphosphonates is given. Their chemical reactivity in the light of their synthetic utility leading to numerous types of functionalized phosphonates is described. The material is presented according to the role played by the trimethylsilyl group.

Fluorinated Phosphonates: Synthesis and Biomedical Application

“…Still the synthesis of α-monofluorophosphonates could be made more controlled by using a specific protective group at a carbanionic phosphonate center. Such methodology, based on controlled reactivity of phosphonates, was indeed worked out by Savignac and co-workers . Transformation of alkylphosphonates to the pure α-monofluoro derivatives has been accomplished in three steps (Scheme ). − Diethyl lithio 1-(trimethylsilyl)alkylphosphonates 41 , the key intermediates in the synthesis of α-monofluorophosphonates, are easily formed from 40 and TMSCl by using LDA or LiHMDS as metalating agent.…”

“…Patois and Savignac have described the generation of the lithiated carbanion [(EtO) 2 P(O)CF(SiMe 3 )] - Li + ( 95 ) from readily accessible phosphonate (EtO) 2 P(O)CBr 2 F by a double halogen−metal exchange reaction with n BuLi in the presence of trimethylsilyl chloride as the trapping agent . The trimethylsilyl group has been shown to be useful as a protecting group for further elaboration of the phosphonate skeleton and as a directing group for a Peterson-type olefination (vide infra). , Carbanion 95 safely undergoes alkylation with alkyl iodides or triflates leading to the corresponding C-alkylated α-fluoroalkylphosphonate esters. Owing to the presence of an activating fluorine substituent, the C−Si bond in the phosphonates 96 is very sensitive, and the Me 3 Si group was easily eliminated with EtOLi in EtOH to produce the α-monofluoroalkylphosphonates 97 in high yields and free of byproducts (Scheme ). , Another illustration of the advantages of this methodology is provided by the synthesis of diethyl α-fluorophosphonocarboxylates 99 shown in Scheme .…”

“…The focus of discussion here will be on reactions in which the (RO) 2 P(O)CF 2 M species, where M = Li, MgCl, ZnBr, CdBr, and Cu (Table ), act as a masked [(RO) 2 P(O)CF 2 ] - carbanionic equivalent. These can be prepared by a variety of methods of which the main ones are (i) deprotonation of (RO) 2 P(O)CF 2 H with a suitable organometallic base, , (ii) halogen−metal exchange between (RO) 2 P(O)CF 2 Br and alkyl lithium or Grignard reagent, ,− (iii) direct insertion of metal (Zn or Cd) into the carbon−halide bond of (RO) 2 P(O)CF 2 Br or (RO) 2 P(O)CF 2 I, , (iv) thiophilic reaction of (RO) 2 P(O)CF 2 SMe with tert -butyl lithium, , and (v) desilylation of (RO) 2 P(O)CF 2 SiMe 3 initiated by means of fluoride ion. , …”

“…The generation of difluoromethylenephosphonate carbanion [(EtO) 2 P(O)CF 2 ] - by fluoride ion from silicon species (EtO) 2 P(O)CF 2 SiMe 3 ( 126 ) constitutes a promising extension of the carbanionic approach to α,α-difluoroalkylphosphonates. Several groups have demonstrated that desilylation of phosphonate 126 initiated by CsF, KF, or TBAF is an effective way to transfer the phosphonate carbanion to electrophilic carbonyl centers . Thus, the reaction of 126 with aromatic or heteroaromatic aldehydes in the presence of CsF proceeds easily at room temperature in THF to give the silylated adducts, which are readily hydrolyzed to diethyl α,α-difluoro-β-hydroxyphosphonates in 57−87% yields …”

“…These can be prepared by a variety of methods of which the main ones are (i) deprotonation of (RO) 2 P(O)CF 2 H with a suitable organometallic base, 29,183 (ii) halogen-metal exchange between (RO) 2 P(O)CF 2 Br and alkyl lithium or Grignard reagent, 38,[184][185][186] (iii) direct insertion of metal (Zn or Cd) into the carbon-halide bond of (RO) 2 P-(O)CF 2 Br or (RO) 2 P(O)CF 2 I, 187,188 (iv) thiophilic reaction of (RO) 2 P(O)CF 2 SMe with tert-butyl lithium, 130,189 and (v) desilylation of (RO) 2 P(O)CF 2 SiMe 3 initiated by means of fluoride ion. 102,190 Diethyl lithiodifluoromethylphosphonate (125a) was first prepared more than 20 years ago by addition of LDA to (EtO) 2 P(O)CF 2 H in THF at -78 °C. 29 The phosphonodifluoromethyl anion is thermally unstable and at 0 °C rapidly dissociates to form lithio diethyl phosphite and difluorocarbene.…”