Abstract:The preparation of monohalogenated tetraalkyl methylenediphosphonates 5 has been studied. Upon electrophilic halogenation lithiated chloro-, bromo-and iodomethylenediphosphonates 4a-c are selectively prepared from unprotected lithiated methylenediphosphonates 2 whereas the protected ones 3 are unreactive. Condensation of lithiated dihalogenomethanes with diethyl chlorophosphate 7 leads to the formation of lithiated chloro-, and bromomethylenediphosphonates 4a,b. A possible reaction pathway via intermediate car… Show more
“…Then, subsequent reactions with chlorophosphates would lead to the Z- isomers of 1 . Similar intermediates have been reported for the deprotonated form of methylenediphosphonates, β-ketophosphonates, or phosphine oxides. − 1 …”
The new bifunctional ligands Ph(2)PCH[double bond]CPh[OP(O)(OR)(2)] (1) (1a, R = Et; 1b, R = Ph) represent the first examples of P,O derivatives resulting from the association of a phosphine moiety and an enolphosphate group. The Z stereochemistry about the double bond provides a favorable situation for these ligands to act as P,O-chelates. Neutral and cationic Pd(II) complexes have been synthesized and characterized, in which 1a or 1b acts either as a P-monodentate ligand or a P,O-chelate, via coordination of the oxygen atom of the P[double bond]O group. In the latter case, it has been observed that phosphines 1a and 1b can display a hemilabile behavior, owing to successive dissociation and recoordination of the O atom. Competition experiments revealed that phosphine 1a presents a higher chelating ability than 1b, a feature ascribed to the more electrodonating properties of the ethoxy groups in 1a compared to the phenoxy groups in 1b. P,O-Chelation affords seven-membered metallocycles, which is unusual for P,O-chelates. Complexes trans-[PdCl(2)[Ph(2)PCH[double bond]C(Ph)OP(O)(OPh)(2)](2)] (2b), [PdCl[Ph(2)PCHdouble bond]C(Ph)OP(O)(OEt)(2)](mu-Cl)](2) (3a), [complex--see text] (8a'), and [complex--see text] (10a) have been structurally characterized. Interestingly, the seven-membered rings in 8a' and 10a adopt a sofa conformation with the double bond lying almost perpendicular to the plane containing the Pd, the two P, and the two O atoms.
“…Then, subsequent reactions with chlorophosphates would lead to the Z- isomers of 1 . Similar intermediates have been reported for the deprotonated form of methylenediphosphonates, β-ketophosphonates, or phosphine oxides. − 1 …”
The new bifunctional ligands Ph(2)PCH[double bond]CPh[OP(O)(OR)(2)] (1) (1a, R = Et; 1b, R = Ph) represent the first examples of P,O derivatives resulting from the association of a phosphine moiety and an enolphosphate group. The Z stereochemistry about the double bond provides a favorable situation for these ligands to act as P,O-chelates. Neutral and cationic Pd(II) complexes have been synthesized and characterized, in which 1a or 1b acts either as a P-monodentate ligand or a P,O-chelate, via coordination of the oxygen atom of the P[double bond]O group. In the latter case, it has been observed that phosphines 1a and 1b can display a hemilabile behavior, owing to successive dissociation and recoordination of the O atom. Competition experiments revealed that phosphine 1a presents a higher chelating ability than 1b, a feature ascribed to the more electrodonating properties of the ethoxy groups in 1a compared to the phenoxy groups in 1b. P,O-Chelation affords seven-membered metallocycles, which is unusual for P,O-chelates. Complexes trans-[PdCl(2)[Ph(2)PCH[double bond]C(Ph)OP(O)(OPh)(2)](2)] (2b), [PdCl[Ph(2)PCHdouble bond]C(Ph)OP(O)(OEt)(2)](mu-Cl)](2) (3a), [complex--see text] (8a'), and [complex--see text] (10a) have been structurally characterized. Interestingly, the seven-membered rings in 8a' and 10a adopt a sofa conformation with the double bond lying almost perpendicular to the plane containing the Pd, the two P, and the two O atoms.
“…The oxidation of the geminal dianion 1 was undertaken by using hexachloroethane in diethyl ether (Scheme ). The reaction was monitored by 31 P NMR spectroscopy and showed the complete formation of a sole compound ( 2 ), characterized by a singlet at δ =45.5 ppm (vs. δ =20.6 ppm for 1 ), within a few minutes 10. Compound 2 was isolated in quantitative yield after removal of LiCl by centrifugation and fully characterized by NMR spectroscopy ( 1 H and 13 C).…”
“…Treatment of 48 with NaOBr provided triethyl dibromophosphonoacetate (49) in good yield, and the product could be reduced to the monobrominated analog 50 in the presence of 0.96 equiv. Suitable bases include n-BuLi, 90 LDA, 91 LiHMDS, 92 and NaH. 77 Several researchers have utilized this methodology to obtain a-bromo and a,a-dibromophosphonoacetates on similar scaffolds with moderate to excellent yields.…”
Section: A-bromophosphonocarboxylates and Abromobisphosphonatesmentioning
confidence: 99%
“…Quenching the anion with an electrophilic bromine source subsequently provides the expected a-brominated phosphonocarboxylate and bisphosphonate analog. Suitable bases include n-BuLi, 90 LDA, 91 LiHMDS, 92 and NaH. 68,81,[93][94][95] The McKenna group was able to develop a-halo derivatives of a-hydroxy compounds 53a and 53b (Scheme 15), which are known anti-osteoporotic agents that act through blockage of prenylation.…”
Section: A-bromophosphonates On a Carbohydrate Scaffoldmentioning
Substrate phosphorylation is a key modulator of signal transduction. Abnormal phosphorylation in vivo is implicated in many diseases including cancer, diabetes, and Alzheimer's disease. Inhibitors of phosphaterecognizing proteins have potential as medicinal agents as well as tools to study phosphorylation pathways. A well-known and common inhibition strategy is to synthetically replace the labile phosphate moiety with a non-hydrolyzable phosphonate. Fully saturated, a-fluoro and a,a-difluorophosphonates are often effective phosphate bioisosteres and have been well studied. More recently a-brominated phosphonates have begun to emerge as inhibitors of phosphate recognizing enzymes, some of which operate by irreversible mechanisms. Herein we discuss the synthetic approaches to aliphatic and benzylic a-bromophosphonates and their biological activities.Scheme 5 The synthesis of an aliphatic a-bromophosphonate derivative. 52 Scheme 6 An improved synthetic strategy to alkyl abromophosphonates. 53This journal is
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