A Practical Synthesis of Cycloalkylphosphonates from Trichloromethylphosphonates

New route to 1-formylalkylphosphonates using diethyl trichloromethylphosphonate as a precursor

“…which is illustrated in Scheme 4, for the hydrolysis of the phosphorylated mixed acetal 8 into the 1formylalkylphosphonate 7, would involve initial nucleophilic attack of the silyl group to generate the intermediate r-silylated x-substituted formyl phosphonate 10. Given the X-position of the silyl group to the formyl group in 10, [1,3]-rearrangement of 10 to deliver the transient silylated enol ether 9 becomes feasible, this one being more sensitive to acid hydrolysis than the corresponding ethoxy enol ether 6.…”

Diethyl Trichloromethylphosphonate

“…30 Notably, the double alkylation with γ/ωdibromoalkanes, in a two-step sequence, gives access to mediumsize cycloalkylphosphonates (four-to seven-membered rings, 18-70% yields) from which the silyl group can be removed by treatment with TBAF (eq 12). 32 α-Alkyl-α-silyl-chloromethylphosphonates obtained from the silylated carbanion can be involved in subsequent reactions with ethyl formate to afford 1-formylalkylphosphonates in good yields (eq 13). 33 Finally, the stabilized carbanion can be quenched with deuterium oxide.…”

Controlled Reactivity of Phosphonates by Temporary Silicon Connection

“…Since the C-Si bond is not activated by the presence of an electron-withdrawing group, the trimethylsilyl group of 60 was removed by the use of moist TBAF in THF solution (Scheme 23). 72 The same principle has been applied to the synthesis of phosphonates bearing two symmetrical or unsymmetrical, saturated or unsaturated, alkyl groups on the a-carbon atom. 73…”

“…Other applications of 1-(trimethylsilyl)methylphosphonates include the reaction with bielectrophilic reagents for the preparation of three-, four-, five-and six-membered cycloalkylphosphonates 61. 72 The diethyl trichloromethylphosphonate 23 is particularly well suited to this approach and the exchange of the three halogen atoms with n-BuLi followed by sequential addition of TMSCl and wdibromoalkanes 59 results in the formation of a series of silylated cycloalkylphosphonates 60. Since the C-Si bond is not activated by the presence of an electron-withdrawing group, the trimethylsilyl group of 60 was removed by the use of moist TBAF in THF solution (Scheme 23).…”