| Abstract
| - The synthesis of suitably protected p-aminophenyl H-phosphinic acids and esters from the correspondingpara-substituted aryl halides has been accomplished via the Pd-catalyzed cross-coupling reaction ofanilinium hypophosphite, either in the absence or presence of a tetraalkyl orthosilicate, to provide thefree H-phosphinic acid or the corresponding ester, respectively. Subsequent conjugate addition of eithera PIII species or phosphorus anion, generated in situ from either the free H-phosphinic acid or ester, toa 2-methylene glutaric acid ester provided the aryl phosphinic acid analogue of p-aminobenzoyl glutamicacid. Alkylation of these suitably protected p-aminophenyl phosphinic acid esters with a 6-(bromomethyl)pteridine or the corresponding (bromomethyl)pyridopyrmidine, followed by hydrolytic removal ofprotecting groups, provided the target aryl phosphinic acid analogues of folic acid and related antifolates.Alternatively, for the synthesis of the folate or 5-deazafolate analogues on a slightly larger scale, reductiveamination with either N2-acetyl or N2-pivaloyl-6-formylpterin or the corresponding formylpyridopyrmidineand the same suitably protected p-aminophenyl phosphinic acid esters, followed by removal of protectinggroups, is preferred. In the course of this research, it was observed that the nucleophilicity of both theaniline nitrogen and various PIII species derived from p-aminophenyl phosphinic acid derivatives issignificantly reduced compared to that of the unsubstituted counterpart.
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