Synthetic methodology utilizing two
aryne intermediates (i.e.,
a formal benzdiyne) enables the rapid generation of structurally complex
molecules with diverse functionality. This report describes the sequential
generation of two ortho-benzyne intermediates for
the synthesis of 2,3-disubstituted aryl phosphonates. Aryl phosphonates
have proven useful in medicinal chemistry and materials science, and
the reported methodology provides a two-step route to functionally
dense variants by way of 3-phosphonyl benzyne intermediates. The process
begins with regioselective trapping of a 3-trifloxybenzyne intermediate
by an O-silyl phosphite in an Abramov-like reaction
to bond the strained Csp carbons with phosphorus and silicon. Standard
aryne-generating conditions follow to convert the resulting 2-silylphenyl
triflate into a 3-phosphonyl benzyne, which readily reacts with numerous
aryne trapping reactants to form a variety of 2,3-difunctionalized
aryl phosphonate products. DFT computational studies shed light on
important mechanistic details and revealed that 3-phosphonyl benzynes
are highly polarizable. Specifically, the distortion in the internal
bond angles at each of the Csp atoms was strongly influenced by both
the electronegativity of the phosphonate ester groups as well as the
dielectric of the computational solvation model. These effects were
verified experimentally as the regioselectivity of benzyl azide trapping
increased with more electronegative esters and/or increasingly polar
solvents. Conversely, replacing the conventional solvent, acetonitrile,
with nonpolar alternatives provided attenuated or even inverted selectivities.
Overall, these studies showcase new reactivity of benzyne intermediates
and extend the aryne relay methodology to include organophosphonates.
Furthermore, this work demonstrates that the regioselectivity of aryne
trapping reactions could be tuned by simply changing the solvent.
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