Abstract
A broad range of acyclic primary and secondary 2,4,6‐triisopropylbenzoate (TIB) esters have been used in lithiation‐borylation reactions, but cyclic TIB esters have not. We have studied the use of cyclic TIB esters in lithiation‐borylation reactions and looked at the effect of ring size (3‐ → 6‐membered rings) on the three key steps of the lithiation‐borylation protocol: deprotonation, borylation and 1,2‐metalate rearrangement. Although all rings sizes could be deprotonated, the cyclohexyl case was impractically slow, and the cyclopentyl example underwent α‐elimination faster than deprotonation at −78 °C and so could not be used. Both cyclobutyl and cyclopropyl cases underwent rapid borylation, but only the cyclobutyl substrate underwent 1,2‐metalate rearrangement. Thus, the cyclobutyl TIB ester occupies a “Goldilocks zone,” being small enough for deprotonation and large enough to enable 1,2‐migration. The generality of the reaction was explored with a broad range of boronic esters.
Highlights
Boronic ester homologation represents a powerful method in asymmetric synthesis.[1]
Angewandte Chemie International Edition published by Wiley-VCH GmbH
Angewandte Chemie International Edition published by Wiley-VCH GmbH Angew
Summary
Boronic ester homologation represents a powerful method in asymmetric synthesis.[1]. Originally done through substrate control using a chiral diol on the boronic ester backbone[2] it was later shown that reagent control offered greater flexibility and when used in an iterative manner was more effective and more efficient. Angewandte Chemie International Edition published by Wiley-VCH GmbH We report that of the 3–6-membered rings investigated, only 4-membered rings can be successfully employed They occupy a “Goldilocks zone”, where small rings are required for deprotonation and large rings are required for 1,2migration (Scheme 1 b), this study revealed a further important factor in determining success, the stability of the intermediate lithiated TIB ester towards a-elimination. This work is of fundamental interest, but it is of practical utility since the success with 4-membered rings leads to cyclobutane products which are useful and highly soughtafter, in medicinal chemistry as they provide a defined spatial arrangement of groups due to their rigid scaffolds.[17]
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