Studies on the Lithiation, Borylation, and 1,2‐Metalate Rearrangement of O‐Cycloalkyl 2,4,6‐Triisopropylbenzoates

• Published in: Angewandte Chemie International Edition 2021-05, Vol.60 (20), p.11436-11441
• Main Authors: Mykura, Rory C., Songara, Pradip, Luc, Eugenia, Rogers, Jack, Stammers, Ellie, Aggarwal, Varinder K.
• Format: Article
• Language: English
• Subjects: boronic esters; carbocycles; cyclobutane; C−C coupling; Esters; lithiated carbamates; Organic compounds; Substrates
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202101374

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. A series of O‐cycloalkyl benzoates were studied to understand their ability to undergo a lithiation–borylation reaction. Ring size was the key feature: too large and the system could not be lithiated; too small and the system could not undergo 1,2‐migration. The cyclobutyl system occupies a “Goldilock's zone” where the lithiation–borylation reaction works well and shows broad substrate scope.