Controlling selectivity in N-heterocycle directed borylation of indoles
1EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, EH9 3FJ, UK. michael.ingleson@ed.ac.uk.
Controlling indole borylation is achieved by varying directing group heterocycle size. Five-membered rings favor C7 borylation, while six-membered rings favor C2 borylation, offering regioselective synthesis.
Area of Science:
- Organic Chemistry
- Synthetic Methodology
- Heterocyclic Chemistry
Background:
- Electrophilic borylation of indoles is a key transformation in organic synthesis.
- Regioselectivity in indole functionalization, particularly at C2 and C7 positions, remains a challenge.
- N1-installed directing groups offer a strategy to control site-selectivity in C-H functionalization.
Purpose of the Study:
- To investigate the influence of directing group heterocycle size on regioselectivity in electrophilic indole borylation.
- To elucidate the mechanistic pathways governing C2 versus C7 borylation.
- To establish a predictive model for controlling borylation outcomes based on directing group structure.
Main Methods:
- Synthesis of N1-heterocycle substituted indoles.
- Electrophilic borylation using boron trihalides (BX3, X = Cl, Br).
- Computational studies (Density Functional Theory) to analyze reaction mechanisms and energy barriers.
Main Results:
- Six-membered heterocycle directing groups (pyridine, pyrimidine) predominantly yield C2 borylation.
- Five-membered heterocycle directing groups (thiazole, benzoxazole) achieve C7 borylation.
- Computational analysis reveals borylation proceeds via borenium cations, with arenium cation formation as the highest energy barrier.
- Thermodynamic favorability favors C7 borylation, but kinetic control can lead to C2 products with specific directing groups (e.g., pyrimidine).
Conclusions:
- The size of the N-heterocycle directing group is a critical determinant of regioselectivity in indole C-H borylation.
- Five-membered heterocycles direct borylation to the C7 position, while six-membered heterocycles direct to the C2 position.
- This study provides a valuable tool for controlling C2 vs. C7 selectivity in indole borylation reactions.
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