Quantitative analysis of steric effects on the regioselectivity of the Larock heteroannulation reaction

Alkylphenylacetylene derivatives were synthesized and used as reactants in the Larock heteroannulation reaction to investigate the steric influence on regioselectivity. Large alkyl groups preferentially yielded 2-alkyl-3-phenylindole products, while smaller alkyl groups provided 3-alkyl-2-phenylindo...

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Bibliographic Details
Published in:Organic & biomolecular chemistry 2023-02, Vol.21 (7), p.151-1513
Main Authors: Thangsan, Poomsith, Rukkijakan, Thanya, Thanaussavadate, Bongkotrat, Yiamsawat, Kanyapat, Sirijaraensre, Jakkapan, Gable, Kevin P, Chuawong, Pitak
Format: Article
Language:English
Subjects:
Chemical reactions
Chemical synthesis
Correlation
Logarithms
Organic chemistry
Organic compounds
Parameters
Prediction models
Quantitative analysis
Regioselectivity
Steric effects
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Summary:Alkylphenylacetylene derivatives were synthesized and used as reactants in the Larock heteroannulation reaction to investigate the steric influence on regioselectivity. Large alkyl groups preferentially yielded 2-alkyl-3-phenylindole products, while smaller alkyl groups provided 3-alkyl-2-phenylindole as major products. The logarithm of regioisomeric product ratios exhibited good correlations with various steric parameters. Notably, the Charton values provided the best correlation when excluding the cyclopropyl group. In addition, the Boltzmann-weighted Sterimol parameter (wSterimol) was utilized to generate a good predictive model, indicating the B 1 wSterimol as the significant regiochemical determining parameter with no obvious deviation for the cyclopropyl group. Relative atomic distances within the DFT-optimized transition state structures revealed good correlations with the logarithm of regioisomeric ratios. Furthermore, the cyclopropyl adsorption complex indicated electronic contribution, explaining the peculiar behavior of this substituent in the experimental observation. A comprehensive predictive model for regioselectivity in the Larock heteroannulation reaction was constructed. The model provides support for a general blueprint for understanding the steric influence on the reaction selectivity.
ISSN:1477-0520
1477-0539
DOI:10.1039/d2ob02089k