TY - JOUR

T1 - Flipping the Metalation of 4-Dimethylaminopyridine: Steric Repulsion versus London Dispersion Attraction

AU - Верхов, Валерий Александрович

AU - Губанова, Александра Николаевна

AU - Тонкоглазова, Дарья Игоревна

AU - Тупикина, Елена Юрьевна

AU - Антонов, Александр Сергеевич

PY - 2024/11/12

Y1 - 2024/11/12

N2 - Non-covalent interactions, including the coordination of an organolithium reagent by a directing group and the steric hindrance from substituents, play a crucial role in determining the selectivity of metalation reactions. Here, we demonstrate the effective utilization of steric interactions for flipping the lithiation of 4-dimethylaminopyridine (DMAP). Introduction of a Me3Si substituent to the position 1 of DMAP or simple complexation with t-BuLi allows selective C3-lithiation, due to the steric hindrance of a C2−H bond by the bulky moiety at the pyridine nitrogen. This simple approach creates a convenient way to achieve the selective C3-functionalization of DMAP. In contrast, the utilization of an even bulkier i-Pr3Si substituent leads to exclusive C2-functionalization due to the dispersion interactions with organometallic bases. For the first time, it is demonstrated that the i-Pr3Si moiety can serve as a directing group, providing a new type of directed ortho-metalation effect.

AB - Non-covalent interactions, including the coordination of an organolithium reagent by a directing group and the steric hindrance from substituents, play a crucial role in determining the selectivity of metalation reactions. Here, we demonstrate the effective utilization of steric interactions for flipping the lithiation of 4-dimethylaminopyridine (DMAP). Introduction of a Me3Si substituent to the position 1 of DMAP or simple complexation with t-BuLi allows selective C3-lithiation, due to the steric hindrance of a C2−H bond by the bulky moiety at the pyridine nitrogen. This simple approach creates a convenient way to achieve the selective C3-functionalization of DMAP. In contrast, the utilization of an even bulkier i-Pr3Si substituent leads to exclusive C2-functionalization due to the dispersion interactions with organometallic bases. For the first time, it is demonstrated that the i-Pr3Si moiety can serve as a directing group, providing a new type of directed ortho-metalation effect.

KW - Dispersion interaction

KW - Metalation

KW - Organolithium

KW - Pyridine

KW - Steric hindrance

UR - https://www.mendeley.com/catalogue/16372acc-9386-36c0-950d-7ec00c2bc269/

U2 - 10.1002/chem.202403422

DO - 10.1002/chem.202403422

M3 - Article

JO - Chemistry - A European Journal

JF - Chemistry - A European Journal

SN - 0947-6539

M1 - e202403422

ER -