Direct Access to Carbenoids from Alkyl and α-Acyloxy Halide`s for Boron Homologations: Method Development and Mechanistic Insights
Abstract
Despite the widespread utility of carbenoids in boron homologations, practical challenges in accessing unstabilized gem-halometal carbenoids limit their broader synthetic application.A major bottleneck is the historical reliance on gem-dihalide precursors, which restricts the accessible substrate scope.Bypassing gem-dihalides via direct deprotonation of unactivated alkyl halides offers an ideal but historically elusive alternative due to competing base-mediated elimination and substitution reactions.Here we introduce a straightforward deprotonation/boron homologation protocol for both alkyl and α-acyloxy halides using hindered amide bases (over 50 examples).The method was effective for both primary and secondary alkyl halide substrates, tolerating a wide range of functional groups including base-sensitive moieties.The α-acyloxy boronic esters, generated via an efficient aldehyde addition and homologation sequence, readily undergo diverse downstream substitutions with Grignard and organolithium nucleophiles.Finally, combining DFT-based natural bond orbital analysis with statistical modeling of the resulting descriptors, we establish that the energy of the σ(C-H) natural bond orbital predicts the site of deprotonation across every substrate examined, and we trace this selectivity to the interplay of increased scharacter and reduced steric (Pauli) repulsion at the C-H bond geminal to the halogen.
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BibTeX
@misc{chen2026direct,
title = {{Direct Access to Carbenoids from Alkyl and α-Acyloxy Halide`s for Boron Homologations: Method Development and Mechanistic Insights}},
author = {Cheng-Chun Chen and Chung-En Su and Jin Qian and Griffin W. Batson and Andrew Zahrt and Andy A. Thomas},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15002023/v2},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15002023/v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Direct Access to Carbenoids from Alkyl and α-Acyloxy Halide`s for Boron Homologations: Method Development and Mechanistic Insights
AU - Cheng-Chun Chen
AU - Chung-En Su
AU - Jin Qian
AU - Griffin W. Batson
AU - Andrew Zahrt
AU - Andy A. Thomas
PY - 2026
DA - 2026/10/21
PB - ChemRxiv
DO - 10.26434/chemrxiv.15002023/v2
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15002023/v2
AB - Despite the widespread utility of carbenoids in boron homologations, practical challenges in accessing unstabilized gem-halometal carbenoids limit their broader synthetic application.A major bottleneck is the historical reliance on gem-dihalide precursors, which restricts the accessible substrate scope.Bypassing gem-dihalides via direct deprotonation of unactivated alkyl halides offers an ideal but historically elusive alternative due to competing base-mediated elimination and substitution reactions.Here we introduce a straightforward deprotonation/boron homologation protocol for both alkyl and α-acyloxy halides using hindered amide bases (over 50 examples).The method was effective for both primary and secondary alkyl halide substrates, tolerating a wide range of functional groups including base-sensitive moieties.The α-acyloxy boronic esters, generated via an efficient aldehyde addition and homologation sequence, readily undergo diverse downstream substitutions with Grignard and organolithium nucleophiles.Finally, combining DFT-based natural bond orbital analysis with statistical modeling of the resulting descriptors, we establish that the energy of the σ(C-H) natural bond orbital predicts the site of deprotonation across every substrate examined, and we trace this selectivity to the interplay of increased scharacter and reduced steric (Pauli) repulsion at the C-H bond geminal to the halogen.
ER -