ZnMe2‑Mediated, Direct Alkylation
of Electron-Deficient N‑Heteroarenes with 1,1-Diborylalkanes:
Scope and Mechanism
Posted on 2020-07-13 - 16:42
The regioselective,
direct alkylation of electron-deficient N-heteroarenes
is, in principle, a powerful and efficient way of accessing alkylated
N-heteroarenes that are important core structures of many biologically
active compounds and pharmaceutical agents. Herein, we report a ZnMe2-promoted, direct C2- or C4-selective primary and secondary
alkylation of pyridines and quinolines using 1,1-diborylalkanes as
alkylation sources. While substituted pyridines and quinolines exclusively
afford C2-alkylated products, simple pyridine delivers C4-alkylated
pyridine with excellent regioselectivity. The reaction scope is remarkably
broad, and a range of C2- or C4-alkylated electron-deficient N-heteroarenes
are obtained in good yields. Experimental and computational mechanistic
studies imply that ZnMe2 serves not only as an activator
of 1,1-diborylalkanes to generate (α-borylalkyl)methylalkoxy
zincate, which acts as a Lewis acid to bind to the nitrogen atom of
the heterocycles and controls the regioselectivity, but also as an
oxidant for rearomatizing the dihydro-N-heteroarene intermediates
to release the product.
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Jo, Woohyun; Baek, Seung-yeol; Hwang, Chiwon; Heo, Joon; Baik, Mu-Hyun; Cho, Seung Hwan (2020). ZnMe2‑Mediated, Direct Alkylation
of Electron-Deficient N‑Heteroarenes with 1,1-Diborylalkanes:
Scope and Mechanism. ACS Publications. Collection. https://doi.org/10.1021/jacs.0c06827
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AUTHORS (6)
WJ
Woohyun Jo
SB
Seung-yeol Baek
CH
Chiwon Hwang
JH
Joon Heo
MB
Mu-Hyun Baik
SC
Seung Hwan Cho