Abstract
A selective and practical bromine–metal exchange on bromoheterocyclics bearing substituents with an acidic proton under non-cryogenic conditions was developed by a simple modification of an existing protocol. Our protocol of using a combination of i-PrMgCl and n-BuLi has not only solved the problem of intermolecular quenching that often occurred when using alkyl lithium alone as the reagent for halogen–lithium exchange, but also offered a highly selective method for performing bromo–metal exchange on dibrominated arene compounds through chelation effect.
Highlights
Substituted heterocyclics are an important class of heterocyclic building blocks that are routinely used in the synthesis of medicinal and agrochemical products [1]
The use of more reactive alkyl lithium reagents only made limited success because of nucleophilic attack on the pyridine ring by n-BuLi as well as the formation of corresponding protonated products due to intermolecular quenching [22–25] (Br–Li exchange is usually fast enough to compete with the removal of an acidic proton by n-BuLi)
This paper, we wish to halogen–metal report that halogen–metal exchange on heterocyclic bearing an can acidic can be performed efficiently through ause combined use ofand i-PrMgCl acidic proton beproton performed efficiently through a combined of i-PrMgCl n-BuLi and under n-BuLi under essentiallyconditions noncryogenic and that high regioselectivity canon be halogen–metal achieved on essentially noncryogenic and conditions that high regioselectivity can be achieved halogen–metal exchange substrate twovia bromo groupseffect
Summary
Substituted heterocyclics are an important class of heterocyclic building blocks that are routinely used in the synthesis of medicinal and agrochemical products [1]. The additional functional groups can tolerate the process of halogen–metal exchange, which considerably enhanced its synthetic utility For those substrates that bearing an acidic proton (Compound 1, Scheme 1), i-PrMgCl is generally not reactive enough to affect Br–Mg exchange. Under these circumstances, the use of more reactive alkyl lithium reagents only made limited success because of nucleophilic attack on the pyridine ring by n-BuLi as well as the formation of corresponding protonated products due to intermolecular quenching [22–25] (Br–Li exchange is usually fast enough to compete with the removal of an acidic proton by n-BuLi).
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