Free alcohol-directed remote C(sp3)-H heteroarylation

We have disclosed a practical and elusive metal-free alcohol-directed heteroarylation of remote unactivated C(sp3)-H bonds.

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Unactivated C(sp3)-H bonds are abundant in nature. How to directly transform them into valuable chemicals is a goal of chemists. Over the past few decades, controllable radical reactions emerge as a powerful tool for the site-specific C(sp3)-H activation complementary to transition-metal catalysis. Heteroaryls are ubiquitous in drugs and bioactive compounds. The Minisci-type functionalization offers an efficient radical approach to incorporate heteroaryls into complex molecules. In this scenario, we are prompted to implement the elusive free alcohol-mediated C(sp3)-H heteroarylation. 

Recently, our group is focusing on the alkoxy radical-mediated reactions. Generation of alkoxy radicals directly from free alcohols remains a formidable challenge due to the high BDE (~105 kcal/mol) of alcoholic O-H bonds. Alternatively, many indirect routes by conversion of alcohols to other precursors are sought to generate alkoxy radicals. 

At the beginning of this project, we found that many side reactions such as beta-C-C bond scission, oxidation of alcohol, and intramolecular cyclization took place along with the desired C-H heteroarylation. How to suppress these side reactions is the key to improve the reaction efficiency. After an extensive survey of reaction conditions, the use of PIFA (phenyliodine bis(trifluoroacetate)) significantly promoted the generation of alkoxy radical from free alcohol under irradiation of blue LEDs,  affording the Minisci-type product. The scope of heteroaryls was fairly broad including quinoline, pyridine, isoquinoline, phenanthridine, acridine, pyrazine, pyrimidine, quinoxaline, and 4-hydroxyquinazoline. All primary, secondary, and tertiary alcohols proved to be suitable substrates, providing the desired products with good to excellent yields. 

The Minisci reactions, in general, require the addition of stoichiometric amounts of protic acids to activate heteroaryls via protonation. In contrast, in our protocol protic acid is generated in situ, avoiding the addition of extra acids and thus rendering a neutral conditions to guarantee the broad functional group tolerance.

Overall, this mild and practical strategy provides a powerful tool for the remote C(sp3)-H heteroarylation of alcohols. A variety of synthetically valuable alkylated heteroaryls are produced, which may find particular use in medicinal chemistry in near future. Many new transformations based on this strategy are under exploration in our laboratories.

You can read the full story in our Nature Communications article here.

Chen Zhu

Professor , Soochow university