Iron-Catalyzed Oxyfunctionalization of Aliphatic Amines at Remote Benzylic C–H Sites

Abstract

We report the development of an iron-catalyzed method for the selective oxyfunctionalization of C(sp3)–H bonds in aliphatic amine substrates. This transformation is highly selective for benzylic C–H bonds that are remote (i.e., at least 3-carbons) from the amine functional group. High site selectivity is achieved by in situ protonation of the amine with trifluoroacetic acid, which deactivates more traditionally reactive C–H sites that are α-to nitrogen. The scope and synthetic utility of this method are demonstrated via the synthesis and derivatization of a variety of amine-containing biologically active molecules.

Remote C(sp3)–H Oxygenation of Protonated Aliphatic Amines with Potassium Persulfate

“…1 As such, methods for the selective C– H functionalization of aliphatic amines would be valuable for the synthesis and late-stage modification of many biologically active molecules. 2 A variety of methods have been developed for the functionalization of the weak C(sp 3 )–H bonds α-to nitrogen in these substrates. 2b,3 In contrast, it remains much more challenging to selectively functionalize less activated C(sp 3 )–H bonds that are remote from nitrogen.…”

“…2 A variety of methods have been developed for the functionalization of the weak C(sp 3 )–H bonds α-to nitrogen in these substrates. 2b,3 In contrast, it remains much more challenging to selectively functionalize less activated C(sp 3 )–H bonds that are remote from nitrogen. 4,5 The incorporation of various nitrogen protecting groups including carbamates, 6 amides, 7 imides, 2a,8 and sulfonamides 3f,9 has been used to deactivate the α-C–H bonds and enable C(sp 3 )–H functionalization at alternate sites.…”

“…Similarly, directing groups have been appended to nitrogen to enforce remote C(sp 3 )–H functionalization. 2c,10 However, these strategies both require the additional steps of protecting group installation and removal. Furthermore, they are only applicable to 1° and/or 2° amine substrates.…”

“…2d,11 Protonation of the nitrogen reversibly converts it into a strong electron-withdrawing group, 12 thereby deactivating the α-C–H bonds. 13 We 2d,11b and others 2a,11a have utilized this protonation strategy to achieve several different types of amine C(sp 3 )–H functionalization reactions. However, existing methods have significant limitations.…”

“…For instance, the earliest reported example of this approach exhibited a small substrate scope and required the impractical oxidant methyl(trifluoromethyl)dioxirane (TFDO). 11a,14 More recent approaches have utilized transition metal catalysts, 2a,2d,11b which can be expensive and also difficult to separate from the products. Finally, in most reported examples, the scope is largely restricted to the oxygenation of remote primary, 11b tertiary, 2a or benzylic 2d C(sp 3 )–H bonds.…”