Abstract
C−H Functionalization of amines is a prominent challenge due to the strong complexation of amines to transition metal catalysts, and therefore typically requires derivatization at nitrogen with a directing group. Transient directing groups (TDGs) permit C−H functionalization in a single operation, without needing these additional steps for directing group installation and removal. Here we report a palladium catalyzed γ‐C−H arylation of amines using catalytic amounts of alkyl acetals as transient activators (e.g. commercially available (2,2‐dimethoxyethoxy)benzene). This simple additive enables arylation of amines with a wide range of aryl iodides. Key structural features of the novel TDG are examined, demonstrating an important role for the masked carbonyl and ether functionalities. Detailed kinetic (RPKA) and mechanistic investigations determine the order in all reagents, and identify cyclopalladation as the turnover limiting step. Finally, the discovery of an unprecedented off‐cycle free‐amine directed ϵ‐cyclopalladation of the arylation product is reported.
Highlights
Amines are crucial structural features in biological molecules, pharmaceuticals and agrochemical products.[1]
The secondary coordinating groups were intended to provide a chelate to stabilize intermediates on the catalytic cycle,[14] limit imine isomerization, increase aldehyde electrophilicity and prevent cyclometalation of the directing group. Such functionalized aldehydes are typically unstable to storage, and we considered the use of acetals as more accessible alternatives, being prepared and commercially available. This would be the first example of this type of transient directing group in any CÀH functionalization reaction
A screen of different potential Transient directing groups (TDGs) was conducted using palladium acetate with silver trifluoroacetate in acetic acid and water as solvent (Scheme 2)
Summary
Amines are crucial structural features in biological molecules, pharmaceuticals and agrochemical products.[1]. Numerous simple aliphatic amines are commercially available and react at nitrogen with well-established transformations. Transitionmetal-catalyzed C(sp3)ÀH functionalization offers huge potential for such value adding transformations of feedstock chemicals.[2]. Free amine substrates deactivate metal catalysts by strong coordination, and readily undergo oxidation by b-hydride elimination,[3] typically preventing the desired transformation. Important recent developments have derivatized nitrogen with amide or sulfonamide directing groups to modify the coordinating ability of the amine and to direct CÀH functionalization.[4]. This requires additional steps for directing group installation and removal. Very few C(sp3)ÀH functionalization methods have been successful on unprotected amines. Gaunt developed palladium-catalyzed functionalization of hindered secondary amine substrates,[5] to avoid forma-
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