Palladium-Catalyzed C(sp3 )-H Arylation of Primary Amines Using a Catalytic Alkyl Acetal to Form a Transient Directing Group

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.

Keywords: C−H functionalization; amines; homogeneous catalysis; palladium; reaction kinetics.

Scheme 1

Palladium catalyzed C(sp³)−H arylation of unprotected amines.

Scheme 2

Screen of alkyl acetals as transient directing groups for amine arylation. Yields determined by ¹H NMR using 1,3,5‐trimethoxybenzene as an internal standard.

Scheme 3

Reaction scope of aryl iodides using acetals 8 and 12 as transient directing groups.

Scheme 4

Reaction scope of aliphatic amines. [a] Yields in blue refer to acetal 8, and red to acetal 12. [b] Using 1.5 equiv AgTFA, 3 h.

Scheme 5

Analysis of structural features of the optimal directing group. Yields determined by ¹H NMR using 1,3,5‐trimethoxybenzene as an internal standard.

Figure 1

Zero order rate dependence of acetal 8. Yields determined by ¹H NMR using 1,3,5‐trimethoxybenzene as an internal standard on discrete reactions.

Scheme 6

Substrate deuteration and KIE.

Figure 2

Same excess and product inhibition experiments. Showing a) concentrations of additional product formed; and b) normalized values for direct comparison (+1 h for and expected product concentration for same excess experiments).15

Scheme 7

ϵ‐Cyclopalladation of product amine 2 f.

Scheme 8

Proposed dual catalytic cycle.