Nickel‐Catalyzed Dehydrogenative Cross‐Coupling: Direct Transformation of Aldehydes into Esters and Amides

Abstract

By exploring a new mode of nickel-catalyzed crosscoupling, a method to directly transform both aromatic and aliphatic aldehydes into either esters or amides has been developed. The success of this oxidative coupling depends on the appropriate choice of catalyst and organic oxidant, including the use of either a,a,a-trifluoroacetophenone or excess aldehyde. Mechanistic data that supports a catalytic cycle involving oxidative addition into the aldehyde C À H bond is also presented.Developing nickel catalysts for the selective oxidation of CÀH bonds is an emerging strategy that overcomes the need for precious metals and enables new transformations.[1] Our laboratory has previously focused on the oxidation of aldehydes under Rh, Ru, and Co catalysis.[2] Inspired by the promise of base metals, we considered that Ni-catalyzed cross-couplings of aldehydes could be classified into three general types: redox-neutral, reductive, and oxidative ( Figure 1). For example, Ogoshis cross-coupling between two aldehydes is a redox-neutral method that generates ester bonds.[3] In comparison, reductive coupling reactions generate carbon-carbon bonds in the presence of an external reductant (e.g., Et 2 Zn).[4] A complementary Ni-catalyzed cross-coupling in the presence of an external oxidant, however, represents an undeveloped mode of reactivity that warrants study.[5] Herein, we showcase a unified approach for transforming aldehyde CÀH bonds into both CÀO and CÀN bonds using Ni-catalyzed dehydrogenative cross-couplings. [6] The transformation of aldehydes into esters and amides in one step is an attractive goal that has been pursued using precious-metal catalysts, [7] base-metal catalysts with strong oxidants, [8] and N-heterocyclic carbene (NHC) catalysis.[9]Whereas these methods are promising, a method that couples aromatic and aliphatic aldehydes with alcohols, anilines, and amines has yet to be achieved. Towards addressing this challenge, we chose to examine carbonyl compounds as mild oxidants by hydrogen transfer.[10]Our initial studies focused on cross-coupling benzaldehyde (1 a) and 2-propanol (2 a) in the presence of various hydrogen acceptors. We discovered that NHC ligands in 1,4-dioxane produced the most promising results (Scheme 1). [11] In the absence of any Ni salts, we observed no reactivity. However, in the presence of [Ni(cod) 2 ] with benzaldehyde as both the substrate and hydrogen acceptor, we observed the formation of the desired ester 4 a and Tishchenko homodimer 5 a in a 5.9:1 ratio. To suppress the Tishchenko pathway, we sought an acceptor that undergoes reduction faster than benzaldehyde (1 a). Whereas the addition of acetone (3 a) and cyclobutanone (3 b) decreased the rate of the desired crosscoupling, both benzophenone (3 c) and a,a,a-trifluoroacetophenone (3 d) showed a remarkable enhancement in rate and selectivity for 4 a. As a result, we were able to use equimolar quantities of the coupling partners and 1

Mechanistic Insights into the Nickel-Catalyzed Cross-Coupling Reaction of Benzaldehyde with Benzyl Alcohol via C–H Activation: A Theoretical Investigation

“…According to the experimental study, 23 the dehydrogenative cross-coupling reaction of benzaldehyde and benzyl alcohol to generate benzyl benzoate in the presence of IPr ligand and Ni(cod) 2 catalyst is chosen as the model reaction for the mechanistic investigation (Scheme 1D). The a,a,a-trifluoroacetophenone is defined as both oxidant and hydrogen acceptor due to its remarkable enhancement in reaction rate and selectivity.…”

“…21,22 Very recently, an unprecedented breakthrough of nickel-catalyzed dehydrogenative cross-coupling reaction of direct transformation of aldehydes into esters by C−H bond activation with a,a,atrifluoroacetophenone as the oxidant (Scheme 1D) is realized by Dong's group. 23 Gratifyingly, this transformation is accomplished in one step, and the a,a,a-trifluoroacetophenone is used as both oxidant and hydrogen acceptor. Notable features of preparing esters in this technique are the mild reaction conditions and high functional group tolerance and convenience, which demonstrate the great potential of this reaction.…”

Nonclassical Routes for Amide Bond Formation

“…A procedure for dehydrogenative cross-coupling of aldehydes and amines by means of Ni-catalysis was devised in 2015 by Dong and Whittaker. 166 By combining [Ni(cod) 2 ] (5.0 mol %) and an organic oxidant (α,α,αtrifluoroacetophenone, 99), direct transformation of aldehydes into amides (Scheme 65) and esters was possible. A preliminary mechanistic pathway for this transformation is proposed on Scheme 65.…”

Carbonyl Compounds′ Journey to Amide Bond Formation

“…Whittaker and Dong developed a new and efficient nickel‐catalyzed strategy for the synthesis of esters and amides through a dehydrogenative cross‐coupling reaction of aldehydes with alcohols and amines, respectively (Scheme a) . The reaction was performed in the presence of [Ni(cod) 2 ] as a catalyst, IPr as a ligand, and 2,2,2‐trifluoroacetophenone as a hydrogen acceptor.…”