Conversion of amides to esters by the nickel-catalysed activation of amide C–N bonds

Abstract

Amides are common functional groups that have been well studied for more than a century.1 They serve as the key building blocks of proteins and are present in an broad range of other natural and synthetic compounds. Amides are known to be poor electrophiles, which is typically attributed to resonance stability of the amide bond.1,2 Whereas Nature can easily cleave amides through the action of enzymes, such as proteases,3 the ability to selectively break the C–N bond of an amide using synthetic chemistry is quite difficult. In this manuscript, we demonstrate that amide C–N bonds can be activated and cleaved using nickel catalysts. We have used this methodology to convert amides to esters, which is a challenging and underdeveloped transformation. The reaction methodology proceeds under exceptionally mild reaction conditions, and avoids the use of a large excess of an alcohol nucleophile. Density functional theory (DFT) calculations provide insight into the thermodynamics and catalytic cycle of this unusual transformation. Our results provide a new strategy to harness amide functional groups as synthons and are expected fuel the further use of amides for the construction of carbon–heteroatom or carbon–carbon bonds using non-precious metal catalysis.

Nickel‐Catalyzed Activation of Acyl C−O Bonds of Methyl Esters

“…This finding is consistent with the overall reaction (i.e., ester 5 + amine 6 → amide 7 + methanol) being energetically uphill, which would be expected based on our recent studies. [10] However, the addition of Al(O t Bu) 3 was found to have a critical beneficial effect and led to the formation of amide 7 in 89% yield. [12] As described in the latter part of the manuscript, we propose that Al(O t Bu) 3 benefits the reaction both kinetically and thermodynamically.…”

Direct Transformations of Amides: Tactics and Recent Progress

“…酰胺催化转化的第二类方法始于 2015 年, Garg 和 Houk 小组合作, 率先实现了温和条件下酰胺向酯的镍 催化转化(图式 11a) [52] . 尽管该反应只局限于 N-芳基苯 甲酰胺类化合物, 但仍然是酰胺催化转化的重要突破, 因而与 Ni(价格较低廉且地球丰产金属)催化的其它转化 一起, 被美国化学会《美国化学与工程新闻》(C & EN News)评为 2015 年化学的突破之一 [53,54] .…”

Machine Learning for Organic Synthesis: Are Robots Replacing Chemists?

“…The development of quantum‐chemical approaches has already opened some opportunities in this direction, and in many cases, the outcomes of experiments can be efficiently modeled in silico 1, 2, 3, 4, 5, 6. The advent of artificial intelligence (AI) algorithms to automatize, improve, and generalize predictions is gaining importance in this field, and several recent studies have been published in this area.…”