Abstract
Two robust and efficient mechanochemical protocols for the synthesis of an array of N-arylamides have been developed. This was achieved by a C-N cross-coupling between O-pivaloyl hydroxamic acids and aryl iodides or aryl boronic acids, in the presence of a stoichiometric amount of a copper mediator. The effectiveness of this method is highlighted by the high-yielding (up to 94 %), scalable (up to 8 mmol), and rapid (20 minutes) synthesis of N-aryl amides (15 examples), using a variety of deactivated and sterically encumbered substrates, whilst employing mild conditions and in the absence of solvents. In addition, it was determined that whilst the O-pivaloyl hydroxamic acid precursors can be synthesised mechanochemically, iron contamination originating from the steel jars was found to occur which can hinder the efficacy of this process. Furthermore, 3D printing was used to produce custom milling jars that could successfully accommodate a scaled-up version of the two protocols.
Highlights
The amide functionality has proven to be extremely important in most areas of organic chemistry and is present in a vast number of contemporary pharmaceuticals, agrochemicals, polymers, as well as natural products and biological molecules.[1,2,3] Since there is an intrinsic need for large scale production of amide-bearing compounds, it is imperative that improved and sustainable methods are developed to provide high atom efficiency, low energy consumption, and minimal waste, whilst maintaining acceptable yields.[4]
There are several examples in the literature[21,22,23] where protected hydroxamic acids are converted into amides, and it is clear that high temperatures, inert atmospheres, harsh solvents and moderate to long reaction times are in most cases indispensable to achieve the desired outcome
We report here the synthesis of amides using two mechanochemical protocols
Summary
Title: Mechanochemically Mediated Synthesis of N-Aryl Amides from O-protected Hydroxamic Acids. Authors: Gareth Owen Lloyd, Emmanouil Broumidis, Mary C. This manuscript has been accepted after peer review and appears as an Accepted Article online prior to editing, proofing, and formal publication of the final Version of Record (VoR). The VoR will be published online in Early View as soon as possible and may be different to this Accepted Article as a result of editing. Readers should obtain the VoR from the journal website shown below when it is published to ensure accuracy of information. The authors are responsible for the content of this Accepted Article. Supporting information for this article is given via a link at the end of the document
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