Behind the Science: Stereoselective N–H Insertion-Arylation Reactions of Nitrodiazoesters

Behind the Science: Stereoselective N–H Insertion-Arylation Reactions of Nitrodiazoesters

Author: Richard Threlfall, Anita Mattson

Dr. Richard Threlfall, Managing Editor for the Asian Journal of Organic Chemistry, talks to Professor Anita Mattson, The Ohio State University, Columbus, USA, about her article that has recently been accepted for publication in the Asian Journal of Organic Chemistry.

Phosphoric acid derivatives operate as effective catalysts for the synthesis of glycines in high yield through multicomponent coupling reactions of nitrodiazoesters, anilines, and indoles. This process requires double polarity reversal, or umpolung, of the ester functionality: two nucleophiles undergo addition to the carbon α to an ester. Modest control over the absolute stereochemistry of the glycine products is attainable under the influence of chiral BINOL-based phosphoric-acid-derived catalysis.

What was the inspiration behind this study?

Metal-free catalysis is a powerful tool in the development of innovative strategies for the efficient construction of useful products. We are inspired to explore metal-free catalysis to control reactivity patterns typically dominated by transition metals. This work showcases the ability of phosphoric acid catalysis to elicit carbene-like reactivity from diazo compounds, a reactivity pattern that usually requires a transition-metal catalyst.

What is the main significance of your results?

There are two aspects that we find particularly significant. First, we have discovered, for the first time, that phosphoric acid derivatives operate as catalysts for N–H insertion/arylation reactions of nitrodiazoesters.
Second, chiral phosphoric acid catalysis provides promising levels of enantiocontrol in the syntheses of glycine derivatives via multicomponent coupling reactions of nitrodiazo compounds.

What is the broader impact of this paper for the scientific community?

We hope this work will inspire others to consider exploring metal-free catalysts in processes that typically rely on transition metals.

Why was your attention focused on chiral phosphoric acids?

Chiral phosphoric acids are becoming versatile organocatalysts that enable the effective, enantioselective syntheses of useful products. At the onset of our studies, to the best of our knowledge, these useful catalysts had not been studied in reactions of nitrodiazo compounds.
We were delighted to find that phosphoric acid catalysis not only promote interesting multicomponent coupling reactions of nitrodiazoesters, but they also offer promising levels of stereocontrol.

Double umpolung is an unusual reaction pathway, can you elaborate on the mechanism?

Methodologies that capitalize on umpolung, or polarity reversal, can offer direct access to useful functional groups that are otherwise difficult to construct using conventional approaches. In this work, two nucleophiles undergo addition to the α- carbon of the ester functionality, a position that typically is nucleophilic but is now twice electrophilic. This unique double umpolung enables the double functionalization of esters in a single flask! The mechanism of the process is not well understood at this time but we are working hard to learn how the bonds are formed and how the chiral phosphoric acid catalyst is able to influence the stereochemical outcome.

Organocatalysis is a popular theme at the moment. What is it about your research that is particularly significant?

Organocatalysis is emerging as a remarkable synthetic tool. Our work is innovative, in our opinion, because we are harnessing the power of organocatalysts to achieve useful reactivity patterns that are typically dominated by transition-metal catalysts. In addition to the insertion reactions presented in this report, metal-free carbonylations, cross-couplings, and arylations are ongoing topics of study in our laboratory.

How long did this investigation take?

These investigations belong to a larger, ongoing program in our laboratory dedicated toward the development of unique reactivity patterns for hydrogen-bond-donor catalysts that was initiated in late 2009. The data collected for this specific manuscript took about five months. However, it was made possible only by a key discovery made by Sonia So in October of 2011: urea-catalyzed N–H insertion/arylation reactions of nitrodiazoesters.

Why did you choose to target this class of products?

Glycine products are useful in the construction of bioactive target molecules, both natural and unnatural. Our methodology allows for direct access to this useful functionality in a single flask by using an innovative multicomponent coupling approach from simple starting materials.

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