Nucleophilic nitrenoids

Nucleophilic nitrenoids are N-centred reagents that donate electron density to an electrophile, and then subsequently lose a leaving group, behaving as nitrene equivalents over a reaction. We have been exploring their use in gold-catalysed reactions to develop efficient new methods for nitrogen heterocycle synthesis.

We proposed that a nucleophilic nitrenoid could be used to deliver a new entry into cycloadditions, by reacting to generate a metal carbene from a pi-acid activated alkyne and delivering the means to quench it. In 2011 we reported the first example of this type of process. Since then, related approaches have been used in a wider variety of transformations.

For an early review of this area, see Miguel’s invited review in the Asian Journal of Organic Chemistry.

We are currently looking at expanding the potential of this approach and applying these methods to target synthesis.

A chemdraw diagram showing the use of a nucleophilic nitrneoid reacting with an alkyne under gold catalysis to generate an a-amino gold carbene that cyclises to generate a nitrogen heterocycle. Illustrated with an example from our publication Angew Chem Int Ed 2011 50 8931
Our initial study introducing the annulation concept
A chemdraw diagram showing some scope of the oxazole forming reaction found in Adv. Synth. catal. 2016, 358, 226
Some examples of the oxazole formation and its scope
A chemdraw diagram shoiwng the reaction of alkynyl thioethers with amindes to make sulfenylated oxazoles in the procedure in Angew. Chem. Int. Ed. 2017, 56, 13310
Different regiocontrol achieved with alkynyl thioethers versus ynamides
The imidazo forming annulation can be extended to other ring systems
A diagram showing the formation of N-acyl pyridinium N aminides as detailed iin Adv. Synth. Catal. 2016, 358, 226
The aminide nitrenoids
These reactions are readily performed on gram scale
New N,N-dipole equivalents for annulations
The reaction shows good tolerance for structural and functional variety
Non-aromatic and functionalised systems can also be used
New nitrenoids as 1,3-N,N-dipole equivalents for annulations