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Van 't Hoff Institute for Molecular Sciences Van 't Hoff Institute for Molecular Sciences

New cobalt catalyst for highly selective synthesis of cyclic amines

Very Important Paper in 'Chemistry, a European Journal'

8 May 2017

Researchers of the University of Amsterdam's Van 't Hoff Institute for Molecular Sciences (HIMS) have developed a cobalt-based catalyst for the direct synthesis of various N-heterocycles from aliphatic azides by means of intramolecular ring-closing C−H bond amination. Their result has just been published online by 'Chemistry, a European Journal', as a Very Important Paper.
The publication is featured on the cover of the print edition of 'Chemistry, a European Journal'. Image: Chem.Eur.J.

Amines are prevalent as a functional group in both bulk and fine chemicals. Using a cobalt-based catalyst the HIMS researchers were able to establish an extremely high reactivity as well as a unprecedented selectivity in preparing cyclic amines via an atom-efficient C-H amination protocol, inserting a nitrogen atom into an unactivated C-H bond. They show that pyrrolidines, oxazolidines, imidazolidines, isoindolines and tetrahydroisoquinoline can be obtained in good to excellent yields in a single reaction step with an air- and moisture-stable catalyst.

The research was performed at the Homogeneous, Supramolecular and Bio-Inspired Catalysis group under supervision of professor Bas de Bruin. The work was sponsored by NWO (VICI grant), the ERC and the UvA (Research Priority Area Sustainable Chemistry). Besides three PhD students, a postdoc and their PIs, also a master student and a bachelor student from the UVA were involved in the project. They are co-authors of the paper. Clearly, education and research go hand-in-hand at the UvA. 

Metallo-radical-type mechanism

Cover illustration: A snake bites its own tail in the cobalt-catalysed activation of aliphatic azides, enabling the direct synthesis of several N-heterocycles from aliphatic azides in good to excellent yields. Image: HIMS. Click to enlarge.

Kinetic studies of the reaction in combination with DFT calculations reveal a metallo-radical-type mechanism involving rate-limiting azide activation to form the key cobalt(III)-nitrene radical intermediate. A subsequent low barrier intramolecular hydrogen-atom transfer from a benzylic C−H bond to the nitrene-radical intermediate followed by a radical rebound step leads to formation of the desired N-heterocyclic ring products.

Kinetic isotope competition experiments are in agreement with a radical-type C−H bond-activation step which occurs after the rate-limiting azide activation step. The use of di-tert-butyldicarbonate (Boc2O) significantly enhances the reaction rate by preventing competitive binding of the formed amine product. Under these conditions, the reaction shows clean first-order kinetics in both the [catalyst] and the [azide substrate], and is zero-order in [Boc2O]. Modest enantioselectivities (29–46 % ee in the temperature range of 100–80 °C) could be achieved in the ring closure of (4-azidobutyl)benzene using a new chiral cobalt-porphyrin catalyst equipped with four (1S)-(−)-camphanic-ester groups.

Article

Kuijpers, P. F., Tiekink, M. J., Breukelaar, W. B., Broere, D. L. J., van Leest, N. P., van der Vlugt, J. I., Reek, J. N. H. and de Bruin, B.: Cobalt-Porphyrin-Catalysed Intramolecular Ring-Closing C−H Amination of Aliphatic Azides: A Nitrene-Radical Approach to Saturated Heterocycles. Chem. Eur. J. (2017),23, 1–9 DOI:10.1002/chem.201700358

Homogeneous, Supramolecular and Bio-Inspired Catalysis research group Research Priority Area Sustainable Chemistry