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CHEM21 case study: Base Metal Catalysed C-H Amination

This case study was provided by Prof. Bert Maes’ ORSY team at the University of Stuttgart.

Purines and their derivatives exhibit a broad range of biological activity, making them important structural motifs in the pharmaceutical industry.[1][2][3] The development of efficient synthetic methods for the formation of purines is an active area of research; the main challenge to obtaining good purine based receptor (ant)agonists and enzyme inhibitors is overcoming the lack of selectivity for a particular enzyme. Modifying the substitution pattern and alterations on the purine core can both result in improved selectivity and increased reactivity. As such, synthetic approaches that construct new scaffolds based on purines that can be easily functionalised are important.

Interestingly, heteroarenes annulated to the C8-N9 unit of the purine core have received less interest than their C8-N7 counterparts,[4][5][6][7][8][9][10][11][12][13] despite being present in the structures of variety of pharmaceutical agents such as in phosphodiesterase type 5 (PED5) inhibitors.[12]  However, current synthetic strategies to achieve such scaffolds do not allow for efficient post-modification of the pyrimidine substitution pattern.[14] Given the potential of such purine cores, CHEM21 researchers developed an efficient synthesis of substituted 1,3-bis(4‑methoxybenzyl)pyrido[1,2e]purine-2,4(1H,3H)-diones based on an iron catalysed direct amination reaction on 5-(pyridin-2-ylamino)pyrimidine-2,4(1 H,3H)-diones, using oxygen as the oxidant in the process (Scheme 1). The products from this transformation would allow for further elaboration in a late stage synthesis.[14]

Scheme 1: Iron catalysed C-H amination for the formation of C8-N9 purines (Maes et al.,2013 [[14]])
Scheme 1: Iron catalysed C-H amination for the formation of C8-N9 purines (Maes et al.,2013 [[14]])

Intermolecular copper-mediated direct amination of aromatics with amidines involving C(sp2)-H using oxygen as an oxidant had been previously reported by both Buchwald[15] and Zhu,[16] however when these approaches were applied to the parent substrate, the product was only achieved in 25 and 28% for the Buchwald and Zhu methods respectively (Scheme 2).[14]  Given the low yields observed with the copper catalyst due to issues of selectivity, the CHEM21 researchers investigated the use of an iron based catalyst given its higher crustal abundance and much lower cost.[14]

Scheme 2: Buchwald and Zhu Copper catalysed C-H amination methods applied to the synthesis of C8-N9 purines (Maes et al.,2013 [14])
Scheme 2: Buchwald and Zhu  Copper catalysed C-H amination methods applied to the synthesis of C8-N9 purines (Maes et al.,2013 [14])

The method developed by the CHEM21 researchers boasts of excellent functional group tolerance, and exhibited higher chemoselectivity than the copper catalysts especially with respect to substrates furnished with halogens, which would allow further functionalisation of the annulated ring post-synthesis.[14]

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  14. J. Maes, T. R. M. Rauws and B. U. W. Maes, Synthesis of C8N9 Annulated Purines by Iron-Catalyzed CH Amination, Chem. Eur. J., 2013, 19, 9137–9141.
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