Synthetic toolbox: Base metal catalysis

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]])

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])

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]

  1. M. Legraverend and D. S. Grierson, The purines: Potent and versatile small molecule inhibitors and modulators of key biological targets, Biorg. Med. Chem., 2006, 14, 3987-4006.
  2. S. Blanchard, C. Kai Soh, C. Ping Lee, A. Poulsen, Z. Bonday, K. Lin Goh, K. Chuan Goh, M. Kiat Goh, M. Khalid Pasha, H. Wang, M. Williams, J. M. Wood, K. Ethirajulu and B. W. Dymock, 2-Anilino-4-aryl-8H-purine derivatives as inhibitors of PDK1, Bioorg. Med. Chem. Lett., 2012, 22, 2880-2884.
  3. J. Lu Liang, S. - E. Park, Y. Kwon and Y. Jahng, Synthesis of benzo-annulated tryptanthrins and their biological properties, Biorg. Med. Chem., 2012, 20, 4962-4967.
  4. E. - M. Priego, Jvon Frijta Kuenzel, A. P. Ijzerman, M. - J. Camarasa and M. - J. Pérez-Pérez, Pyrido[2,1-f]purine-2,4-dione Derivatives as a Novel Class of Highly Potent Human A3 Adenosine Receptor Antagonists, J. Med. Chem., 2002, 45, 3337-3344.
  5. P. Giovanni Baraldi, D. Preti, M. Aghazadeh Tabrizi, F. Fruttarolo, R. Romagnoli, N. Abdel Zaid, A. R. Moorman, S. Merighi, K. Varani and P. Andrea Borea, New Pyrrolo[2,1-f]purine-2,4-dione and Imidazo[2,1-f]purine-2,4-dione Derivatives as Potent and Selective Human A3 Adenosine Receptor Antagonists, J. Med. Chem., 2005, 48, 4697-4701.
  6. D. Ye, X. Zhang, Y. Zhou, D. Zhang, L. Zhang, H. Wang, H. Jiang and H. Liu, Gold- and Silver-Catalyzed Intramolecular Hydroamination of Terminal Alkynes: Water-Triggered Chemo- and Regioselective Synthesis of Fused Tricyclic Xanthines, Adv. Synth. Catal., 2009, 351, 2770-2778.
  7. K. Lafleur, D. Huang, T. Zhou, A. Caflisch and C. Nevado, Structure-Based Optimization of Potent and Selective Inhibitors of the Tyrosine Kinase Erythropoietin Producing Human Hepatocellular Carcinoma Receptor B4 (EphB4), J. Med. Chem., 2009, 52, 6433-6446.
  8. K. Liubchak, A. Tolmachev, O. O. Grygorenko and K. Nazarenko, An approach to alicyclic ring-fused xanthines, Tetrahedron, 2012, 68, 8564-8571.
  9. I. Čerňa, R. Pohl, B. Klepetářová and M. Hocek, Intramolecular Direct C−H Arylation Approach to Fused Purines. Synthesis of Purino[8,9-f]phenanthridines and 5,6-Dihydropurino[8,9-a]isoquinolines§Dedicated to the memory of Keith Fagnou, J. Org. Chem., 2010, 75, 2302-2308.
  10. K. E. Litinas and A. Thalassitis, Synthesis of fused dihydropyrido[e]purines via ring closing metathesis, Tetrahedron Lett., 2010, 51, 6451-6453.
  11. G. Meng, H. - Y. Niu, G. - R. Qu, J. S. Fossey, J. - P. Li and H. - M. Guo, Synthesis of fused N-heterocycles via tandem C-H activation, Chem. Commun., 2012, 48, 9601-9603.
  12. G. Xia, J. Li, A. Peng, S. Lai, S. Zhang, J. Shen, Z. Liu, X. Chen and R. Ji, Synthesis and phosphodiesterase 5 inhibitory activity of novel pyrido[1,2-e]purin-4(3H)-one derivatives, Bioorg. Med. Chem. Lett., 2005, 15, 2790-2794.
  13. J. C. Debouzy, S. Crouzy, V. Dabouis, A. Gueiffier, B. Brasme, C. Bachelet, A. Favier, J. P. Simorre, L. Mazet and A. Peinnequin, The Interactions of Substituted Pyrido[1,2-e]purines with Oligonucleotides Depend on the Amphiphilic Properties of Their Side Chain, Arch. Biochem. Biophys., 1999, 367, 202-215.
  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.
  15. G. Brasche and S. L. Buchwald, CH Functionalization/CN Bond Formation: Copper-Catalyzed Synthesis of Benzimidazoles from Amidines, Angew. Chem. Int. Ed., 2008, 47, 1932-1934.
  16. H. Wang, Y. Wang, C. Peng, J. Zhang and Q. Zhu, A Direct Intramolecular C−H Amination Reaction Cocatalyzed by Copper(II) and Iron(III) as Part of an Efficient Route for the Synthesis of Pyrido[1,2-a]benzimidazoles from N-Aryl-2-aminopyridines, J. Am. Chem. Soc., 2010, 132, 13217-13219.