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Condensation/ Multi-component Reactions MCR/Oxidation Approaches to Pyridines

Mechanism + Description

Hantzsch-type pyridine synthesis

Bolhmann-Rahtz pyridine synthesis

Construction of carbon skeleton then ring closure by addition / elimination

General comments

The construction of pyridines using condensation reactions/addition-elimination reactions is widely used to make a wide range of functionalized pyridines. These reactions can be run as linear sequences to build up the precursor to ring formation, or more commonly run as multi-component reactions (MCR) in which the precursor to cyclisation is built up from simple reactive synthons and amines. Typically, carbon-carbon bonds are formed by Michael or aldol type reactions. This can be done via sequential additions of reagents or as ‘one pot’ type processes—all in.

Exemplar pyridine ring forming reactions are:

  • Guareschi−Thorpe reaction
  • Bohlmann−Rahtz reaction
  • Hantzsch reaction
  • Kröhnke reaction

The two main routes are used: Hantzsch-type, which gives rise to a tetrahydropyridine product that requires an oxidation reaction to give the product pyridine, and Guareschi−Thorpe / Bohlmann−Rahtz approaches that give the aromatic pyridine directly by substitution/elimination of small molecules like water, alcohols or amines.

Key references

Gao, B.; Sun, Y.; Wang, J.; Yuan, Z.; Zu, L.; Zhang, X.; Liu, W. Efficient and divergent synthesis of polyfunctionalized 2-pyridones from β-keto amides. RSC Adv. 2018, 8, 33625-33630.

Tron, G. C.; Minassi, A.; Sorba, G.; Fausone, M.; Appendino, G. Icilio Guareschi and his amazing “1897 reaction”. Beilstein J. Org. Chem. 2021, 17, 1335–1351.

Kröhnke, F.; Zecher, W.; Curtze, J.; Drechsler, D.; Pfleghar, K.; Schnalke, K. E.; Weis, W. Syntheses Using the Michael Adddition of Phridinium Salts. Agnew. Chem. Int. Ed. 1962, 1, 626-632

Bagley, M. C.; Dale, J. W.; Bower, J. A New Modification of the Bohlmann-Rahtz Pyridine Synthesis Synlett, 2001, 1149-1151.

Ciufolini, M. A.; Chan, B. K. Methodology for the Synthesis of Pyridines and Pyridones: Development and Applications. Heterocycles 2007, 74, 101–124.

Aulakh, V. S.; Ciufolini, M. A. An Improved Synthesis of Pyridine−Thiazole Cores of Thiopeptide Antibiotics. J. Org. Chem. 2009, 74, 5750–5753.

Katsuyama, I.; Ogawa, S.; Yamaguchi, Y.; Funabiki, K.; Matsui, M.; Muramatsu, H.; Shibata, K. A Convenient and Regioselective Synthesis of 4-Trifluoromethylpyridines. Synthesis 1997, 11, 1321-1324.

Phillips, A. P. Hantzsch’s Pyridine Synthesis. J. Am. Chem. Soc. 1949, 71, 12, 4003–4007.

Abdella, A. M.; Abdelmoniem, A. M.; Abdelhamid, I. A.; Elwahy, A. H. M. Synthesis of heterocyclic compounds via Michael and Hantzsch reactions. J. Heterocyclic Chem. 2020, 57, 1476-1523.

Xia, J.-J.; Wang, G.-W. One-Pot Synthesis and Aromatization of 1,4-Dihydropyridines in Refluxing Water. Synthesis 2005, 14, 2379-2383.

Azizi, N.; Haghayegh, M. S. Greener and Additive-Free Reactions in Deep Eutectic Solvent: One-Pot, Three-Component Synthesis of Highly Substituted Pyridines. Chemistry Select 2017, 2, 8870–8873.

Evdokimov, N. M.; Magedov, I. V.; Kireev, A. S.; Kornienko, A. One-Step, Three-Component Synthesis of Pyridines and 1,4-Dihydropyridines with Manifold Medicinal Utility. Org. Lett. 2006, 8, 899–902.

Allais, C.; Grassot, J.-M.; Rodriguez, J.; Constantieux, T. Metal-Free Multicomponent Syntheses of Pyridines. Chem. Rev. 2014, 114, 10829−10868

Reddy, T. R.; Reddy, G. R.;  Reddy, L. S.; Jammula , S.; Lingappa, Y.; Kapavarapu, R.; Meda, C. L. T.; Parsa, K. V. L.; Pal, M. Montmorillonite K-10 mediated green synthesis of cyano pyridine: Their evaluation as potential inhibitors of PDE4. Eur. J. Med. Chem. 2012, 48,  265-274

Shan, Y.; Su, L.; Zhao, Z.; Chen, D. The Construction of Nitrogen-Containing Heterocycles from Alkynyl Imines. Adv. Synth. Catal. 2021, 363, 906–923.

Bagley, M. C.; Fusillo, V.; Jenkins, R. L.; Lubinu, M. C.; Mason, C. One-step synthesis of pyridines and dihydropyridines in a continuous flow microwave reactor. Beilstein J. Org. Chem. 2013, 9, 1957–1968.

Xiong, X.; Bagley, M. C.; Chapaneri, K. A new mild method for the one-pot synthesis of pyridines. Tetrahedron Letts. 2004, 46, 6121–6124.

Marcoux, J.-F.; Marcotte, F. A.; Wu, J.; Dormer, P. G.; Davies, I. W.; Hughes, D.; Reider, P. J. General Preparation of Pyridines and Pyridones via the Annulation of Ketones and Esters.  J. Org. Chem. 2001, 66, 4194-4199.

Vchislo, N. V.; Verochkina, E. A. Pyridines on the basis of α,β-unsaturated aldehydes. Chemistry of Heterocyclic Compounds. 2019, 55(7), 598–600.

Palacios, F.; Herrán, E.; Alonso, C.; Rubiales, G. Regioselective cycloaddition of 3-azatrienes with enamines. Synthesis of pyridines derived from β-amino acids. Tetrahedron 2006, 62, 7661–7666.

Movassaghi, M.; Hill, M. D.; Ahmad, O. K. Direct Synthesis of Pyridine Derivatives. J. Am. Chem. Soc. 2007, 129, 10096–10097.

OXIDATION

Zard, S. Z. The xanthate route to pyridines. Tetrahedron 2020, 76, 130802.

 

Scale-up examples – condensation/ Multi-component reactions MCR/Oxidation approaches to pyridines

Rageot, D.; Beaufils, F.; Borsari, C.; Dall’Asen, A.; Neuburger, M.; Hebeisen, P.; Wymann, M. P. Scalable, Economical, and Practical Synthesis of 4-(Difluoromethyl)pyridin-2-amine, a Key Intermediate for Lipid Kinase Inhibitors. Org. Process Res. Dev.  2019, 23, 2416–2424.
1.5 kg scale

Org. Process Res. Dev. 1997, 1, 370-378.
2 kg scale

Org. Process Res. Dev. 1997, 1, 370-378.
2 g scale

Org. Process Res. Dev. 2015, 19, 454−462.
800 g scale

Org. Process Res. Dev. 2020, 24, 1763–1771.
2 kg scale

Org. Process Res. Dev. 2011, 15, 788–796.
150 g scale

Org. Process Res. Dev. 2012, 16, 595−604.
400 g scale

Org. Process Res. Dev. 2012, 16, 1652−1659.
3  kg scale

Org. Process Res. Dev. 2012, 16, 1739−1745.
300 g scale

Org. Process Res. Dev. 2006, 10, 1157–1166.
60 g scale

 

Green Review – Condensation/ Multi-component reactions MCR/Oxidation approaches to pyridines

  1. Atom efficiency (by-products, molecular weight)
    Generally good efficiency and atom economy with simple by-products like water, ethanol, methanol, etc.

    In general, MCR reactions to give pyridine products can be slow with moderate yields, but these syntheses can be amenable to techniques like microwave heating or flow chemistry to improve conversion time and yields.
  2. Safety Concerns
    No major concerns.

    Alkynes and alkenes are high-energy compounds and appropriate safety studies should be carried out before scale-up, especially with one pot or all in reactions.

    Hydroxylamine and hydrazine are potentially explosive and highly toxic in the case of hydrazine.

    When oxidizing a Hantzsch intermediate, key concerns are safe operation with flammable organic solvents (air/hydrogen peroxide and other reagents that can generate O2), and the potential of oxidizing agents to form unstable mixtures with some reagents/solvents. Oxygen in the presence of air can form an explosive mixture, and measures should be taken to limit the O2 concentration below the limit that would support combustion.
  3. Toxicity and environmental/aquatic impact
    Main concern is around loss of precious metal/ heavy metal catalysts into waste streams. Most precious and heavy metal levels are tightly regulated. The same applies to potential metal carry-through into the API. Hydrophobic, high mol. weight phosphines and phosphine oxides can be persistent and bioaccumulative and should not be discharged into aqueous waste streams.

    Relevant regulatory guidance on permitted metal levels in API’s should be consulted.
    Metals Removal Guide
    Guidance.pptx

    There may be issues with discharging aqueous waste with high NH3 content. Ammonia is harmful to the aquatic ecosystem.
  4. Cost, availability, & sustainable feedstocks
    Most reagents are cheap and readily available on scale. Most are probably still produced from petrochemical feedstocks.
  5. Sustainable implications
    No major concerns. Some pyridines can be produced from bio renewable feedstocks, but not in great structural diversity of scale as yet.