Pyridine Ring Synthesis
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This guide focuses on the construction of the pyridine ring system rather than manipulation of pyridines.
The pyridine ring is a very common structural heterocyclic motif appearing in pharmaceuticals, agrochemicals. Simple pyridines like picolines are made in the bulk chemical industry used catalyzed reactions of aldehydes / ketones and ammonia at high temperature and pressure, often in flow/gas phase reactions. Carbon-carbon bonds are formed by aldol type reactions, reaction with ammonia, cyclisation and oxidation/ elimination to produce the aromatic heterocycle. Simple pyridines can also be extracted from natural products like coal tar.
A wide range of different catalytic and stoichiometric reactions have been utilized for the synthesis of pyridine rings. Some of the most common disconnections are shown in the scheme below:
A review of ~600 papers in Organic Process Research & Development (OPR&D) revealed very few described syntheses of the actual pyridine ring. Thus, for pyridines, the case would appear to be very similar to fluorinated synthons—for scaled syntheses, starting materials with the basic features in place are brought in from fine/bulk chemical manufacturers and manipulated to more advanced intermediates for use in the final product. The source of the pyridine ring is not disclosed, and the vast bulk of chemistry reported is functionalization for substituent manipulation or reaction(s) at the pyridine ring carbon atoms.
General Literature Reviews: Achiral Hydrogenation
Scriven, E. F. V. (ed) Pyridines: From Lab to Production. Elsevier, 2013.
Baumann, M.; Baxendale, I. R. An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles. Beilstein J. Org. Chem. 2013, 9, 2265–2319.
Hill, M. D. Recent Strategies for the Synthesis of Pyridine Derivatives. Chem Eur. J. 2010, 16, 12052-12062.
Heller, B.; Hapke, M. The fascinating construction of pyridine ring systems by transition metal-catalysed [2 + 2 + 2] cycloaddition reactions. Chem. Soc. Rev., 2007, 36, 1085-1094.
Levy, S. L.; Othmer, D. F. Synthesis of pyridines. Ind. Eng. Chem. 1955, 47, 789–796.
Suresh Kumar Reddy, K.; Srinivasakannan, C.; Raghavan, K. V. Catalytic Vapor Phase Pyridine Synthesis: A Process Review. Catal Surv. Asia 2012, 16, 28–35.
Brody, F.; Ruby, P. R. Synthetic and Natural Sources of the Pyridine Ring. In Chemistry of Heterocyclic Compounds: Pyridine and its Derivatives, Part One, Volume 14; Klingsberg, E., Ed.; Chemistry of Heterocyclic Compounds: A Series Of Monographs, Wiley Online Library, 2008, 99-589.
Newkome, G. R. Chemistry of Heterocyclic Compounds: Pyridine and its Derivatives, Part 5, Volume 14 1985.
Farberov, M. I.; Antonova, V. V.; Ustavshchikov, B. F.; Titova, N. A. Synthesis of pyridine bases from aldehydes and ammonia (review). In Chemistry of Heterocyclic Compounds: Pyridine and its Derivatives, Part 5, Volume 14, Newkome, G. R., Ed. John Wiley & Sons, 1984.
Singh, G. S.; Tabane, T. H. Chapter 7 - Synthetic Approaches to Small- and Medium-Size Aza-Heterocycles in Aqueous Media. In Green Synthetic Approaches for Biologically Relevant Heterocycles, 2015, Pages 163-184.
Gros, P.; Fort, Y. Modern Synthetic Methods for Preparation of N-Containing Bisheteroaromatic Compounds. Curr. Org. Chem. 2003, 7, 629 – 648.
Vchislo, N. V.; Verochkina, E. A. Pyridines on the basis of α,β-unsaturated aldehydes (microreview) Chemistry of Heterocyclic Compounds. 2019, 55, 598–600.
Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th Edition. Wiley-Blackwell, 2013.
Other web-based resources:
Green Criteria for Pyridine Ring Synthesis
- If possible, uncatalyzed multi-component reactions are preferred.
- Direct formation of the aromatic system by elimination of a small molecule, e.g., water, alcohol, etc., is preferential to having to oxidize a dihydropyridine.
- Oxidation of tetra/dihydropyridines should use atom efficient green oxidants—O2/H2O2 preferred over heavy metals and poor atom efficient oxidants like Oxone™ and DDQ.
- One pot or telescoped processes are preferred over long linear sequences with multiple isolations.
- Large molar excesses of reagents should be avoided if possible.
- Solvents with CMR properties/alerts should be avoided.
- If using catalytic methods, base metals (e.g., Cu, Ni, Fe) should be considered in preference to Ir, Ru, Pd or other precious metal catalysts.