Metal-catalysed pyridine ring synthesis

Mechanism + Description

Use of metal catalysts to from pyridines from simple building block using pathways disfavored by normal thermal chemistry.

 

General comments

Metal catalysis is used in a wide range of pyridine chemistry:

  • Oxidation of di and tetrahydropyridines to pyridines
  • Function group interconversion on pyridine ring substituents
  • Further annulation of existing pyridine rings into more complex heterocycles

A wide range of metal-catalyzed transformations are also known to form tetrahydropyridine and pyridine rings. Characteristically, these are very convergent and atom efficient. Examples being ring closing metathesis reactions and catalysis of cycloaddition reactions that do not occur or are too slow thermally. [2 + 2 + 2] cycloadditions are rarely used because they are enthalpy and entropy disfavoured barriers. Metal catalysis can provide alternative lower energy pathways, e.g. [2+2+2] cycloaddition of acetylenes and nitriles to form pyridine rings.

 

Key references

Donohoe, T. J.; Jones, C. R.; Barbosa, L. C. A. Total Synthesis of (±)-Streptonigrin: De Novo Construction of a Pentasubstituted Pyridine using Ring-Closing Metathesis. J. Am. Chem. Soc. 2011, 133, 16418–16421.

Donohoe, T. J.; Fishlock, L. P.; Basutto, J. A.; Bower, J. F.; Procopioub, P. A.; Thompson, A. L. Varela,  J. A.; Castedo, L.; Saa, C. Scope of Ru(II)-Catalyzed Synthesis of Pyridines from Alkynes. J. Org. Chem. 2003, 68, 8595–8598.

Roglans, A.; Pla-Quintana, A.; Solà, M. Mechanistic Studies of Transition-Metal-Catalyzed [2 + 2 + 2]. Chem. Rev. 2021, 121, 1894−1979.

Sim, Y.-K.; Lee, H.; Park, J.-W.; Kim, D.-S.; Jun, C.-H. A method for the synthesis of pyridines from aldehydes, alkynes and NH4OAc involving Rh-catalyzed hydroacylation and N-annulation. Chem. Commun. 2012, 48, 11787–1178.

Yi, Y.; Zhao, M.-N.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Synthesis of symmetrical pyridines by iron-catalyzed cyclization of ketoxime acetates and aldehydes. Green Chem. 2017,19, 1023–1027.

Maji, M.; Panja, D.; Borthakur, I.; Kundu, S. Recent advances in sustainable synthesis of N-heterocycles following acceptorless dehydrogenative coupling protocol using alcohols. Org. Chem. Front. 2021, 8, 2673–2709.

Neely, J. M.; Rovis, T. Pyridine synthesis by [4 + 2] cycloadditions of 1-azadienes: hetero-Diels Alder and transition metal-catalysed approaches. Org. Chem. Front. 2014, 1, 1010–1015

Dzhemilev, U. M.; Selimov, F. A; Tolstikov, G. A. Metal complex catalysis in a synthesis of pyridine bases. ARKIVOC 2001 (ix) 85–116.

Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan, V. Transition Metal-Mediated Synthesis of Monocyclic Aromatic Heterocycles. Chem. Rev. 2013, 113, 3084−3213.

Varela, J, A.; Saá, C. Construction of Pyridine Rings by Metal-Mediated [2 + 2 + 2] Cycloaddition. Chem. Rev. 2003, 103, 3787–3802.
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