Kröhnke pyridine synthesis
Kröhnke pyridine synthesis | |
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Named after | Fritz Kröhnke |
Reaction type | Ring forming reaction |
Identifiers | |
RSC ontology ID | RXNO:0000420 |
The Kröhnke pyridine synthesis is reaction in organic synthesis between α-pyridinium methyl ketone salts and α, β-unsaturated carbonyl compounds used to generate highly functionalized pyridines. Pyridines occur widely in natural and synthetic products, so there is wide interest in routes for their synthesis. The method is named after Fritz Kröhnke.
Reaction development
Discovery
In his work at the
Mechanism
The mechanism of the Kröhnke pyridine synthesis begins with
Reagent synthesis and reaction conditions
The starting materials for the Kröhnke synthesis are often trivial to prepare, lending to the convenience and broad scope of the method. Preparation of the α-pyridinium methyl ketone salts can be easily achieved by treatment of the corresponding bromomethyl ketone with pyridine. The α,β-unsaturated ketones are often available commercially or can be prepared using a number of known methods. Additionally,
The reaction conditions for the Kröhnke synthesis are generally facile and the reactions often proceed in high yields with reaction temperatures generally not exceeding 140 °C.
1,3-dicarbonyl compounds have also been shown to be viable starting materials in place of the α-pyridinium methyl ketone salts.
Advantages over other methods
The Kröhnke synthesis for making pyridines possesses a number of succinct advantages over other methods. Unlike the Hantzsch synthesis,
Another advantage of the Kröhnke synthesis is its high
Scope and limitations
The broad scope of the Kröhnke pyridine synthesis has made it particularly useful for the synthesis of poly aryl systems including pyridyl,
Variations and combinatorial studies
The Kröhnke method is featured in a solvent-free synthesis of triarylpyridines that proceeds via a
In 1992, Robinson and co-workers developed a similar pyridine synthesis using enamino nitriles as one of the three-carbon fragments in place of an α-pyridinium methyl ketone.[13] This improvement increases the reactivity of the system and allows for formation of fully substituted pyridines whereas use of an α-pyridinium methyl ketone requires that the 3- or 5- position on the resulting pyridine be unsubstituted. Kröhnke condensation of enamino nitrile 20 with enone 21 yielded fused pyridine 22.
The mechanism of this Kröhnke-type reaction likely proceeds via a vinylogous
A clean one-pot Kröhnke method in aqueous media generates 4’-aryl-2,2’:6’, 2’’-terpyridines.[14] Reaction of aryl aldehyde 26 with two equivalents of 2-acetylpyridine (27) yielded terpyridines of the form 28.
In addition to variations on the original method, a number of combinatorial studies using the Kröhnke synthesis and its variations have been employed to synthesize vast libraries of highly functionalized pyridines. Janda and co-workers utilized the general Kröhnke reaction scheme to generate a 220 compound library.[15] Various methyl ketones 29 and aldehydes 30 were coupled via aldol condensation to give enones of the form 31. These compounds were then reacted with various α-pyridinium methyl ketones 32 to give the desired tri-substituted pyridine 33.
In 2009, Tu and coworkers developed a 3 fragment, one-pot combinatorial strategy for developing 3-cyanoterpyridines 34and 1-amino-2-acylterpyridines 35.
Synthetic applications to ligands and biologically active molecules
The Kröhnke methodology has also been utilized to generate a number of interesting metal-binding ligands since polypyridyl complexes such as bipyridine (bipy) have been used extensively as ligands. The Kröhnke synthesis was used to prepare a family of tetrahydroquinoline-based N, S-type ligands.[17] 2-thiophenylacetophenone (36) was reacted with iodine gas and pyridine in quantitative yield to generate acylmethylpyridinium iodide 37. Reaction with a chiral cyclic α, β-unsaturated ketone derived from 2-(+)-carene yielded the desired N, S-type ligand 38.
Novel, chiral P, N-ligands have been prepared using the Kröhnke method.[18] α-pyridinium acyl ketone salt 39 was cyclized with pinocarvone derivative 40 to generate pyridine 41. The benzylic position of 41 was methylated and subsequent SnAr reaction with potassium diphenylphosphide to generate ligand 42.
The Kröhnke reaction has also enjoyed applicability to the synthesis of a number of biologically active compounds in addition to ones cataloged in combinatorial studies. Kelly and co-workers developed a route to cyclo-2,2′:4′,4′′:2′′,2′′′:4′′′,4′′′′:2′′′′,2′′′′′:4′′′′′,4-sexipyridine utilizing the Kröhnke reactions as the key
Another use of the Kröhnke pyridine synthesis was the generation of a number of 2,4,6-trisubstituted pyridines that were investigated as potential topoisomerase 1 inhibitors.[20] 2-acetylthiophene (46) was treated with iodine and pyridine to generate α-pyridinium acyl ketone 47. Reaction with Michael acceptor 48 under standard conditions yielded functionalized pyridine 49 in 60% overall yield.
Ultimately, the Kröhnke pyridine synthesis offers a facile and straightforward approach to the synthesis of a wide breadth of functionalized pyridines and poly aryl systems. The Kröhnke methodology has been applied to a number of strategies towards interesting ligands and biologically relevant molecules. Additionally, the Kröhnke reaction and its variations offer a number of advantages than alternative methods to pyridine synthesis ranging from one-pot, organic solvent-free variations to high atom economy.
See also
- Hantzsch pyridine synthesis
- Gattermann–Skita synthesis
- Chichibabin pyridine synthesis
- Ciamician-Dennstedt rearrangement
- Bönnemann cyclization
References
- .
- ^ Potts, K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G. J. Am. Chem. Soc. 1981, 103, 3584-3586.
- ^ Kelly, T. R.; Lee, Y. J.; Mears, R. J. J. Org. Chem. 1997, 62, 2774-2781
- ^ Kröhnke, F.; Zecher, W.; Angew. Chem. 1963, 75, 189
- ^ Kröhnke, F. Synthesis. 1976, 1, 1-24
- ^ Rehberg, R. W.; Kröhnke, F. Justus Liebigs Ann. Chem.1968, 91, 717
- ^ Hantzsch, A. (1881). "Condensationprodukte aus Aldehydammoniak und Ketonartigen Verbindungen". Chemische Berichte 14 (2): 1637
- ^ Chichibabin, A. E. J. prakt. Chem. 1924, 107, 122
- ^ Kürti László, Barbara Czakó. Strategic Applications of Named Reactions in Organic Synthesis. Elsevier Inc.: Burlington, Massachusetts.
- ^ Kröhnke, F.; Kröck, F. W.; Chem Ber. 1971, 104, 1645
- ^ Adib, M.; Tahermansouri, H.; Koloogani, S. A.; Mohammadi, B.; Bijanzadej, H. R. Tetrahedron Lett.2006, 47, 5957-5960
- ^ Robinson et al. J. Org. Chem. 1992, 57, 7352
- ^ Tu, S.; Jia, R.; Jiang, B.; Zhang, J.; Zhang, Y.; Yao, C.; Ji, S. Tetrahedron, 2007, 63, 381-388
- ^ Janda, K. D.; Wirsching, P.; Fujimori, T. J. Comb. Chem.2003, 5, 625-631
- ^ Tu, S.; Jiang, B.; Hao, W.; Wang, X.; Shi, F. J. Comb. Chem. 2009, 11, 846-850
- ^ Chelucci, G. et al. J. Mol. Catal. A: Chemical, 2003, 191, 1-8
- ^ Andrei V. Malkov, Marco Bella, Irena G. Stara, P. Kocovsky "Modular pyridine-type P,N-ligands derived from monoterpenes: application in asymmetric Heck addition" Tetrahedron Lett. 2001, 42, 3045-3048.
- ^ Kelly, T. J. Org. Chem. 1997, 62, 2774-2781
- ^ Lee, E.-S. Med. Chem. Lett. 2004, 14, 1333-1337