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. 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. 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 macrocyclization step. Polypyridine complex 43 was treated with N-Bromosuccinimide in wet tetrahydrofuran followed by pyridine to generate the acylmethylpyridinium salt 44 which can then undergo the macrocyclization under standard conditions to yield the desired product 45. The Kröhnke method in this synthesis was crucial due to the failure of other cyclization techniques such as the Glaser coupling or Ullmann coupling.
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. 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.