Synthesis of highly substituted alkynylpyridines and development of new methodologies for the synthesis of 1,4-oxazepines, 1,4-thiazepines and 5-methylpyridines /

Kelgökmen, Yılmaz
Convenient syntheses of pyridines, 1,4-oxazepines and 1,4-thiazepines have become an important research area among organic chemists since they constitute scaffolds of many medicinal substances. Recently, N-propargylic β-enaminones have been widely used for the facile synthesis of potent biologically active heterocycles. Many research groups have focused on the proper synthesis of various heterocycles by using N-propargylic β-enaminones. One of the such recent reports using these precursors is the formation of 5-iodopyridines by iodine-mediated electrophilic cyclization reaction. Accordingly, in this thesis work, the first aim is to further functionalize 5-iodopyridines by utilizing Sonogashira cross-coupling reaction. With this way, we have synthesized 28 new 5-alkynylpyridines in 40-99% yields. Secondly, for the synthesis of 1,4-oxazepines, we have reinvestigated ZnCl2-mediated 7-exo-dig cyclization in refluxing CHCl3 to get higher yields in shorter reaction durations. Thus, we have achieved the smooth synthesis of many 2-methylene-2,3-dihydro-1,4-oxazepine derivatives in good to high yields (66-95%) in 1.5-12.0 h. In some cases, conversion of alkyl-substituted 1,4-oxazepines to the corresponding pyrrole derivatives has been observed to some extent during their isolation on silica gel. In the third part of the thesis work, we have prepared novel starting N-propargylic thio-β-enaminones from the corresponding N-propargylic β-enaminone precursors by using Lawesson's reagent (LR). Then, we have examined the cyclization reactions of these thio-β-enaminones by using ZnCl2 in refluxing CHCl3. We have synthesized 20 novel 2-methylene-2,3-dihydro-1,4-thiazepines in 67-90% yields by using this unprecedented synthetic methodology. Finally, base-catalyzed cyclization reactions of N-propargylic thio-β-enaminones have been investigated, which afforded methyl-substituted pyridines via sulfur extrusion. Accordingly, in the presence of diisopropylamine (DIPA) at room temperature, many alkylpyridines have been synthesized in moderate to high yields (46-85%), except for one derivative (13%).


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Heterocyclic compounds have a great importance in medicinal chemistry because of their presence in a number of pharmaceuticals. Among them, pyrroles and 1,4-thiazepines play a vital role in pharmaceutical chemistry because of their presence in a number of bioactive molecules and natural products. For this reason, the development of new synthetic methods for the synthesis of these compounds has attracted much attention. Recently, the cyclization of functionally-substituted alkynes has emerged as a valuable t...
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Citation Formats
Y. Kelgökmen, “Synthesis of highly substituted alkynylpyridines and development of new methodologies for the synthesis of 1,4-oxazepines, 1,4-thiazepines and 5-methylpyridines /,” Ph.D. - Doctoral Program, Middle East Technical University, 2018.