Development of novel routes to pyridines

Gehre, Alexander (2008) Development of novel routes to pyridines. Doctoral thesis, Northumbria University.

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Abstract

Pyridines occupy a central part in modern day organic chemistry. Recent studies in various fields of chemistry, biology and physics have featured numerous examples and applications of these compounds. The purpose of this study was to produce a library of polysubstituted pyridines, 2,2'-bipyridines and 2,2':6',2"-terpyridines via pathways that allowed unusual or even unique substitution patterns. To achieve a generic pyridine synthesis that delivers a diversity of products tailored to different industrial needs, a strategy by which the target molecule is constructed in a [2+2+2]-manner was chosen, i.e. the six atoms of the pyridine ring and their pendant functionalities are traced back to three building blocks, each delivering two atoms to the pyridine ring. A range of a-acetoxy-a-chloro-P-keto esters were prepared in three steps from commercially available P-keto esters through a-chlorination with sulfuryl chloride, a-acetoxylation with acetic acid and triethylamine and a second a-chlorination in good overall yields (69 — 89 %) without the need for chromatographic purification. These a-acetoxy-a-chloro-j3-keto esters served as equivalents for a,[3-diketo esters (building block 1) in the synthesis of various 1,2,4- triazines through condensation with picolinohydrazonamides or thiosemicarbazides (building block 2). A subsequent aza Diels-Alder reaction of these 1,2,4-triazines with electron-rich dienophiles (building block 3) such as 2,5-norbornadiene, 1-pyrrolidino- 1 -cyclopentene and 2,3-dihydrofuran furnished an array of novel polysubstitued (bi)pyridines. The two-step sequence of condensation and aza Diels-Alder reaction could be advanced into a 'one-pot' synthesis on several occasions. Furthermore, we devised a feasible synthetic alternative towards a,(3-diketo esters. Alpha-picolinoyl-3-keto esters were prepared from the same starting materials as the a-acetoxy-a¬chloro-P-keto esters in a shortened two-step sequence of a-chlorination of P-keto esters with sulfuryl chloride and replacement of the chloro group by a picolinoyl group using picolinic acid and KHCO3. The overall yields of a-picolinoyl-f3-keto esters (55 — 91 %) were comparable to those of the a-acetoxy-a-chloro-P-keto esters. Copper(II) acetate-facilitated methanolysis of a-picolinoyl-P-keto esters and immediate oxidation of the in situ generated a-hydroxy-P-keto esters by excess copper(II) acetate afforded a,(3-diketo esters which reacted with hydrazonamides in the same manner as the a-chloro-a-acetoxy-P-keto esters. However, in terms of product purity and yield the `chloroacetate route' remains the superior strategy.

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