Synthetic applications of N–N linked heterocycles. Part 12. The preparation of 4-alkylthio- and 4-arylthio-pyridines by regiospecific attack of thioalkoxide lons on N-(4-oxopyridin-1-yl)pyridinium salts

Abstract

Thiolate ions add regiospecifically to N-(4-oxopyridin-l -yl)pyridinium salts (2)-(7) to give in good to excellent yields only the 1,4-dihydropyridine adducts (8)-(13), regardless of whether or not the pyridone moiety carries substituents for sterically shielding the 2and 6-positions of the pyridinium ring. The addition is believed to be thermodynamically controlled. Decomposition of the dihydro-adducts under free-radical conditions, or by pyrolysis, gives good yields of pyridin-4-yl thioethers (1 4) and (1 6) though the reaction failed with the 2-methyl adducts ( 9). An improved synthesis of 6-methyl-4-oxopyran-2-carboxylic acid is also described.

Selective formation of heteroaryl thioethers via a phosphonium ion coupling reaction

“…We began our study with phosphonium salt 1a , formed according to reported procedure by sequentially adding Tf 2 O, PPh 3 and DBU to a solution of 2-phenylpyridine in dichloromethane at −78 °C, 4a and a range of distinct thiols as coupling partners. The procedure involves deprotonating the thiol at 0 °C with sodium hydride in THF followed by adding the phosphonium salt and stirring at room temperature until the reaction is complete.…”

“…Our laboratory recently disclosed a general approach to directly transform pyridines and diazines into phosphonium salts and subsequently react them with heteroatom nucleophiles to form C–O, C–S and C–N bonds. 4 Herein, we present a detailed account of a two-step protocol to form heteroaryl thioethers (Figure 1B). The reaction has a broad scope, in both the thiol and heterocycle components, and generally forms the C–S bond with exclusive regioselectivity.…”

Synthesis of Pyridine and Dihydropyridine Derivatives by Regio- and Stereoselective Addition toN-Activated Pyridines

“…Later they reported the addition of alkyl and aryl thiols to N -(2,6-dimethyl-4-oxopyridin-1-yl)pyridinium salts to provide 4-thiopyridines in good to excellent yields following cleavage by AIBN in CCl 4 (Table ). The initial addition was found to be reversible in aqueous media, although it was driven to cleavage in MeCN . This was presumed to be due in part to the increased p K a of the thiol in acetonitrile, shifting the equilibrium of the reaction and favoring the formation of the thioether.…”

“…The initial addition was found to be reversible in aqueous media, although it was driven to cleavage in MeCN. 447 This was presumed to be due in part to the increased pK a of the thiol in acetonitrile, shifting the equilibrium of the reaction and favoring the formation of the thioether.…”