Heterocycles make up an exceedingly important class of compounds. In fact more than half of all known organic compounds are heterocycles. Many natural drugs such as quinine, papaverine, emetine, theophylline, atropine, procaine, codeine, morphine and reserpine are heterocycles. Almost all the compounds we know as synthetic drugs such as diazepam, chlorpromazine, isoniazid, metronidazole, azidothymidine, barbiturates, antipyrine, captopril and methotrexate are also heterocycles. Some dyes (e.g. mauveine), luminophores, (e.g. acridine orange), pesticides (e.g. diazinon) and herbicides (e.g. paraquat) are also heterocyclic in nature.
All these natural and synthetic heterocyclic compounds can and do participate in chemical reactions in the human body. Furthermore, all biological processes are chemical in nature. Such fundamental manifestations of life as the provision of energy, transmission of nerve impulses, sight, metabolism and the transfer of hereditary information are all based on chemical reactions involving the participation of many heterocyclic compounds, such as vitamins, enzymes, coenzymes, ATP, DNA, RNA and serotonin. Why does nature utilize heterocycles? The answer to this question is provided by the fact that heterocyles are able to get involved in an extraordinarily wide range of reaction types. Depending on the pH of the medium, they may behave as acids or bases, forming anions or cations. Some interact readily with electrophilic reagents, others with nucleophiles, yet others with both. Some are easily oxidized, but resist reduction, while others can be readily hydrogenated but are stable toward the action of oxidizing agents. Certain amphoteric heterolcyclic systems simultaneously demonstrate all of the above-mentioned properties. The ability of many heterocycles to produce stable complexes with metal ions has a great biochemical significance. The presence of different heteroatoms makes tautomerism ubiquitous in the heterocyclic series. Such versatile reactivity is linked to the electronic distributions in heterocyclic molecules. Evidently, all the natural products and the synthetic drugs mentioned above are good examples of natureâ€™s preference for heterocycles whose biological activity cannot be determined by one or a combination of two or three of the above-mentioned properties.
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Functionalization of nitrogen heterocycles constitutes a powerful tool for the synthesis of natural products and bioactive substances.1 According to a recent MDL Drug Data Report pyridines are the most common heterocycles in pharmaceutically active compounds.2 Nevertheless, nature selected the heterocycles pyrrole and pyridine, and not the homocycles aniline and nitrobenzene, as the basis of most essential biological systems. Moreover, heterocycles are chemically more flexible and better able to respond to the many demands of biochemical systems. Particularly, 2-Thiopyridines are useful starting materials for the preparation of unique building blocks in the synthesis of new drug candidates.3
Review of literature
Copper-catalysed coupling reactions were first reported by Ullmann and, since that seminal discovery, have found increasing utility as tools for the construction of carbon_hetero-atom bonds. Taniguchi et.al., reported the methodology for a copper-catalyzed preparation of diaryl thioethers compounds from aryl iodides and diphenyl diphenyldisulfides using copper
Catalyst (CuI or Cu2O) and magnesium metal (Scheme 1). This reaction can be carried out under neutral conditions according to an addition of magnesium metal as the reductive reagent.
Cheng et.al., reported a cobalt-catalyzed coupling of aryl halides with thiophenols and alkanethiols is reported. A variety of aryl sulfides can be prepared in good yields using 1-2 mol % of CoI2 (dppe) and Zn. This cobalt-catalyzed coupling represents an interesting addition to previously known methods to synthesize thioethers (Scheme 2).
The nucleophilic substitution reactions of halopyridines with sulfur nucleophiles has been reported using HMPA as a base under microwave irradiation (Scheme 3). These reactions probably proceed via SNAr mechanism and the relative reactivity of halopyridines in substitution reactions fallows 2-halopyridine > 4-halopyridine > 3-halopyridine.
Very recently Michael E. Kopach et.al., reported a synthesis of 2-benzenesulfonylpyridine, which is a key starting material for the manufacture of an investigational new drug candidate at Eli Lilly and Company. An optimized green chemical process was developed which features a novel tandem SNAr/oxidation under mild conditions to produce the target sulfones (Scheme 4). For the SNAr reaction they have used the K2CO3 as the base and highly polar DMF as the solvent.
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The most commonly employed methodologies for the synthesis of thioethers use harsh coupling conditions, harmful metal catalyst, bases and highly polar solvents.4 Moreover, these synthetic methods frequently involve elaborate workup procedures and operate for a relatively narrow range of substrates.
Direct nucleophic aromatic substitution (SNAr) provides an alternative approach to these syntheses, but also suffers from the use of strong bases and polar organic solvents.5 Though, water is the most abundant and environmentally friendly solvent in nature, its use for the organic chemistry is limited because of the insolubility of a large number of reactants or the reaction intermediates formed during the reaction.
However, in certain situations,6 the special physical and chemical properties of water, such as high dielectric constant, heat capacity, hydrophobic interactions between reactants, hydrogen bond formation with reactants and acid or base characters may be utilized to promote organic reactions.
Results and Discussion
Initial attempts were focused on exploring the influence of different solvent systems on SNAr reaction of 2-bromopyridine and thiophenol as the model substrates at 100 oC under base and catalyst-free conditions. The reaction was monitored by GC and the results are shown in Table 1.
Table 1 The reaction of 2-bromopyridine with thiophenol in various solvents and under neat conditions.a
aReaction conditions: 2-bromopyridine (1 mmol), thiophenol (1.2 mmol), solvent (5 ml) bGC yields.
cwith 10 mmols of 2-bromopyridine
Among different polar aprotic solvents screened, 1,4-dioxane, NMP and DMSO gave the product in 10-30% yield and the reaction in DMF gave the product, thiopyridine in 50% yield after 24 h (Table 1, entries 1-4). The reaction using a mixture of DMF/H2O (3:1) afforded the product in 67 % yield after 24 h (Table 1, entry 6). The presence of even trace amount of highly polar protic solvent, water resulted in comparatively higher yield suggesting the unique role of water in promoting the reaction. It was observed that none but water (5 mL) alone as the reaction media facilitates this reaction with formation of the product in quantitative yield in shorter reaction times. Therefore, the amount of water used as the solvent for the reaction is also found to be important for the high yield of the product.
To test the feasibility and practicable applicability, a reaction on large-scale (10 mmol) was conducted in water (50 mL) at 100 Â°C, 85% conversion was observed after 8 h by GC and the product was isolated in 81 % yield after purification by column chromatography (Table 1, entry 6). As the yields of the products obtained in ordinary tap water and distilled water were comparable, all the reactions were carried out in tap water so that the consumption of energy and efforts needed to prepare distilled water can be avoided. However, only trace amount of product was formed when the reaction was performed under neat conditions (Table 1, entry 7). The major drawback of water as a solvent is the low solubility of organic substrates in water, which is avoided since the above reactions are performed at 100oC. The dielectric constant of ambient water is 80 and this number quickly reduces to 55 at 100 oC, which implies that water is more like a polar organic solvent at high temperature. Therefore, some substrates that were originally insoluble in water, dissolve at elevated temperatures and undergo reaction.9