Functionalizations pyridine

Moody and coworkers have also applied this methodology to the preparation of a library of functionalized pyridine scaffold 49 with two points of diversity by coupling ynone 47 with enamine 48. 

A process for the preparation of functionalized pyridines from diacetylene and the ethyl ester of /3-aminocrotonic acid and acetylacetonimine (72ZOR1328 75DIS) has been described. Owing to the lower nucleophilicity of nitrogen in the initial enamine esters and enamine ketone, the reaction with diacetylene occurs in the presence of sodium metal (80°C, dioxane, 3 h, yield of up to 20%). 

Tliis iodine-magnesium exdiange can also be perfotnied widi beterocydic iodides, sudi as die functionalized pyridine 16 [21] ot die iodoutactl derivative 17 iSdieme 2.5) [22], In botli cases, tlie interniediate otganomagnesium reagent can... 

Scheme 1 A few routes for the synthesis of 2-pyridones from functionalized pyridines...

Alkyne-nitrile cyclotrimerization is a powerful synthetic methodology for the synthesis of complex heterocyclic aromatic molecules.118 Recently, Fatland et al. developed an aqueous alkyne-nitrile cyclotrimerization of one nitrile with two alkynes for the synthesis of highly functionalized pyridines by a water-soluble cobalt catalyst (Eq. 4.62). The reaction was chemospecific and several different functional groups such as unprotected alcohols, ketones, and amines were compatible with the reaction.119 In addition, photocatalyzed [2+2+2] alkyne or alkyne-nitrile cyclotrimerization in water120 and cyclotrimerization in supercritical H2O110121 have been reported in recent years. 

Calorimetry investigations of zinc ions with functionalized pyridines have been carried out in both dimethylformamide and acetonitrile. The pyridines used were pyridine, 3-methylpyridine, and 4-methylpyridine. In DMF, for all three pyridines, four- and six-coordinate species formed and their formation constants, reaction enthalpies and entropies were determined. The stability increases linearly with increasing basicity of the pyridine derivative. The formation of the 3-methylpyridine complex is enthalpically less favorable and entropically more favorable than... 

Reaction of highly functionalized pyridine 126 with chloroacetonitrile 127 or ct-halocarbonyl compounds under phase-transfer conditions furnished pyrrolo[2,3-r/ thieno[2,3-3]pyridine 128 (Equation 31) <2000PS(163)29>. 

The scope and efficiency of [4+2] cycloaddition reactions used for the synthesis of pyridines continue to improve. Recently, the collection of dienes participating in aza-Diels Alder reactions has expanded to include 3-phosphinyl-l-aza-l,3-butadienes, 3-azatrienes, and l,3-bis(trimethylsiloxy)buta-l, 3-dienes (1,3-bis silyl enol ethers), which form phosphorylated, vinyl-substituted, and 2-(arylsulfonyl)-4-hydroxypyridines, respectively <06T1095 06T7661 06S2551>. In addition, efforts to improve the synthetic efficiency have been notable, as illustrated with the use of microwave technology. As shown below, a synthesis of highly functionalized pyridine 14 from 3-siloxy-l-aza-1,3-butadiene 15 (conveniently prepared from p-keto oxime 16) and electron-deficient acetylenes utilizes microwave irradiation to reduce reaction times and improve yields <06T5454>. 

The intermolecular Heck reaction of halopyridines provides an alternative route to functionalized pyridines, circumventing the functional group compatibility problems encountered in other methods. 3-Bromopyridine has often been used as a substrate for the Heck reaction [124-126]. For example, ketone 155 was obtained from the Heck reaction of 3-bromo-2-methoxy-5-chloropyridine (153) with allylic alcohol 154 [125]. The mechanism for such a synthetically useful coupling warrants additional comments oxidative addition of 3-bromopyridine 153 to Pd(0) proceeds as usual to give the palladium intermediate 156. Subsequent insertion of allylic alcohol 154 to 156 gives intermediate 157. Reductive elimination of 157 gives enol 158, which then isomerizes to afford ketone 155 as the ultimate product This tactic is frequently used in the synthesis of ketones from allylic alcohols. 

The reaction of the three chloro pyridines 244 with lithium in the presence of a catalytic amount of naphthalene (4%) and different electrophiles in THF at —78°C gave, after hydrolysis, the expected functionalized pyridines 245 (Scheme 82) . 

Several functionalized pyridines and dihydropyridines are accessible through the reaction of phosphazenes 6 and 2-azadienes 7 <99JOC6239>. 

The synthetic and industrial importance of this reaction lies in its generality, and the ease with which the amino substituent in the products can be subsequently transformed into other functionalities. Pyridine itself is more difficult to aminate than quinoline or isoquinoline, and it does not react with potassium amide in liquid ammonia even on prolonged treatment. However, pyridine is aminated in good yield by sodamide in toluene, and di- and tri-amination can be achieved with excess sodamide at higher temperatures. The 4-position is substituted last in triamination y-amination is very difficult indeed and only takes place when all a -positions are occupied. 

In contrast to ferrocenes, osmium and ruthenium complexes are capable of forming coordinative bonds with donor centers of GO including histidine imidazoles. There are therefore two ways of bringing coordinated transition metals onto enzyme surfaces, i.e., via natural and artificial donor sites. Artificial centers are commonly made of functionalized pyridines or imidazoles, which must be covalently attached to GO followed by the complexation of an osmium or... 

No further research was performed in this field until three decades later, when Arcadi et al. developed a one-pot entry into functionalized pyridines. Reaction required a catalyst to dehydrogenate a dihydropyridine intermediate to pyridine. At that time, the liberated hydrogen was believed to be a consequence of aromatization [189]. 

An extended application of the resin-capture-release technique is depicted in Scheme 13. With the help of reagent 31, a functionalized pyridine was captured as an acyl pyridinium cation 32 on a solid support which was followed by Grignard addition and hydrolysis under acidic conditions to afford polymer-supported N-acylated dehydropyridinones 33 [39]. Advantageously, any unreacted acylium complex collapses to the parent resin upon workup. These heterocycles, which ideally can serve as scaffolds, are then released under basic conditions. 

The synthesis of 2- and 4-functionalized pyridines, the most useful outcome of Gif chemistry, is based on selective addition of nucleophilic carbon-centered radicals at positions 2and 4of protonated pyridines. 2/4-Pyridyl moieties are regarded as high-value intermediates in the synthesis of compounds of industrial and phar-... 

A similar cyclization sequence, incorporating a functionalized pyridine-containing unit rather than an isoprenoid derivative, is thought to give rise to the acromelic acids. It has been suggested that the various... 

Ji and co-workers [73] have elaborated a simple and efficient approach for the synthesis of highly functionalized pyridines 24 via a one-pot, three-component reaction under microwave irradiation. This method enables the incorporation of a pyrazolo[3,4-h]pyridine and an indole moiety into the same molecule. The synthesis was achieved by reaction of a suitable aldehyde and 3-cyanoacetyl indole with 5-aminopyrazol. Particularly valuable features of this method include high yields, broad substrate scope, and short reaction times. It has been observed that when there are electron-withdrawing groups on the aryl aldehyde this results in a faster and higher yielding reaction (Scheme 21). 

Functionalized pyridines are important starting scaffolds for pharmaceuticals and nonlinear optics. Gros et al. have developed a new approach to the facile synthesis of various... 

The rigid tripodal compound 11 is just one of many that could be prepared from 10. Other functionalized pyridines could be introduced to append a range of functional groups to the tripods. There is clearly the potential for the three aromatic substituents to form interdigitated dimers stabilized by 7r-7r interactions. The formation of such species could be followed by NMR or maybe even UV-visible spectroscopy. 

The basic synthetic strategy developed during this phase of drug development was quite sound and provided an excellent starting point for future process development efforts. The synthesis exhibited significant elements of convergence, starting with two functionalized pyridine precursors, which were only three... 

Completion of the synthesis of caerulomycin C required a crosscoupling with a suitably functionalized pyridine, followed by functional group manipulations to convert the amide to an oxime. We found the best procedure for this cross-coupling to be a Negishi coupling using... 

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