6-Substituted 2-hydroxypyridines

DBU-mediated elimination of the leaving group and aromatization dehvered hydroxypyridines 64 in excellent yields. In addition, a smooth one-pot elimination—triflation sequence generated pyridine triflates 65, which were amenable for further manipulation. Several examples of diversely substituted hydroxypyridines and pyridine triflates made using this methodology are given in Table 5. 

NMR study of complexes [M(COD)(/i-L)]2 (M = Rh, Ir L = substituted hydroxypyridinate) has been carried out. Two fluxional processes interconvert nonequivalent COD protons in [Rh(COD)(2-hydroxypyridinate)], but only the lower-energy process is observed in [Ir(COD)(6-methyl-2-hydroxypyridinate)]. The latter process involves only motion of the bridging ligands while the higher-energy process may involve rotation of the coordinated diene or inversion of the eight-membered metallocyclic ring. 

Molecular orbital calculations have been used to estimate equilibrium constants, although up to the present these attempts have not met with much success. Using calculations of this type, 2- and 4-hydroxypyridine 1-oxide were predicted to be more stable than 1-hydroxypyrid-2- and -4-one by ca. 20 kcal/mole, which corresponds to a ratio of ca. 10 between the forms. It was later shown experimentally that, at least in the series of 4-substituted compounds, there is very little energy difference between the forms and that the ratio between them is about unity. Molecular orbital calculations for... 

Mixed O, N donor molecules are truly extensive and structurally diverse, and only a few selected examples will be presented. In line with other 2-substituted pyridine analogs reported in this chapter, it is worthwhile noting the chemistry of 2-pyridone (or 2-hydroxypyridine, Hopy), which can form O-bonded monodentate complexes such as Co(Hopy)4(N03)2, but as the monoanion is an effective chelate ligand, forming Co(opy)2 and Co(bpy)(opy)2 compounds.454 An unusual solid state melt reaction with Co(OAc)2 yields the dodecanuclear cluster Co12 (OH)6(OAc)6(opy )12.455... 

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>. 

Substitution of hydroxy groups into a pyridinone constitutes a special case, because now alternative tautomeric structures can arise. Glutaconamide, for example, can exist in any of five structures (179), (180), (181), (182) and (183), of which the first three predominate. Again, the situation has been admirably discussed previously (76AHC(Sl)7l), as has the tautomeric situation in 3-hydroxypyridines (184) and (185) and in 3-hydroxypyridine... 

In line with Beak s finding, pyridin-2-one was estimated to be 31 kJ mol-1 less aromatic than the pyridine, and a similar figure of 25 was estimated for pyridine-2-thione. Subsequent results (73JCS(P2)1080, 76AHC(S1)71) on the pyridin-4-one, quinolin-2-one and isoquinolin-1-one series showed that aromatic resonance energy difference for the pyridin-4-one/4-hydroxypyridine system was very similar to that for the 2-substituted compounds, in contrast to Beak s findings. 

Hydroxypyridine reacts with formaldehyde and base to give the 2-hydroxymethyl derivative which reacts further, ultimately to yield the 2,6-disubstituted product. No 4-substitution is detected in this case or with 3-hydroxy-2,6-dimethylpyridine when it is treated under the same conditions (75RCR823). 3-Hydroxypyridine readily undergoes bis-aminomethylation at the 2- and 6-positions. 

Treatment of the iV-methylated product (115) of 3-hydroxypyridine with an ion exchange resin generates the betaine (116 Scheme 97) (71JCS(C)874). Reduction of 1-substituted 3-oxidopyridinium betaines with sodium borohydride gives hexahydro derivatives in good yields <8lH(l6)l883). 

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