Pyridines, 3-substituted, directed metalation

Directed metallation continues to be developed as a convenient method for regiospecific substitution of pyridines. A mild and general procedure for the preparation of structurally diverse 4-alkyl-2-aminopyridines 37 involves the lithiation/alkylation of aminopyridine derivative 36 <96JOC(61)4810>. 

An excellent example of the application of pyridine lithiation is the synthesis of the fully substituted pyridine atpenin B 255, an antibiotic produced by Penicillium. Its first synthesis, in 1994, was achieved by a series of directed metallations (Scheme 126) which started with 2-chloropyridine 256 and introduced the substituents stepwise around the ring. 2-Chloropyridine can be lithiated ortho-directed by the chlorine) by either LDA or by PhLi, and the organolithium 257 was oxidized to 258 with trimethylborate and then peracetic acid. 0-Methylation and substitution of chloride by methoxide gave 2,3-dimethoxypyridine 259 (Scheme 127). 

Schlosser, M. Marull, M. The direct metalation and subsequent functionalization of CFj-substituted pyridines and quinolines. Eur.J. Org. Chem. 2003, 1569-1575. 

A range of 2-aryl 3-substituted pyridine atropoisomers were obtained in 75-90% yields (aryl = phenyl, 2-methoxyphenyl, 2-phenoxyphenyl and 1-naphthyl) by orT/io-directed metallation with LDA (lithium diisopropylamide) - substitution (with RCOR or MeaSiCl), followed by reaction of the... 

Aqueous sodium hypochlorite is another low-priced oxidant. Very efficient oxidative systems were developed which contain a meso-tetraarylporphyrinato-Mn(III) complex salt as the metal catalyst and a QX as the carrier of hypochlorite from the water phase to the organic environment. These reactions are of interest also as cytochrome P-450 models. Early experiments were concerned with epoxidations of alkenes, oxidations of benzyl alcohol and benzyl ether to benzaldehyde, and chlorination of cyclohexane at room temperature or 0°C. A certain difficulty arose from the fact that the porphyrins were not really stable under the reaction conditions. Several research groups published extensively on optimization, factors governing catalytic efficiency, and stability of the catalysts. Most importantly, axial ligands on the Mn porphyrin (e.g., substituted imidazoles, 4-substituted pyridines and their N-oxides), 2 increases rates and selectivities. This can be demonstrated most impressively with pyridine ligands directly tethered to the porphyrin [72]. Secondly, 2,4- and 2,4,6-trihalo- or 3,5-di-tert-butyl-substituted tetraarylporphyrins are more... 

Once it was realized that heteroaromatic sulfonamides could be prepared and converted to sulfonylureas, and that these compounds possessed many of the desirable hebicidal qualities of the benzene sulfonylureas, a large synthetic effort was started to prepare more examples. Using thiophene and pyrazole as representative examples, we have been able to synthesize all of the positional isomers of the mono- and di-substituted sulfonamides. This paper will outline the major synthetic pathways that we have discovered, emphasizing directed metallation processes and nucleophilic substitution reactions, leading to the preparation of these heterocyclic sulfonamides. Many of tiie methods developed for thiophene and pyrazole sulfonamide synthesis have been extended to the synthesis of pyridine and other heteroaromatic sulfonamides. 

Transition metal complexes have been used in a number of reactions leading to the direct synthesis of pyridine derivatives from acyclic compounds and from other heterocycles. It is pertinent also to describe two methods that have been employed to prepare difficultly accessible 3-alkyl-, 3-formyl-, and 3-acylpyridines. By elaborating on reported194,195 procedures used in aromatic reactions, it is possible to convert 3-bromopyridines to products containing a 3-oxoalkyl function196 (Scheme 129). A minor problem in this simple catalytic process is caused by the formation in some cases of 2-substituted pyridines but this is minimized by using dimethyl-formamide as the solvent.196... 

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