Metalation, directed, of pyridines

Mass spectral techniques in heterocyclic chemistry applications and stereochemical considerations in carbohydrates and other oxygen heterocycles, 42, 335 Mass spectrometry of heterocyclic compunds, 7, 301 of nucleic acids, 39, 79 Medium-large and large 7r-excessive heteroannulenes, 23, 55 Meso-ionic compounds, 19, 1 Metal catalysts, action on pyridines, 2, 179 Metalation, directed, of pyridines, quinolines, and diazines, 52, 187... 

In the metalation reaction of pyridine 5 with tBuLi the methoxy substituent exhibits a directing effect. Solvated (tBuLi)4 aggregate 19 coordinates to the oxygen of the methoxy group to give 20. Successive deprotonation yields the ortljo-lithiated species 21, which is stabilized by 0-Li coordination. 

Heteroaromatics LDA (and LiTMP) are advantageous bases for the directed ortto-metalation chemistry of pyridines and, to a much lesser extent, pyrimidines.Several halopyridines can be lithiated ortho to the halo substituent and trapped with various electrophiles (eq 55). ... 

High-valency metal fluoride fluorination of pyridine [82JFC(21)171], quinoline [82JFC(21)413], and 2-methylfurans [91 JFC(51)179] has been reported. With 2-methylfuran a complex mixture of stereoisomers of partially fluorinated oxolans was obtained. These can be dehydrofluorinated to fluorooxolens and no furans have been observed. Conformation and structural group were found to influence the direction and readiness toward dehydrofluorination [91 JFC(52) 165]. 

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>. 

Silicon linker 76 was used for direct loading of aromatic compounds to supports for the assembly of pyridine-based tricyclics (Scheme 39) [87], Following the initial coupling of an aromatic bromide to the resin by halogen/metal exchange in the presence of tert-butyl lithium, a... 

In recent years, a variety of aryl boronic acids are commercially available, albeit in some cases they may be expensive for large scale purposes. During our work in the mid-1990 s boronic acid (II) was not commercially available and so two different protocols were used to prepare this acid. The first approach involved the transmetallation with n-butyl lithium of aryl bromide (I) and trapping the lithio species generated with trialkyl borate followed by an acid quench. Aryl bromide (I) is easily prepared by reaction of o-bromobenzenesulfonyl chloride with 2-propanol in the presence of pyridine as a base. The second approach was a directed metallation of isopropyl ester of benzene sulfonic acid (VII), to generate the same lithio species and reaction with trialkyl borate. The sulfonyl ester is prepared by reaction of 2-propanol with benzenesulfonyl chloride. From a long-term strategy the latter approach is... 

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... 

CHLOROCYCLOBUTANE, 51, 106 Mesitylene, cyanation, 50, 54 METHALATION OF 2-METHYLPYRIDINE DERIVATIVES ETHYL 6-METHYL-PYRIDINE-2-ACETATE, 52, 75 Metalation, directed, 53, 59 Methallyl alcohol, with phenyl-mercuric acetate to yield 2-methyl-3-phenylpropional-dehyde, 51, 17 METHALLYLBENZENE, 52, 115 7r-Methallylnickel bromide, 52, 115... 

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). 

The direct metalation of pyridine has been achieved by the use of a 1 1 mixture of -BuLi and r-BuOK (84CC257, 84JOC3857), with a mixture of... 

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