Pyridine, 4- -, lithiation

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). 

In a recently reported synthesis of pyridines, lithiated methoxyallenes react with nitriles in the presence of trifluoroacetic acid (Scheme 107) <2004CEJ4283>. The mechanism is postulated to proceed via initial protonation followed by nucleophilic addition of the trifluoroacetate ion with subsequent intramolecular acyl transfer and aldol condensation to give the pyridine. An additional pyridine formation starting from azaenyne allenes forms a-5-didehydro-3-picoline diradicals, which can be trapped by 1,4-cyclohexadiene, chloroform, and methanol to produce various pyridines <20040L2059>. 

A major advance in pyridine lithiation is the use of the mixed base produced from two mole equivalents of -butyllithium with one of dimethylaminoethanol, i.e., it is a 1 1 mixture of -BuLi and Me2N(CH2)2OLi (BuLi-LiDMAE) structure 367 shows how this regioselective -lithiation is believed to occur. <2002EJO3375, 2003JOC2028>. 

Chloroperoxidase catalysis by, 58, 302 in chlorination of pyrazoles, 57, 337 Chlorophyll, thioaldehyde synthetic intermediate to, 55, 3 Chlorosulfonyl isocyanate, reaction with 2-arylhydrazono-3-oxobutanoate, 59, 148 Chromatography, of [l,2,4]triazolo[l,5-a]-pyrimidines, 57, 106 Chrom-3-enes, see 2//-l-Benzopyrans Chromium tricarbonyl complexes of 3,5-diphenyl-l-(alkyl- or oxido-)-thiabenzenes, 59, 206, 227 indoles, lithiation of, 56, 181, 184 of pyridine, 58, 160 pyridines, lithiation of, 56, 230, 239 of 2f/-thiopyrans, 59, 227 Chromones, see l-Benzopyran-4-ones Cinnamonitrile, a-cyano-, condensations with thio-, seleno-amides, 59, 184, 186 Cinnoline, nitration, MO calculation, 59, 302... 

Reaction of lithiated allene with methoxymethyl isothiocyanate afforded 107, after trapping with methyl iodide. The newly formed 107 isomerizes under mild conditions to triene 108. This compound is ideally setup to experience an electrocyclization to dihydropyridine 109. Heating in the presence of acid facilitates aromatization of 109 to pyridines 110. 

The lithiation of 2-F- and 3-F-pyridines has been investigated with different reagents and reaction conditions. 

Conversions of diazonium salts into halogenated derivatives have been reported for compounds of type 128 and 129 [73JCS(P1)2901 80JCS(P 1)2398], Although some 7-substituted pyrazolo[ 1,5-u]pyridines have been made from the lithiated precursors, no halogeno products have been reported (92JOC5538). 

It was not possible to brominate the [l,2,4]triazolo[l,5-a]pyridine species (137) directly with bromine or NBS, but the 5- and 8-bromo (66CPB523) and 3-chloro (66JOC265) derivatives were made from the diazonium salts. More recently regiospecific 5-lithiation of 137 has provided access to the 5-bromo derivative in 94% yield (92JOC5538). 

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>. 

Lithiation of 3,5-dibromopyridine with IDA and subsequent reaction with electrophiles provide 4-alkyl-3,5-dibromopyridines in high yield <96TL(37)2565>. The synthesis of aza-anthraquinones 39 via metallation of the pyridine ring of 38 was reported by Epsztajn <96T(52)11025>. 

Carbene complexes have also been prepared by transmetallation reactions. Lithiated azoles react with gold chloride compounds and after protonation or alkylation the corresponding dihydro-azol-ylidene compounds, e.g., (381) or (382), are obtained.22 9-2264 Silver salts of benz-imidazol have also been used to obtain carbene derivatives.2265 Mononuclear gold(I) carbene complexes also form when trimeric gold(I) imidazolyl reacts with ethyl chlorocarbonate or ethyl idodate.2266,2267 The treatment of gold halide complexes with 2-lithiated pyridine followed by protonation or alkylation also yields carbene complexes such as (383).2268 Some of these carbene complexes show luminescent properties.2269-2271... 

Electrophilic cyclization of the precursors 8, which are available from 3-(methylthio)pyridine by regioselective lithiation, followed by introduction of CBr4, and a subsequent Sonogashira coupling, has resulted in a series of thieno[3,2-b]pyridines 9... 

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