Pyridin-4-ones lithiation

Polysubstituted pyridines can be generated by the regioselective addition of lithiated /3-enaminophosphonates to unsaturated carbonyl compounds. This variation on the classic condensation reaction can also be obtained using a one-pot reaction of metallated phosphonates and sequential addition of nitriles and unsaturated carbonyl compounds (Equation (169) Table 8) <1996TL4977>. 

Blocking either the 2- or 4-position allows lithiation at the other LDA or BuLi can be used to 4-lithiate the 2-blocked 3-fluoropyridines 319,284 320285 and 321,286 287 and BuLi 2-lithiates the 4-blocked 3-fluoropyridine 322.284 288 289 Note the selectivity for removal of the acidified pyridine protons in 321 and 322 over the coordination-activated ones adjacent to the pivalanilide group. A double orthodirecting effect ensures 4-lithiation of 323.290... 

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... 

Albanese, D., Penso, M., Zenoni, M. A practical synthesis of 4-chloro-3-(hydroxymethyl)pyridine by regioselective one-pot lithiation/formylation/reduction of 4-chloropyridine. Synthes/s 1999, 1294-1296. 

Direct lithiation of pyridine is a common method of generating the precursors required for the organopalladium cross-coupling reactions. However, if one is not carefiil, the pyridine ring is susceptible to direct addition of the alkyllithium reagent (Chichibabin reaction) as opposed to deprotonation of the ring. 

The iodo-fluoro-pyridine 119 is lithiated by LDA to give the only possible lithium derivative 120. But iodine is a poor ortho-director and the compound equilibrates by the halogen dance to put the Li atom next to one of the best orffto-directors fluorine.14 Presumably one molecule of 120 removes I from 119 to give 123 from which the 3-1 atom is removed by another molecule of 120 initiating a chain. 

Benzene-ring-lithiated intermediates can be prepared by metal-halogen exchange, even, in the case of indoles, without protection of the NH, i.e. it is possible to produce an N,C-dimetallated species (20.5.2). The 1,3-azoles lithiate very readily, at C-2. One may understand this in terms of a combination of the acidifying effects seen at an a-position of pyridine (both inductive and mesomeric electron withdrawal) with that at the a-positions of thiophene, furan and pyrrole (inductive only). 2-Substituted-l,3-azoles generally lithiate at C-5 °... 

Lithiation of 2- and 4-t-butoxycarbonylaminopyridines can only take place at C-3 a neat sequence involving, hrst, ring hthiation to allow introduction of a methyl group and, second, side-chain methyl hthiation (8.10), provides one route to azaindoles (20.16), as illustrated below for the synthesis of 5-azaindole (pyrrolo[3,2-c]pyridine)." ... 

Lithiated pyridines can be converted into boronic acids, or esters, one example being shown below. ... 

The general pattern is the same if a gold halide is reacted with 2-lithiated pyridine followed by a protonating or an alkylating agent416. Both the gold pyridyl trimer417,418 which precipitates upon treatment with one molar amount and the aurate which forms with an excess of 2-pyridyl lithium may be protonated, but only the latter can be alkylated readily (Scheme 35). 

Aqueous titanium (III) chloride reductively removes cyano and halo groups from substituted pyridines by a two-electron process and promotes reduction of pyridyl ketones and aldehydes to glycols by a one-electron-transfer process.49 a useful review of the reactions of halopyridines with lithiating reagents is now available.50 Choice of reaction conditions can be critical thus, depending on the conditions, 3-fluoropyridine can be converted into either 2- or 4-lithio-3-fluoropyridine and therefore be used as a precursor of both 2,3- and 3,4- disubstituted pyridines. 

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