Benzimidazole, 1- lithiation

The benzo-1,3-azoles (blocked or protected on nitrogen in the case of benzimidazoles) lithiate at the hetero ring 2-position. This allows reaction with the usual range of electrophiles the examples " below show the introduction of iodine (followed by a palladium(0)-catalysed coupling with a boronic acid) and silicon (then the formation of a tris(benzothiazol-2-yl)phosphine). 

Synthesis of 2-Substituted Benzimidazoles via o-Lithiation of N-Protected Derivatives... 

Other 1,3-diazaheterocycles related to the benzimidazole system that can be lithiated include purine nucleosides 53-55 and the related cordy-cepin analogs 56, which undergo lithiation with LDA at the 8-position when the ribose or deoxyribose hydroxy groups, are suitably protected (87CPB72 89JHCI89). Some aspects of the nucleoside metalation work have been recently reviewed (89MII). 

Aza-analogs of benzimidazole have also been successfully lithiated in combination with removable protecting groups, and thus the lithiated I-SEM derivative of 7-azabenzimidazole 57 gave a 93% yield of the 2-... 

Substituted benzimidazoles are readily lithiated in the 2-position (88KGS147). 

V. Metallation. Benzoxazole (83JOM159), benzothiazole (85H-295), and benzimidazole (76CHE1399) are each lithiated in the expected 2-position. In magnesiation with EtMgBr, the reactivity order at the 2-positions was benzothiazole > 4- and 5-chloro-l-methylimidazole > 1-methylbenzimidazole >> 1-methylimidazole (69JGU1816). 

Substituted benzimidazoles are readily lithiated in the 2-position, for example, the 2-iodo <20030L3209, 2003TL8967> and 2-chloro derivatives <2004JOC8115, 2004SL1306, 2005H(65)2721> can be prepared in this way. ... 

Benzimidazole, direct lithiation, 56, 163 Benzimidazoles, N-protected, lithiation. 56, 204... 

Butyllithium reacts with 1,2-dimethylimidazole at -80 °C to lithiate the 2-methyl group, and at higher temperatures some 5-metalation also occurs (74JOC2301). Reaction of 2-methyl-, 5-chloro-2-methyl- and 2-benzyl-benzimidazoles with two molar equivalents of butyllithium in THF-hexane at 0 C results in dilithiation, although subsequent reactions at the side-chain carbanion centre also take place (Scheme 96) (73JOC4379). 

To benzimidazole (1.57 g, 13.3 mmol) in a two-necked flask is added THF (40ml) at 20°C, to give a suspension. Formaldehyde (1ml, l.Oeq., 37% aqueous solution) is then added at 20 C to give a homogeneous solution. After 5 min TLC (silica gel-ethyl acetate) shows that all of the benzimidazole has been consumed and 1-hydroxymethylbenzimidazole has been formed. The solvent is rotary evaporated and the residue is dried in vacuo (24 h). Paraformaldehyde (leq.) in THF under argon can replace the formalin solution. TTie hydroxymethylbenzimidazole can be used without further puriheation in lithiation processes. 

Protected benzimidazoles are smoothly lithiated in the 2-position by LDA, n-hutyllithium and t-hutyllithium. Particularly useful are metallations of benzimidazoles protected by formaldehyde as hemiaminals, or as the 1-(lV,A -dialkylamino)methyl derivatives. Reaction with a variety of electrophilic reagents, followed by acid-catalysed deprotection under mild conditions, leaves the 2-substituted benzimidazoles [31, 32]. 

The chemical shifts of 2-lithiated imidazoles in THF-r j range from 195.9 ppm to 216.1 ppm for compounds 51-54 (Figure 13). Simple imidazoles such as 51-53 exist as the ring form even at 20 °C, whereas benzimidazole exists as a mixture of ring 54a and chain 54b, 8q2 158.4 ppm) tautomers. The nature of the lithiated species (carbene, carbenoid, or simple carbanion) is not easily discerned based on the chemical shifts <1997CB1213>. 

A review on the metaiation and metal-h ogen exchange reactions of imidazole appeared in 1985. Generally, A -protected imidazoles metalate at the 2-position 1,2-disubstituted imidazoles usually met-alate at the 5-position, unless sterically hindered. Even 2,5-dilithiation of imidazoles has been achieved. 1-Substituted 1,3,4-triazoles can be metalated at the S-position and added to carbonyls in good yield. Oxazoles are easily lithiated at the 2-position, but the resultant anion readily fragments. l-(Phenylthiomethyl)benzimidazole can be lithiated at the 2-position at low temperature (Scheme 21), but higher temperatures afford rearrangement products. ... 

Imidazoles and benzimidazoles with a free NH group are weak acids, but sufficiently acidic to be able to form anions in the presence of strong bases <87AHC(4l)l87,88CHE469). This property becomes important in transformations sueh as 7V-alkylation and metallation. Whereas most metal salts hydrolyze very readily in aqueous media, they can be prepared and isolated from anhydrous aprotic solvents. Thus, Af-lithiated imidazoles, prepared under such conditions, react in turn with copper(I) cyanide and an alkyllithium to give cuprates [R(Im)Cu(CN)Li2] which are useful carbanion sources <92TL1041>. Some determined acid values appear in Table 6. 

Nucleophilic attack at C-2 or H-2 is also enhanced by benzannelation (e.g., lithiation takes place there). The 2-proton is quite acidic as is a 2-methylene group. Indeed 2-methylbenzimidazole may be metallated at the methyl group <86CHE868>, and in the presence of base 2-cyano-methylbenzimidazole is both N- and C-alkylated (exocyclically) <88CHE28l>. Detritiation at the 2-position of benzimidazole occurs 10 to 20 times faster than in imidazole <86CJC1240). 

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