Imidazoles 2-lithiation

Imidazole, l-ethoxymethyl-2,4,5-tribromo-lithiation, S, 416 Imidazole, 2-ethyl-chlorination, S, 398 Imidazole, 4-ethyl-synthesis, S, 484 Imidazole, N-ethyl-synthesis, S, 108... 

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... 

Imidazolylboronic acids are not well known. 5-Imidazolylboronic acid was prepared in situ by Ohta s group using selective lithiation at C(5) from 1,2-protected imidazole. However, the subsequent Suzuki coupling with 3-bromoindole gave the expected indolylimidazole in only 7% yield [18]. This observation indicated that more investigation into imidazolylboronic acids is necessary to better understand their synthesis and behavior. 

Synthesis of 2-Substituted Imidazoles via a-LiTHiATiON of N-Protected Derivatives... 

The dimethylaminomethyl group (entry 9) is easily introduced by a Mannich reaction, and lithiation occurs readily at -78°C (88JOC5685). After reaction with a variety of electrophiles, hydrolysis can be performed directly with aqueous acid to give 2-substituted imidazoles in good yield. However, the 2-lithio anion 47 was found to be quite basic, despite the base-weakening effect of coordination with the amino substituent, and thus it was capable of deprotonating the 2-butyl derivative 48 as it was formed by reaction with 1-bromobutane (Scheme 42). No such side-reac-... 

Lithiation and substitution of the benzyl derivative (entries 1-3) at C-5 normally occur readily at -78°C however, as with the analogous imidazole, substitution at the exocyclic methylene occurs in preference when... 

The synthesis of losartan potassium (1) by the process research chemists at Merck is outlined in the following (Griffiths et ak, 1999 Larsen et al., 1994). Phenyltetrazole (8) is protected as the trityl phenyltetrazole 9 (Scheme 9.3). Ortho-lithiation of 9 followed by quenching with triisopropyl borate afforded boronic acid 10 after treatment with aqueous ammonium chloride. Reaction of glycine (11) with methyl pentanimidate (12) in a methanol/water mixture yielded (pentanimidoylamino) acetic acid (13), which underwent a Vilsmeier reaction with phosphorous oxychloride in DMF followed by hydrolysis to give imidazole-4-carbaldehyde 14 in moderate yield. 

Careful choice of reaction conditions also allows 2-lithiation of imidazoles even in the presence of groups susceptible to attack by the reagent. At -100°C in THF 4,5-dicyano-l-methylimidazole forms the 2-lithio compound at -80°C butyllithium attacks one of the nitrile functions (92JHC1091). 1-Alkoxyimidazoles are lithiated by n-butyllithium (THF, -78°C) at the 2-position (98JOC12). 

A flexible means of access to functionalized supports for solid-phase synthesis is based on metallated, cross-linked polystyrene, which reacts smoothly with a wide range of electrophiles. Cross-linked polystyrene can be lithiated directly by treatment with n-butyllithium and TMEDA in cyclohexane at 60-70 °C [1-3] to yield a product containing mainly meta- and para-Iithiated phenyl groups [4], Metallation of noncross-linked polystyrene with potassium ferf-amylate/3-(lithiomethyl)heptane has also been reported [5], The latter type of base can, unlike butyllithium/TMEDA [6], also lead to benzylic metallation [7]. The C-Iithiation of more acidic arenes or heteroar-enes, such as imidazoles [8], thiophenes [9], and furans [9], has also been performed on insoluble supports (Figure 4.1). These reactions proceed, like those in solution, with high regioselectivity. 

Starting from the moment that lithiated imidazoles where used in the synthesis of substituted imidazoles attempts have been made to transmetallate them into organozinc53, organocopper and organopalladium56 species. These transmetallations are a further extension of the scope of the organometallic methods (figure 14). 

The catalytic asymmetric rearrangement of functionalized cyclohexene and cyclopentene oxides to give chiral allylic alcohols has been studied using sub-stoichiometric amounts of a chiral lithium amide in combination with a stoichiometric amount of different lithiated imidazoles (Scheme 47).79... 

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