Imidazole functionalisation

The synthesis of Fc-modified imidazolium salts, as precursors for the carbene ligands, usually involves the reaction of a (substituted) imidazole with a ferrocenylmethyl halide [166], a classic route for functionalised NHC, the reaction of a (substituted) imidazole with ferrocenylmethyl trimethylammonium halide [166-170], the reaction of an imidazole functionalised diazonium salt with ferrocene [144] or the formation of the inudazole ring using hydroxymethylferrocene [171] or ferrocenylmethylamine [168] as starting materials (see Figure 4.45). 

Several imidazole functionalised dimethoxytrityl protecting groups have been investigated for their ability to catalyse internucleoside bond formation using phosphate triester chemistry. 

Schuster, M., Roger, T., Noda, A., Kreuer, K.D., Maier, J., About the choice of the protogenic group in PEM separator materials for intermediate temperature, low humidity operation A critical comparison of sulfonic acid, phosphonic acid and imidazole functionalised model compounds Fuel Cells, in press (2005). 

H). On the other hand, the synthesis of unsymmetricaUy iV,iV -substituted congeners is less straightforward as a functionalised imidazole has to be isolated prior to alkylation or arylation. Two main methods are available for imidazole functionaU-sation deprotonation with metalUc Na or K leading to an imidazoUde (I) followed by reaction with RX or reaction of glyoxal with a primary amine, an ammonium salt and formaldehyde (J). Al-functionalised imidazole can then be alkylated or... 

SYNTHESES OF IMIDAZOLES VIA DIRECT FUNCTIONALISATION OF THE IMIDAZOLE RING... 

For the functionalisation of the C5 position of the imidazole nucleus much stronger basic conditions are needed than for the functionalisaation of the C2 position. The hydrogen atom on the C5 position has a much weaker acidity than the hydrogen atom on the C2 position. Therefore, functionalisation of the C5 proved to be much more difficult and requires the use of an additional protective group for the C2 position if 4(5) mono-substituted imidazoles are desired (table 2). 

The trityl-, dimethylsulfamoyl- and the SEM-groups work best for NH protection in the C5 functionalisation of the imidazoles. Protective groups for the C2 position such as the... 

In conclusion, the deprotonation approach to functionalise imidazoles has proved to be feasable and constitutes a new flexible method for the preparation of especially 4(5)-mono-substituted imidazoles in a straight forward manner (figure 12). 

The field of imidazole chemistry is still full of new and exciting developments. Both in the field of condensation approaches as in the direct functionalisation with the aid of organometallic reagents many new methods and approaches have emerged in the last decade. The use of a solid phase synthesis approach proved to be possible and it is exciting see what the future might bring in this respect. 

A method with an enormous potential for dextran modification is the homogeneous one-pot synthesis after in situ activation of the carboxylic acids with CDI, which is a rather well known technique in general organic chemistry and was published in 1962 [ 197]. It is especially suitable for the functionalisation of the biopolymers, because during conversion the reactive imidazolide of the acid is generated and only CO2 and imidazole are formed as by-products (Fig. 29). 

Finally, there are a few examples where task-specific ionic liquids have been employed. These examples encompass an imidazolium ionic liquid with a chiral alkyl chain used to induce chirality,[13] an imidazole-imidazolium liquid which acts as both ligand and solvent[14] and a nitrile-functionalised pyridinium ionic liquid which also serve as ligand and solvent.[15] The application of these specific solvents is discussed in greater detail below. 

Linker-free oxazoline functionalised NHC can be synthesised using a modular approach. In this modular approach, a standard aUcyl or aryl substituted imidazole (module 1) is reacted with a 2-halo substituted oxazoline (module 2) to form the corresponding oxazoline functionalised imidazolium salt (see Figure 3.25). In a second step, the oxazoline functionalised NHC can then be reacted with a suitable metal precursor to form the corresponding transition metal carbene complex [93,98,102] (see Figure 3.26). 

In order to prevent enamination, different strategies can be employed. The easiest way is to eliminate the extra CH unit that causes enamination in the first place. To this effect, imino functionalised imidazolium salts were developed that have the imino functionality directly attached to the imidazole ring of the NHC unit (see Figure 3.37). 

Note Esterification of the hydroxy functionalised imidazole was achieved by an enzyme catalysis reaction (C. antarctica) [173-175],... 

Yang et al. used a similar protocol (an ether functionality supported on a primary alkyl halide carrier) to introduce an acetal on either side of the imidazole ring generating an ether functionalised ionic liquid (IL) imidazolium salt [183] (see Rguie 3.58). The anion could be varied without loss of the IL property (melting point below 1(X) °C) [184]. Synthesis of the transition metal carbene complexes (palladium) was done by carbene transfer ftom the corresponding silver(I) complexes or by reaction with the metal acetate (nickel) [162] (see Figure 3.64). 

A few years earlier, Herrmann et al. published a carboxylic ester functionalised imi-dazolium salt that was synthesised directly from imidazole and bromoacetic acid ethyl ester [216]. Owing to its method of synthesis the imidazolium salt is C -symmetric with two ester functional wingUp groups. Generation of the rhodium(I) and palladium(II) carbene complexes was realised by reaction of the imidazolium salt with a rhodium alkoxide precursor or with palladium(II) acetate in the presence of NaOEt and Nal (see Figure 3.76). The silver(I) oxide method had not been discussed in the literature at the time [11]. 

Having introduced the golden rule of phosphine chemistry to its carbene analogues we will proceed to break it several times in the following brief sununary of routes to synthesise phosphino functionalised carbenes. The best way to synthesise an imidazolium salt is to react an N-substituted imidazole with an alkyl or aryl halide [235], Thus, it is a good idea to utilise a functionalised alkyl halide. The functional group can then be used to introduce the phosphino group. 

Examples for o-phenylene scaffolds for bis-carbene ligands come from the research groups of Peris [344,345] and Herrmann [346]. Synthesis of the bis-imidazolium salt is achieved by reaction of a,a -xylene dichloride and the N-substituted imidazole. The rhodium(l) and iridinm(I) complexes can then be made by addition of the imidazolium salt to a solution of [M(cod)Cl]2 (M = Rh, Ir) in ethanol or acetonitrile (with NEtj as auxiliary base) (see Figure 3.108). The rhodium complexes were used successfully in the hydrosi-lylation of styrene [344] whereas both the rhodium and iridium complexes were used for the direct borylation of arenes making functionalised arylboronic acid esters accessible by a simple one-pot reaction [346]. 

It seems that the racemic mixture of A-hydroxycyclohexyl imidazole is used in further reactions, normally even without mention of chirality [14,15]. Double functionalisation is facile, as the two wingtip groups need to be introduced stepwise. Ray et al. [14] used this opportunity to introduce a keto group in the second step by reacting iV-hydroxycyclohexyl imidazole with chloracetophenone (see Figure 4.2). 

The epoxide can provide another reactive functional group in order to engage two imidazole molecules in simultaneous quartemisation reactions thus producing a hydroxy functionalised bis-imidazolium salt that can be used as a tridentate ligand. Such an example was reported by Arnold et al. in the reaction between 2 equiv. of A-tert-butyl imidazole and... 

Note Functionalisation of a carbene with a hydroxy group on a variable length tether can be effected by reaction of an N-substituted imidazole with a bromo-alkanol. 

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