N-substituted imidazoles

By far the most common starting material is l-methylimidazole. This is readily available at a reasonable cost, and provides access to the majority of cations likely to be of interest to most researchers. There is only a limited range of other N-substituted imidazoles commercially available, however, and many are relatively expensive. The synthesis of l-alkylimidazoles may be achieved without great difficulty, though, as indicated in Scheme 2.1-2. 

The mechanism of the reaction has not been eiuddated. Presumably iodine eliminates the imidazole ring from N-substituted imidazole derivatives such as clotrimazole, and this then couples with diazotized sulfanilic acid to yield an azo dye. 

Note The reaction is very specific for N-substituted imidazole derivatives. In serum investigations the detection limit was 50 ng clotrimazole per milliliter serum. The reagent can be employed on silica gel, kieselguhr and Si 50000 layers. 

With sUght modifications of these conditions it is possible to prepare mono N-substituted imidazoles (Scheme 5), the reaction working well with aliphatic amines but not with many aromatic amines. The imsymmetrical... 

Burgess followed a similar strategy for the preparation of the salts 8 (Scheme 7). On that occasion several routes to mono-N-substituted imidazoles were explored yielding the desired compoimds in variable yields depending on the nature of the amines. The chirality was introduced via alkylating reagents 9 bearing chiral oxazolines [15]. 

Gade and Bellemin-Laponnaz have reported the synthesis, in good yields, of chiral oxazoline-imidazoliums salts 10a (Scheme 8) obtained by reaction of 2-bromo-4(S)-t-butyl oxazoline with several mono-N-substituted imidazoles [16]. Similaly an imidazolium salt 10b bearing a paracyclophane substituent was prepared by Bolm [17]. 

Table 3-4. Acylation of 4-methyl-2-pentanol with acetic anhydride to produce the acetate, with the indicated N-substituted imidazoles as catalysts. 1451...

Table 20-1. N-Substituted imidazoles and triazoles prepared by transfer reactions of azolides A—F with tertiary alcohols of the triphenylmethanol type and analogues.

Reports of [ 2 + 2] cycloaddition of nitrogen containing heterocycles to alkenes are so numerous that attention can be drawn here to only a few. Recent examples include the acetone-sensitized photoaddition of 4-oxazolin-2-one (248) to ethylene to give the cis-adduct 249,203 the photocycloadditions of N-substituted imidazoles to acrylonitrile204 and of N-methyl-4-hydroxy-quinol-2-one to cyclohexene,205 and the photoaddition of pentafluoro-pyridine to ethylene to give the 1 1- and 1 2-adducts 250 and 251,... 

The microwave activation of Michael additions in the preparation of N-substituted imidazoles afforded excellent yields in very short reaction times under mild reaction conditions, Scheme 10.9. Basic clays (Li+, Cs+) exchanged montmorillonites were found to be very active and selective catalysts for the Michael addition of imidazole and ethyl acrylate [54]. 

By analogy with oxazoles and N-substituted imidazoles, thiazoles and benzothiazoles unsubstituted at C-2 undergo direct metalation at that position, with sodium, lithium, or magnesium reagents (Scheme 91)[79MI1 ... 

Generally speaking, 2-aminothiazoles, -oxazoles, and N-substituted imidazoles react with or-halogenoketones more easily than NH compounds, though 2-amino-4,5-dimethyloxazole and 3-amino-l-methyl-4-phenylpyrazole are reported214 not to undergo the Tschitschibabin reaction. 

The 4-proton chemical shifts in the NMR spectra of 1,3,5-trisubstituted pyrazoles correlate with Lo, indicating that such effects are electronic rather than anisotropic,360 while correlations for the PMR spectra of antiparasitic 2-(substituted styry 1)-5-nitro-N-substituted imidazoles have also received attention.361... 

N-propinylazoles of the BAY d 9603 type have a close structural relationship to the tritylazoles. They have a wide range of activity, particularly effective against mould fungi. Starting material here is the readily available diphenyl-propinol obtained by ethinyla-tion of benzophenone. The method for the conversion of this carbinol into the corresponding N-substituted imidazole is the reaction with carbonyl or thionyl-bis-imidazole, or preferably with the tris-imidazolide of phosphoric acid in a polar solvent. All other alkylation methods in which carbocations occur as intermediates completely fail. 

Iwasaki, S. (1976) Photochemistry of imidazolides. I. The photo-Fries-type rearrangement of N-substituted imidazoles. Helvetica Chimica Acta, 59 (8), 2738-2752. 

An interesting application of PET mediated bond cleavage reaction from azirine 63 has been reported by Mattay et al. [67] for synthesizing N-substituted imidazoles (65) via the (3 + 2) cycloaddition reaction of resultant 2-azaallenyl radical cations with imines 64. Synthesis of pyrrolophane 3,4-dimethyl ester (68) has been reported recently [68] by the ring opening of 66 followed by inter-molecular cycloaddition with dimethyl acetylene dicarboxylate (67) as shown in Scheme 13. 

Imidazoles substituted in the 1-position can be hydroxymethylated at C-2 with formaldehyde or paraformaldehyde,400,401 whereas imidazoles unsubstituted at N-l are hydroxymethylated at C-4 or C-5. For example, 4-methylimidazole yields 4-methyl-5-hydroxy-methylimidazole.402 If there is a deactivating substituent in the ring (e.g., 4-nitroimidazole) hydroxymethylation will not take place. Thermal condensation of N-substituted imidazoles with other aldehydes (except acetaldehyde) or the reaction of aldehydes with 2-lithioimidazoles results in the formation of 2-hydroxyalkylimida-zoles.210... 

Catalysis arising solely from hydrophobic interactions between the reactants in model systems has been investigated recently by Knowles and Parsons (1967, 1969). The effects of hydrophobic interactions on the rate of hydrolysis, aminolysis, and imidazole-catalyzed hydrolysis of p-nitrophenyl esters were elucidated by varying the hydrocarbon chain length of the -nitrophenyl ester, the primary amine, and the N-substituted imidazole and determining the second order rate constants at concentrations well below the CMCs of the reactants, conditions under which cationic (amine) and neutral (ester) micellar catalysis is... 

The epoxide method can be used with epoxides of acyclic [ 165-168] and cyclic [169-172] alkenes with a visible bias for cyclohexene oxide as the epoxide of choice. The epoxide is usually reacted with unsubstituted imidazole creating a neutral molecule. If the epoxide is reacted with an N-substituted imidazole, a zwitterionic molecule is created as the hydroxide functional group in the sidearm lacks the imidazole NH hydrogen atom to be proto-nated. In this case, addition of one equivalent of acid provides protonation to the alcohol and the counteranion for the formation of the imidazolium salt. 

Incorporation of a furan moiety as a carbene wingtip group was introduced by Nielsen et al. The synthesis is facile enough starting with a bromination (NBS) of 2,5-dimethyl-furan and subsequent reaction with two equivalents of N-substituted imidazole to yield a bis-imidazolium furan [187] (see Figure 3.67). 

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]. 

A totally different approach to bis-carbene ligands on a cyclic scaffold comes from Burgess and coworkers [351], They start from AA -dimethyl-l,2-diaminocyclohexane and acetylate this compound with chloroacetic acid chloride. Addition of an N-substituted imidazole yields the chiral bis-imidazolium salt (see Figure 3.110). Reaction with silver(I) oxide and carbene transfer to palladium(II) completes the reaction sequence. 

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. 

Moore et al. [274] introduced a sulfonato functionality into a NHC wingtip group to make the resulting transition metal carbene complexes water soluble. Introduction of the functional group was achieved in a modification of the epoxide method previously used by Arnold et al. [33] and Glas et al. [12] for the synthesis of alkoxide functionalised carbenes (see Section 4.1). Reaction of an N-substituted imidazole with... 

In addition, there exists a group of carboxylic acid functionalised carbene ligands that have the appearance of being derived from the amino acid glycine, but their synthesis was actually achieved by quartemising N-substituted imidazole with a bromoacetic acid ester [71,72], A representative example for this synthetic route is presented in Figure 6.29. 

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