Imidazole with diazonium salts

Chemical evidence for the structure of imidazol-4-ones has been summarized,although rather different conclusions would now be drawm from this evidence. For example, in the light of present knowledge, the ease with which imidazol-4-ones react with diazonium salts suggests that an appreciable amount of the 4-hydroxyimidazole exists... 

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). 

The dyes formed when imidazoles couple with diazonium salts (Section 4.07.1.4.8) in alkaline medium could exist as the usually accepted azo form (95 R = H) or the hydrazone form (96). Comparison of the UV and visible spectra of the dyes with a non-tautomeric model (95 R = Me) demonstrated unequivocally that if such an equilibrium as shown in Scheme 32 exists, then the azo structure predominates (79BAP249). 

In reactions of the imidazole neutral molecule or cation, attack by electrophiles at C-5 is preferred. However, when there is a free NH in the ring, tautomerism makes the 4- and 5-positions equivalent. Conditions in which the imidazole anion exists are reported to be characterized by electrophilic substitution at C-2. There would appear to be exceptions to this generalization, e.g. halogenation (Section 4.07.1.4.5). When the preferred positions are blocked it is usually possible to induce electrophiles to enter alternative ring positions and multiple substitution is commonly possible. In fact it is difficult to prepare mono-bromoimidazole, and imidazole can be dinitrated. More than one benzeneazo group can couple when imidazole reacts with diazonium salts. 

Under alkaline conditions, alkyl nitrites nitrosate imidazoles which possess a free NH group in the 4-position (70AHC(12)103). Nitrosation of 3,5-dimethylpyrazole gives the 4-diazonium salt by further reaction of the nitroso compound with more NO". 5-Pyrazolinones are often nitrosated readily at the 4-position. 3-Alkyl-5-acetamidoisothiazoles undergo 4-nitrosation. 

Aromatic diazonium salts react easily in neutral aqueous solution with thiols such as N-acetylcysteine, forming compounds of the type Ar — N2 —S —CH2CH(NHAc) COOH. Nifontov et al. (1990) suggested that such compounds, e.g., that of 5-diazo-imidazole-4-carboxylate, function as a form of transport depot for cytotoxic diazo-carboxylate in the human body. 

In Brown s classification a diazonium ion is a reagent of very low reactivity and correspondingly high substrate selectivity and regioselectivity. This follows from the fact that benzenediazonium salts do not normally react with weakly nucleophilic benzene derivatives such as toluene. More reactive heteroaromatic diazonium ions such as substituted imidazole-2-diazonium ions will even react with benzene (see Sec. 12.5). 

Imidazole-2-diazonium fluoroborate is an irreversible blocker of the phencyclidine binding site of the nicotinic cholinergic receptor, and it is only effective when the receptor is in a desensitized state, at variance with other aryldiazonium salts (85MI1). 

Reaction of lH-imidazole-4-carboxilic acid amide with nitrous acid leads to the diazonium salt (5-diazenyl-l-H-imidazole-4-carboxilic acid amide). Condensation of the diazonium salt with methylisocyanate leads to initial formation of unstable urea which cyclizes under the reaction condition to give 3,4-dihydro-3-methyl-4-oxoimidazo(5,l-d)-l,2,3,5-tetrazine-8-carboxamide (temozolomide). 

Diazonium salts of both 2- and 4-aminoimidazoles have been prepared, with a strongly acidic medium being preferred for the reactions. On occasion it is possible to isolate the intermediate nitrosoamines which are resistant to the action of dilute acid on storage, but which are subject to denitrosation when heated in alcohol solutions. The nitrosoamines can be converted into the diazonium salts. Diazonium fluoroborates have proved synthetically valuable for they can be transformed into the 2-nitro-, 2-azido- and 2-fluoro-imidazoles (80AHC(27)24l). The derived diazonium salts are also capable of coupling reactions (Scheme 118) (72CHE1533). 

Perhaps more useful are the transformations of diazonium salts. Imidazole-2-diazonium fluoroborate can be converted into the 2-fluoro- and 2-nitroimidazoles, the former by heating or photolysis, the latter with sodium... 

The CH2 group of co-imidazol-l-yl)acetophenone 1004 is sufficiently activated by the carbonyl and the imidazole group that it readily reacts with aldehydes, aromatic diazonium salts (to form diazo compounds) and acrylonitrile. The reaction of 1004 with phenyl isothiocyanate in the presenceof KOH results in the formation of adduct 1005 that is not isolated but further condensed with phenacyl bromide to afford thienylimidazole 1006 in 87% yield (Scheme 241) <2003SC153>. In the presence of a 2-sulfanyl group 1007, the enolate of ot-imidazolyl acetophenone 1008 no longer reacts with aldehydes or even alkyl halides except for Mel 1009 <200282691 >. 

The reaction of diazonium salts with aqueous solutions of 1,2-diaminocyclohexane mixed with formaldehyde affords the l-[2-aryl-l-diazenyl]-3-( 3-[2-aryl-diazenyl]perhydrobenzo[ imidazol-l-yl methyl)perhy-drobenzoMimidazoles 1252 in 23-66% yields (Scheme 314) <2006JHC217>. 

An example of radical cyclization onto an imidazole ring is provided by the reaction of the diazonium salt of 130 (Eq. 30) with H3PO2 again, attack is at The photocyclization of 1-styrylimidazoles has been... 

Primary amino groups on imidazole react with nitrous acid to give diazonium salts by way of primary nitrosamines. These salts can sometimes be isolated and converted into stable diazo anhydrides if the imidazole has a free NH group. Reviews of diazoazole chemistry have appeared... 

---