Imidazole diazonium

Nucleophilic displacements of imidazole diazonium salts have some synthetic utility, particularly for the introduction of groups at C-2. Thus 2-nitroimidazoles" and 2-azidoimidazoles" are available via the diazonium fluoroborates. The formation of halogen-substituted imidazoles by the photolytic (but not thermal) decomposition of diazonium fluoroborates has proved useful. " " While 2- and 4-fluoro- and 2-chloro-imidazoles can be prepared in this way, the reaction fails for iodo- and bromo imidazoles." ... 

The photochemical decomposition of imidazole diazonium fluoroborates to fluoroimidazoles has been discussed earlier (Section IV,C). 

Nucleophilic displacements of imidazole diazonium salts have some synthetic utility, particularly for the introduction of groups at C-2. Thus... 

Diazo coupling is expected to occur only with highly reactive systems, and experiment bears this out. Diazonium ions couple with the anions of N-unsubstituted imidazoles at the 2-position (e.g. 125 yields 126) and with indazoles (127) in the 3-position. In general, other azoles react only when they contain an amino, hydroxyl, or potential hydroxyl group, e.g. the 4-hydroxypyrazole (128), the triazolinone (129) and the thiazolidinedione (130) (all these reactions occur on the corresponding anions). 

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. 

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... 

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-4-diazonium tetrafluoroborates can be prepared, and they show exceptional stability (73JA4619). In the imidazole series, however. 

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). 

Pyrrolidino- bzw. 3-Piperidino-acrylsaure-ester cyclisieren mit Phenyldiazonium-tetrafluoro-borat unter Einbau eines N-Atoms aus dem Diazonium-Salz zu 2-Methoxy carbonyl-6,7-di-hydro-5 H-yrrolo[l, 2-d imidazol ) (40%) bzw. 2-Methoxycarbonyl-5,6,7,8-tetrahydro-[Pg.59]

Nitro-imidazole kpnnen nur durch andere Methoden wie z. B. den Austausch der 2-Amino-Gruppe uber das Diazonium-Salz (s.S. 169) oder iiber Metallierung in 2-Stellung hergestellt werden (s.S. 149). 

Der Austausch von Amino-Gruppen am Imidazol-Ring fiihrt praktisch immer liber das Di-azonium-Salz. In den meisten Fallen werden die Diazonium-Salze aber nicht isoliert, sondern in situ weiter umgesetzt. Am haufigsten wird die Amino-Gruppe durch die Nitro-Gruppe oder ein Fluor-Atom ausgetauscht. 

Nucleophilic processes that introduce chlorine include displacement of diazonium functions, but these are not well known in the imidazoles because of the instability of many simple aminoimidazoles. In one instance the lack of success may have been a function of the high stability of 5-ethoxycarbonyl-4-diazoimidazole. Other 1-substituted 4-diazonium salts showed expected reactivity, and 1-substituted 5-aminoimidazoles formed sufficiently reactive diazonium salts to give good yields of the 5-chloro compounds [80JCS(P1)2310]. Most of the thrust in this reaction strategy has focused on the preparation of fluoroimidazoles (see B,2,d). 

The Balz-Schiemann synthesis can be applied not only to substituted anilines but also to aminobiphcnyls1,131 or amino-substituted fused polyaromatic compounds, such as naphthalene,1114,119,129 anthracene,136 phenanthrene,1135 acenaphthene,133 fluorene,1,131,134 benzanthracene,130 136 pyrene,136 chrysene,136 fluoranthene,131 fluorenone,1,131 anthra-quinone,1,137,139,140 benzanthrone,1,117,118 phenanthraquinone,138 or xanthone.132 Fluorinated pyridines,1,141"146 methylpyridincs,126,147 149 pyridinecarboxylic acids,150 quinolines,1,151 isoquinolines,152 quinazolone,1 thiazoles,153,154 isothiazoles,156 benzothiazoles,157 thiadiazoles,155 and thiophenes154 can also be obtained from the corresponding aminated heterocycles. Modified Balz-Schiemann methods are recommended for amino nitrogen-containing heterocycles, the diazonium salts of which are rather water-soluble and unstable (a violent explosion was reported for pyridine-3-diazonium tetrafluoroborate).159 These new techniques have also been specially adapted for pyrazol-, imidazol-, or triazolamines which fail to react under classical conditions.158... 

The most important applications of the in situ photochemical fluorodediazoniation start from heterocyclic amines for which the diazonium tetrafluoroborates are impossible to isolate. In this way, fluorinated imidazoles,123-253,254-257 261 benzimidazoles,262 pyrazoles,254-256,262 indazoles,158 thiazoles,259 and triazoles259-262 have been prepared (Table 4). Some of these are the precursors of biologically active compounds such as fluoro-substituted histidines or histamines,123,253-257,258 or 5-fluoro-l/ -D-ribofuranosylimidazole-4-carboxamide.261... 

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