5- Amino-4-unsubstituted imidazoles

Five approaches to the synthesis of 5-amino-4-unsubstituted imidazoles (96) have been described and are summarized in Scheme 9. These are (a) reduction of 5-nitroimidazoles (97), (b) hydrolysis of carbamates and amides (98), (c) decarboxylation of imidazole carboxylic acids (99), (,d) ring transformations of 5-aminothiazoles (100), and (e) cyclisation of nitrile derivatives (101). 

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). 

The amino acid histidine contains an imidazole ring. We have just seen that unsubstituted imidazole as a base has p/Ca 7.0. From the Henderson-Hasselbalch equation... 

The imidazole side-chain of histidine has a value of 6.0, making it a weaker base than the unsubstituted imidazole. This reflects the electron-withdrawing inductive effect of the amino group, or, more correctly the ammonium ion, since amino acids at pH values around neutrality exist as doubly charged zwitterionic forms (see Box 4.7). Using the Henderson-Hasselbalch equation, this translates to approximately 9% ionization of the heterocyclic side-chain of histidine at pH 7 (see Box 4.7). In proteins, plCa values for histidine side-chains are estimated to be in range 6-7, so that the level of ionization will, therefore, be somewhere between 9 and 50%, depending upon the protein. 

A novel approach to adenine and hypoxanthine derivatives involves a high-temperature intramolecular cyclization of 4(5)-substituted-amino-5(4)-unsubstituted-imidazole intermediates. For example, reaction of 1,2-dimethylimidazol-5-amine with (ethoxymethylene)urethane gives the Af -ethoxycarbonyl-jV -(imidazol-5-yl)formimidamide which under thermal cyclization is rapidly transformed into 8,9-dimethylhypoxanthine (3). 

The earliest method of this type was the old Marckwald synthesis (1] in which a suitable a-aminocarbonyl compound is cyclized with cyanate, thiocyanate or isothiocyanatc. More recent modifications have employed the acetals of the a-amino aldehyde or ketone or an a-amino acid ester. The two-carbon fragment can also be provided by cyanamide, a thioxamate, a carbodiimidc or an imidic ester. When cyanates, thiocyanates or isothiocyanates are used, the imidazolin-2-ones or -2-thiones (1) are formed initially, but they can be converted into 2-unsubstituted imidazoles quite readily by oxidative or dehydrogenative means (Scheme 4.1.1). The chief limitations of the method arc the difficulty of making some a-aminocarbonyls and the very limited range of 2 substituents which are possible in the eventual imidazole products. The method is nonetheless valuable and widely used, and typically condenses the hydrochloride of an a-amino aldehyde or ketone (or the acetals or ketals), or an a-amino-)6-ketoester with the salt of a cyanic or thiocyanic acid. Usually the aminocarbonyl hydrochloride is warmed in aqueous solution with one equivalent of sodium or potassium cyanate or thiocyanate. An alkyl or aryl isocyanate or isothiocyanate will give an A-substituted imidazole product (2), as will a substituted aminocarbonyl compound (Scheme 4.1.1) [2-4]. 

Diazo coupling in N-unsubstituted imidazoles occurs with equal case at either C-2 or C-4(5) (or both) in reactions which have been shown to involve reaction of the imidazole anion with the diazonium ion [10]. lire intensely coloured azo dyes which are formed have long been used for identification of imidazoles, especially in qualitative chromatography [7]. The azo groups can be reduced to amino or hydrazine groups, providing a useful alternative approach, especially to 2-aminoimidazoles (see Section 8.3),... 

The electrolysis of asymmetric ketones 43 led to the formation of isomers and stereoisomers. Kinetic measurements for the formation of ketimine 43 in saturated ammoniacal methanol indicated that at least 12 h of the reaction time were required to reach the equilibrium in which approximately 40% of 42 was converted into the ketimine 43. However, the electrolysis was completed within 2.5 h and the products 44 were isolated in 50-76% yields. It seems that the sluggish equilibrium gives a significant concentration of ketimine 43 which is oxidized by the 1 generated at the anode, and the equilibrium is shifted towards formation of the product 44. 2,5-Dihydro-IH-imidazols of type 44, which were unsubstituted on nitrogen, are rare compounds. They can be hydrolyzed with hydrochloric acid to afford the corresponding a-amino ketones as versatile synthetic intermediates for a wide variety of heterocyclic compounds, that are otherwise difficult to prepare. 

Amino methyl substituted pyrrolo-benzodiazepine 215 forms a cyclic aminal with aldehydes that can be further oxidized with Mn02 to fused 3-substituted imidazole 216. Alternatively, cyclic imine 217 can be submitted to TosMlC cycli-zation to afford unsubstituted 9H-benzo[e]imidazo[5,l-c]pyrrolo[l,2-fl][l,4]-diazepine 218 (Scheme 45, Section 3.1.1.2 (1993JHC749)). 

An analysis of conformational flexibility of pyrimidine ring in related molecules (purine, aminopyrimidine, and unsubstituted pyrimidine (Scheme 21.4)) indicates that the flat character of the potential energy surface around minimum is a general property of pyrimidine ring. A presence of amino group and fused imidazole ring only promotes increase of conformational flexibility of heterocycle. 

Imidazoles are amphoteric compounds with a basic, pyridine-type nitrogen (they are about 106 times more basic than oxazoles and 104 times more basic than thiazoles173), and (where the NH is unsubstituted) a weakly acidic, pyrrole-type amino nitrogen in the ring. In consequence, imidazoles readily form salts with acids and often form salts (or complexes) with metals. The sparingly soluble silver salts formed by imidazoles have been used by Giesemann et al.174 as intermediates in the synthesis of 1-triphenylmethylimidazoles. Normally, however, the salts formed with acids are more important in isolation and purification procedures. 

An attempt to diacylate an o-chlorophenylhydroxylamine with acetic anhydride-pyridine gave instead a cyclized product in which pyridine had been incorporated. A cleaner sample of the same product was obtained by stirring the diacetate in pyridine at ambient temperature. 2-Amino-3-chloropyrazines may react with a 2-unsubstituted pyridine at ambient temperature to form a fused imidazole system in which the pyridine is also fused. The presence of substituents on the pyridine ring may necessitate the use of DMF as solvent and heat to be suppli. ... 

Amino acid-derived aldehydes can be converted into 5-unsubstituted oxazoles and in a related sense, imidazoles can be produced by introducing ammonia to an 2-acylamino-ketone. ... 

Based on this information, it was decided that a group of 2-(4-methoxyphenyl)-3//-naphth[l,2-c/]imidazoles substituted differently at N-3 should also be synthesized using the same reaction pathway. It was found that the original synthetic pathway did not work for the unsubstituted derivative. Attention was therefore focused on an alternate pathway involving the hydrogenation of 2-amino-1-nitronaphthalene to 1,2-naphthalenediamine (Scheme HI). 

Another pharmaceutically important fused-imidazole ring system is the popular sleeping aid medication zolpidem. Bromination of 4-methylacetophenone and condensation with methylated 2-amino pyridine provides the fused-imidazole in good overall yield. Note that the ring nitrogen on the aminopyridine reaction reacts with the bromide carbon. Mannich-type alkylation at the unsubstituted 5-position provides the dimethylaminomethyl substituent in good yield. Further elaboration yields zolpidem. ... 

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