4-Amino-2-substituted imidazoles

Condensation of aldehydes with 2-amino-2-phenylacetamidooxime (5) gives high yields ( 80%) of 5-aminoimidazoles as their Schiff bases [36]. In a similar reaction, 4-amino-1-substituted imidazoles arc formed in the reaction between the hydrochlorides of bcnzyloxycarbonyl or tosyl derivatives of aminoacetamidine and orthoformic esters (Scheme 3.1.9) [37]. 

Under acidic conditions, amino-substituted imidazoles and triazoles 135 (X = CH, N) underwent intramolecular nucleophilic substitution reaction to give 136 in yields depending on the C(2 ) substituent orientation <1999CAR190, 1999MI441>. Thiouridine derivative 73 (R = Me) (Scheme 12) cyclized similarly to 72 on treatment with hexamethyldisilazane(HMDS)-ammonium sulfate <1992NN603>. 

Imidazoles are electron-rich heterocycless and can undergo inverse electron demand Diels-Alder reactions. Particularly, amino-substituted imidazoles are good dienophiles and cyclize with electron-poor counterparts to provide cycloadducts. For example, intermolecular cycloadditions of 2-substituted imidazole 486 with various... 

The mechanisms of the cascade reactions of amino-substituted imidazoles, pyrroles, and pyrazoles with 1,3,5-triazines have been studied using MP2/6-31 U-K //B3LYP/6-31G calculations in both the gas phase and in solution <05JOC998>. 

The 4(5)-amino-2-substituted imidazoles (45) and (46) have been prepared (50JCS2775) by condensation of aminoacetonitrile (30) with the thio-iminoether hydrochloride salts (40) and (41), respectively. These 4(5)-aminoimidazoles (45, 46) were isolated as their hydrochloride salts in yields of 36 and 90% (Scheme 3). 

General procedures for the synthesis of the imidazole core have been published in 2000. Solvent-free microwave assisted synthesis of 2,4,5-substituted imidazoles 64 from aldehydes 62 and 1,2-dicarbonyl compounds 63 in the presence of ammonium acetate and alumina has been reported <00TL5031>. V-protected a-amino glyoxals 65 were utilized as potential chiral educts for the synthesis of amino acid-derived imidazoles 66 <00TL1275>. 

Oxidative Animation of Nitrones to a-Amino-Substituted Nitroxyl Radicals Similar to the oxidative methoxylation reaction, oxidative animation of 4H -imidazole TV-oxides, in amine saturated alcohol solutions, give stable nitroxyl (282), nitronyl nitroxyl (283), imino nitroxyl (284) and (285) radicals with the amino group at the a-carbon atom of the nitroxyl group (Scheme 2.107) (520, 521). The observed influence of substituents on the ratio of animation products at C2 and C5 atom is close to the ratio observed in the previously mentioned oxidative methoxylation reaction. It allows us to draw conclusions about the preference of the radical cation reaction route. 

Anodic oxidation of o-amino substituted aromatic Schilf bases (38 and 40) to imidazole derivatives 39 and 41 were carried out in CH3CN-O.I mol/1 Et4C104 solution with addition of pyridine as a base, using controlled potential electrolysis and a divided cell [72] (Scheme 22). 

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)). 

The dimethylaminomethyl group (entry 9) is easily introduced by a Mannich reaction, and lithiation occurs readily at -78°C (88JOC5685). After reaction with a variety of electrophiles, hydrolysis can be performed directly with aqueous acid to give 2-substituted imidazoles in good yield. However, the 2-lithio anion 47 was found to be quite basic, despite the base-weakening effect of coordination with the amino substituent, and thus it was capable of deprotonating the 2-butyl derivative 48 as it was formed by reaction with 1-bromobutane (Scheme 42). No such side-reac-... 

In a recent study, Fernandez-Bertran et al. used mechanochemical reactions to prepare a number of hemin complexes with amino acids such as arginine, histidine, lysine, methionine and tryptophan. The basic amino acids react with the hemin peripheral propionic acid groups, while arginine is also able to form a pentacoordinated complex at the Fe(III) centre. The reactions were followed by IR and Mossbauer spectroscopies [77a]. The solid-state reaction of hemin with KCN, Na2S and various substituted imidazoles has also been investigated [77b]. 

There are many heterocyclic molecules in which 1,3,4-thiadiazoles are fused to other ring systems. For example, Molina et al. developed a procedure for building a thiadiazole ring on to a properly substituted imidazole moiety (Scheme 29). Reaction of l-amino-2-methylthio-4-phenylimidazole (161) with triphenylphosphine dibromide in dry benzene furnished the 2-methylthio-4-phenyl-l-triphenylphosphoranylidenamino imidazole (162) in a 95% yield. With aroyl chlorides at elevated temperature, this gave the 2-aryl-6-phenylimidazo[2,l-Z ][l,3,4]thiadiazoles (164) in yields between 50% and 70% via the imidoyl chloride intermediate (163) which could be isolated and shown to cyclize to the thiadiazole. The method developed for the imidazole ring was also applicable to the thiadiazolotriazine ring system <88H(27)1935). 

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... 

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. 

Most syntheses of imidazo-fused systems involve cyclization of amino substituted heterocycles (or their tautomers), suitably substituted at an adjacent ring position. This provides a convenient route to imidazo[2,1 -ft]thiazoles, imidazo[1,2- ]imidazoles (Scheme 4), imidazo[l,2-6]pyrazoles, imidazo[l,5- Jimidazoles and imidazo[l,5-c]thiazoles. 

Many of the biologically active zinc metalloproteins contain a zinc(II) ion bound to one or more imidazole ligands of the amino add residue histidine. For this reason a large number of studies over an extended period have been carried out on zinc and cadmium complexes of imidazole, substituted imidazoles, histidine and related ligands. There has also been much recent activity in this field much structural information is available. 

Reactions of 5f/-2-methyl-l,2,4-triazepino[2,3- ]benzimidazol-4-one 71, prepared by reaction of 1,2-diaminobenz-imidazole 72 with acetoacetic ester 73, with different reagents was described, in the search of new heterocycles with biological activity <2002CHE598>. When lactam 71 was treated with aromatic aldehydes in boiling 1-BuOH with addition of piperidine 74, 577-3-arylidene-2-methyl-l,2,4-triazepino[2,3- ]benzimidazol-4-ones 75a-c were obtained (Scheme 7). Coupling lactam 71 with phenyldiazonium chloride 76 in dioxane afforded the 3-phenylazo-substituted tricycle 77. When 71 was treated with phosphorus pentasulfide 78 in boiling dioxane or pyridine, its thio analog 79 was obtained. The reaction proceeded most efficiently when lactam 71 was refluxed with twofold excess of 78 in dry dioxane. These thiones 79 react with ammonia and amines by nucleophilic substitution. When 79 was refluxed with ammonia, benzylamine, piperidine, or morpholine, the 4-amino-substituted tricycles 80a-d were obtained. All the described compounds were identified by NMR, mass spectrometry, and IR spectroscopy. 

The highly unstable endoperoxides of imidazoles, sometime spectroscopically detected [81a], rearrange to dioxetanes or hydroperoxides or rapidly fragment or polymerize so that from the synthetic perspective, the reaction has a poor scope [54,67,81]. One interesting application has been pointed out by Lipshutz as a general asymmetric synthesis of TV-protected amino acids/dipeptides via appropriately substituted imidazoles (Sch. 48) [82],... 

The effects of substituents on the acidic and basic strengths of imidazoles have been discussed by Hofmann1 and Pozharskii et al.3 in previous reviews. Precise data have been determined175 for the basicity of imidazole in D20-H20 mixtures. Perrin176 has developed methods based on the Hammett equation for predicting the pKa values in water of substituted imidazoles (and other heterocycles), while applications of the Hammett equation have also been made to 2-substituted imidazoles.177 Calculations of j>K values for 2-amino-imidazolium ions suggest that 2-aminoimidazoles are better regarded... 

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. 

The microwave assisted hydrazinolysis of substituted imidazo[l,2-a]pyrimidine (x) gave way to mono (xi) and disubstituted (xii) 2-amino-IH-imidazoles [14]. 

Ermolatev DS, Svidritsky EP, Babaev EV et al (2009) Microwave-assisted synthesis of substituted 2-amino-lH-imidazoles from imidazo[l, 2-a]pyrimidines. Tetrahedron Lett 50 5218-5220... 

When primary amines react with a-acylaminoketones the resulting Schiff bases can be cyclized in the presence of phosphoryl chloride, phosphorus pentachloride, or triphenylphosphine and triethylamine in hexachloroethane to give 1-substituted imidazoles (11) (Scheme 2.1.4). The starting a-acyl-aminocarbonyls are readily prepared from a-amino acids by reduction with sodium amalgam [31, 32] or by the Dakin-West reaction [33, 34], which is most conveniently conducted in the presence of 4-(AUV-dimethylamino)pyridine (DMAP) as an acylation catalyst [35 37]. 

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]. 

A two-step synthesis of 1,4-disubstituted imidazoles (8) from TOSMIC (1) plus an aldehyde, followed by reaction with ammonia or a primary amine, proceeds via a 4-tosyloxazoline (11). The reaction sequence could be classified as 1,2 and 1,5 bond formation, 1,5 bond formation, or transformation of another heterocycle. There are, however, analogies to the aldimine reactions, and so the process is detailed at this stage. Certainly the synthesis is carried out in two steps often with isolation of the oxazoline (see also Chapter 6). Heating (11) with a saturated solution of methanolic ammonia gives a 4-substituted imidazole with methanolic methylamine a 1,4-disubstituted product is isolated as a single regioisomer (Scheme 4.2.4). Some of the oxazolines cannot be isolated as they are unstable oils which have to be heated immediately with the amino compound [12]. Related is the synthesis of 2-carbamoyl-4-(2 -deoxy- 0-D-ribofuranosyl)imidazole [13]. 

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