Of 2H-imidazoles

Condensation of hydroxyamino-ketones (166) with ketones and ammonium acetate leads to the formation of 2H -imidazole-1 -oxides (167) (Scheme 2.59) (324). 

The 2H -imidazole A-oxides (225) have significantly higher oxidation potentials than their AH -imidazole isomers (223) and (224) but oxidation potentials of 2H -imidazole A, A-dioxides (226) are similar to oxidation potentials of AH -imidazole A,A-oxides (219) (Fig. 2.18) (Table 2.7) (427). 

Most routes make use of noncyclic precursors, although there have been two reports involving direct oxidation of 2H-imidazoles. 

An example demonstrating the effect of temperature on product formation is the case of alpha methylene ketones. The latter react in methanol solution at -70 °C with sulfur (S/ketone = 8) in the presence of ammonia and piperidine giving 2H-imidazoles, 4, in high yield (14). However, a diminished yield of this type of product results when the temperature is raised to 0 °C. Interestingly, in the case of 2H-imidazole formation, sulfur is promoting the oxidation of ketone without being incoroorated into the product. 

Gainsford, G.J. and Woolhouse, A.D., Facile photoisomerization of 2H-imidazole N-oxides to 1,3-diaza-6-oxabicyclo[3.1.0]hex-3-enes and synthesis of a l,3-diaza-4,7dioxatricyclo[4-l-0.0]heptane, J. Heterocyclic Chem., 29, 803, 1992. 

Migrations of C- linked substituents around the ring, on to carbon or nitrogen atoms, are common amongst these compounds. This is the van Alphen-Huttel rearrangement and by it 3H-pyrazoles are converted into 1//-pyrazoles, and 2H-imidazoles are thermally iso-merized into IH-imidazoles. 

The reaction of 1-amino-1-deoxyketoses, and their N-alkyl and N-aryl derivatives, with alkyl or aryl isothiocyanates (Huber et al, 1960) was studied in more detail, and new 4-(alditol-l-yl)-l-alkyl(aryl)-3-alkyl(aryl)-l,3-dihydro-2H-imidazole-2-thiones were obtained. These compounds were used as starting materials for the synthesis of OL-histidines, DL-histidine-2-thiol, and other imidazole derivatives of biological interest. 

A. 2,2-Spirocyclohexane-4,5-diphenyl-2H-imidazole (Note 1). A 2-L, threenecked, round-bottomed flask equipped with a mechanical stirrer and a reflux condenser is charged with 1.0 L of glacial acetic acid (Note 2), 158 g (0.75 mol) of... 

Oxidative Fluorination of Nitrones to a-Fluorosubstituted Nitroxyl Radicals Formation of nitroxyl radicals by the radical cation route was observed in reactions of various nitrones with xenon difluoride in dry methylene chloride (520, 523). In this reaction, more than 40 nitrones, including 4H -imidazole N,N -dioxides (219), 4H -imidazole TV-oxides (223) and (224), 2H -imidazole N -oxides (225), 2H -imidazole TV,TV-dioxides (226), 3,3,5,5-tetramethylpyrroline N -oxide (TMPO), derivatives of 3-imidazoline-3-oxides (231) and (232), have been examined. ESR spectra of nitroxyl radicals containing one or two fluorine atoms at a-C have been registered (Scheme 2.108) (523). In the case of... 

For reviews dealing with chemistry of 2H- and 4H-imidazoles, see (a) Sammes MP, Katritzky AR. In Advances in Heterocyclic Chemistry, Katritzky AR (Ed.), Academic Press, New York, Vol. 35, 375-412, 1984 ... 

As is the case with the 1 //-pyrroles and the 1 //-pyrazoles, structures isomeric with the 1//-imidazoles (1) exist that are nonaromatic because of the presence of a tetrahedral carbon atom in the ring. These structures, the 2H-imidazoles (2) and 4//-imidazoles (3), have properties quite different from their 1H counterparts. They also differ from each other in that the polarities of the two conjugated C=N bonds reinforce one another in structures 3, but are in opposition in structures 2. 

A reaction related to the preparation of 11 is the cycllzation of a-bromo-ketones with ammonia and a second ketone to give imidazolines 14, which are oxidized by sulfur in high yields to 2H-imidazoles 15 (Scheme 6) ... 

Conversion of the S=C—NH moiety in the 2//-imidazolethiones 13 to X—C=N, where X is a single-bonded group, generates the 2H-imidazole ring system. This has been accomplished in a number of ways, generally in high yields. 

Quaternization of the 2H-imidazole ring results in the expected down-field shift of methyl signals (e.g., 102). ... 

Most 2H-imidazoles show a parent ion that can be quite prominent.The major fragmentation pathway involves loss of RCN (two possible ways when the C-4 and C-5 substituents are different) and often gives rise to the base peak. Thus the 4-phenyl compounds show a prominent Mt — 103 ion, and structures 51 a common peak at m/e 145 (Mt -RCN). " °... 

Diphenyl-2H-imidazoles 120 have been shown to form methosalts 121 in high yields (Scheme 29) ethyl iodide, however, gave only small amounts of ethosalts. In 4-amino compounds, methylation occurs at the ring N-3. ... 

One interesting difference between the known examples of 2H- and 4H-imidazoles is that nearly all in the latter group contain at least one hetero-linked substituent. This arises because the major synthetic approach is via imidazolone derivatives (see next section) a second important route using 1,2-diketones places an OH group at C-4, and electrophilic additions to 1//-imidazoles also tend to introduce heteroatoms at this site. 

The resonance structures of the 3-substituted imidazole 1-oxides 245 are discussed in Section 1.1.1. According to IUPAC nomenclature, structure 245 is a 1-substituted lH-imidazole 3-oxide since the rules dictate that when R=H the indicated hydrogen position takes numbering precedence. Other names found in the literature are 1-substituted imidazole 3-oxides or 1-substituted 3-oxo-lH-imidazoles. Frequently the numbering is switched to give the names 3-substituted 2H-imidazole 1-oxide, 3-substituted imidazole 1-oxides, or 3-substituted 1 -oxo-3H-imidazoles. In the present review the most commonly used naming, which is accepted by IUPAC, Chem. Abstr. Autonom., is used calling structure 245 a 3-substituted imidazole 1-oxide. Consistently, structure 245 (R=OH, OAlk, or NH2) is named 3-hydroxy, 3-alkoxy, or 3-aminoimidazole 1-oxide, respectively. 

Cycloaddition with thioketones 3-Substituted imidazole 1-oxides 228 react with 2,2,4,4-tetramethylcylobutane-l,3-dithione with formation of l,3-dihydro-2H-imidazol-2-thiones 305 (1998HCA1585, 2011H765). 

An interesting application of the photochemical reactivity of isoxazolin-5-ones (see also Section 12.3) has been reported for the synthesis ofa series of annulated imidazole derivatives of general structure 72, which are obtained in almost quantitative yield. The methodology consists of an initial N-functionalization of the isoxazolin-5-one with a a-chloro-azaheterocycle, leading to 2-(azahetaryl)isoxazol-5(2H)-ones 71. 

The betaine anhydro-2-hydroxy-8-methyl-4-oxo-3 -phenyl-4//- imidazo[2,1 -b ][ 1,3]thi-azinium hydroxide undergoes thermal rearrangement to 2,3-dihydro-7-hydroxy-2-methyl-5-oxo-6-phenyl-3(2H),5H-pyrrolo[l,2-c]imidazolethione. A process involving an initial fission of the 1,2-bond and electrophilic ring closure of the resultant ketene intermediate into the 4-position of the imidazole nucleus is most likely involved in the rearrangement (equation 67) (80JOC2474). 

The photochemical addition of 2H-azirines to the carbonyl group of aldehydes, ketones and esters is completely regiospecific (77H143). Besides the formation of the isomeric oxazolines 18 from 3 and ethyl cyanoformate, there is also formed the imidazole 19 from addition to the C = N in the expected regioselective manner. Thioesters lead to thiazolines 20, while isocyanates and ketenes produce heterocycles 21 (Scheme 4). The photocycloaddition of arylazirines with a variety of multiple bonds proceeds in high yield and provides a convenient route for the synthesis of five-membered heterocyclic rings. Some of the dipolarophiles include azodicarboxylates, acid chlorides, vinylphospho-nium salts and p-quinones. 

As an example, the temperature dependent NMR spectra of 5-benzyl-l -[(4-nitrophenyl)-amino]-4-phenyl-l, 3-dihydro-2H-imidazole-2-thione 26 (R = Ph, Z = NO2) are reproduced in Figure 3. With increasing temperature the signals of the AB quartet of the diastereotopic methylene... 

Figure 3 Temperature dependent H NMR spectra of 5-benzyl-l-[(4-nitrophenyl) amino]-4-phenyl-l,3-dihydro-2H-imidazole-2-thione 26.

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