Conversion to imidazoles

Bifonazole (109) is claimed to be remarkably non-toxic and is marketed as a topical antifungal agent overseas. It can be conveniently synthesized in the by now familiar way by reduction of p-phenylbenzophenone (108) with borohydride, conversion to the chloride with thionyl chloride, and then imidazole displacement to bifonazole (109) [39]. 

A powerful method of introducing a CF3 group into aromatics is the conversion of C02H with SF4. The use of SF4 with heterocyclics is not as widespread but it has been applied to imidazoles [81JFC(17)179], thiazoles, isothiazoles [91 JFC(55) 173], and furans (86BSF974). 

The use of AMximethylsilylimidazole has been suggested in the reaction with acid chlorides to form imidazolides.[3] In fact, the rate of conversion to imidazolides by reaction of iV-trimethylsilylimidazole with acid chlorides is remarkably rapid even at rather low temperatures. On the other hand, the preparation of the N-trimethylsilylimid-azole from imidazole requires the heating of imidazole with hexamethyldisilazane for several hours. 

Conversion to an intermolecular general base-catalysed reaction involving imidazole (1-6 X 10-< )... 

Synthesis of this imidazole is discussed in Section II,C,3. Its use for conversion to purines is outlined in Section VI,A. 

The thioamide function also provides the entry for the construction of a fused imidazole ring, though the sequence is somewhat more complex due to the need to form a new carbon-carbon bond. Reaction of the thioamide (18-1) with methylamine proceeds to give the corresponding amidine this is transformed into a good leaving group by conversion to the A-nitroso derivative (18-2) by treatment with nitrous... 

Materials. Imidazole, benzimidazole, and glucosamine hydrochloride were obtained from the Eastman Kodak Co., and used without further purification, after drying for several days over anhydrous calcium chloride. Stock solutions of nickel nitrate and nickel chloride were analyzed by precipitation with dimethyl-glyoxime. Stock solutions of cadmium nitrate were analyzed gravimetrically by conversion to cadmium sulfate. 

A very wide range of pyrimidines is readily accessible by synthesis. By contrast, there are relatively few good general routes to imidazoles. Consequently, the pyrimidine —> imidazole ring transformation can be a valuable process. Japanese workers have shown, for example, that treatment of 5-acylaminouracils of the type 1 with 5% aqueous sodium hydroxide in ethanol at reflux results in smooth conversion into imidazoles 2 in generally good yield. 

The use of cycloaddition reactions for the synthesis of partially reduced heterocyclic systems was shown to be an attractive approach to dihydrobenzimidazoles, dihydroquinazolines, and dihydro-//n-benzopurines (Scheme 14) <86JOC6i6>. The dihydroxylation of the Diels-Alder adduct dimethyl 3,6-dihydrophthalate (128) with 0s04 and NMO followed by protection of the diol as the iso-propylidene derivative afforded compound (129). Saponification, dehydration with ethoxyethyne, and rearrangement with TMS—N3 effected conversion to the substituted tetrahydroisatoic anhydride (130), and subsequent treatment with formamidine acetate yielded compound (131). The substituents at the 6,7-positions of compound (131) were not amenable, however, for annelation of an imidazole. 

The mechanism of the enaminonitrile - imidazole conversion has been the subject of extensive study, although only a few mechanistic features are known with certainty. The nitrile and the amine must have a cis relationship in the starting material. In the case of diaminomaleonitrile, the initial step would therefore be a photoisomerization to diaminofumaronitrile, via the triplet excited state of the enaminonitrile (equation 22)60. The rearrangement to imidazole, however, is presumed to occur via the singlet excited state, since triplet sensitizers do not promote the reaction and triplet quenchers do not inhibit it56b 59b. 

One of the major difficulties in obtaining NMR spectra of imidazoles is a consequence of their low solubility in most suitable solvents except for water. This may often lead to incomplete, or ill-defined, spectra, particularly where there are a number of exchangeable hydrogen atoms, e.g., in polyhydroxyalkyl-substituted imidazoles. Some imidazoles, for instance, 1-methyl- and 2-acetyl-4-methylimida-zole are readily soluble in deuteriochloroform, while deuteriated pyridine, acetone, or dimethyl sulfoxide may prove useful in other cases. Reddy et ai.220 have suggested conversion of imidazoles into their N-acetyl derivatives which are soluble either in deuteriochloroform or in a mixture of deuteriochloroform and dimethyl sulfoxide. Although, as mentioned above, in neutral organic solvents the 4- and... 

Syntheses of the imidazo[4,5-c][l,5,2]diazaphosphorine system, oxidized at phosphorus, was undertaken to prepare transition state analogs for adenosine aminohydrolase. Conversion of imidazole derivative (735) to (736) required three steps. Treatment of (736) with n-propylamine followed by either acidic or basic ring closure gave (737) (78MI41001). In... 

Such synthetic approaches can only be valid if the other heterocycles are readily available, or if their transformations lead to imidazoles difficult to make by other means. It is certainly important to be able to aromatize imidazolines since a number of ring-synthetic procedures lead to reduced imidazoles. 4-Aminoisoxazoles are sources of a-acylaminoenaminones which cyciize with bases to give 4-acylimidazoles. Oxazole-imidazole conversion has largely historical importance, but it is also implicated in some ring-synthetic procedures (e.g. the Bredereck method, see Chapter 5). Transformations of benzofuroxans into 2-substituted benzimidazole iV-oxides have some synthetic importance. Few, if any, ring contractions appear to have major application. 

The reaction of 2potassium amide in liquid ammonia to give 2-cyanoimidazole, imidazole, and 2-aminopyridine has been investigated (911). It has been found that 2-chloropyrazine containing an excess of in position 1, on treatment with potassium amide in liquid ammonia at — 65° yields 2-aminopyrazine in which the exocyclic nitrogen contains all the excess and an addition-nucleophilic-ring opening-ring closure (ANRORC) mechanism was proposed (822). The mechanism of the conversions into imidazole (823) and... 

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