4.5- Disubstituted imidazole 1-oxide

Benzofuroxans 65 can be transformed into the imidazol-fV-oxides 66 or 2,2-disubstituted imidazole-iVjA -dioxides 64... 

Reaction of 4,5-disubstituted imidazole 1-oxide with trimethylsilyl cyanide (TMSCN) leads to 2-cyanoimidazole. If devoid of substituents at C4 and C5, the cyano (CN) group also enters these positions (1996JOC6971). The reactivity of the 2-, 4-, and 5-position is comparable and 245 reacts with TMSCN affording the isomeric cyanoimidazoles 296-298 in a ratio that depends on the nature of the 3-substituent, solvent polarity, and reaction temperature. These parameters could be optimized to give each of the three cyano compounds as the major product. Mechanisms (iii) and (iv) (Section 1.5.1.3 and 1.5.1.4) account for the formation of 296-298 (Scheme 88). 

Reaction of 4,5-disubstituted imidazole 1-oxides 263 with POCl3 or POBr3 produces 2-chloro or 2-bromoimidazole 301 (Hal = Cl or Br) (1975JCS(P1)275, 2002AG(E)2290). A possible mechanism in line with that in play by acylation comprises O-phosphorylation to be followed by addition of halogenide ion and subsequent elimination of halophosphoric acid as outlined in Scheme 89. 

When the 6-position is unsubstituted, oxidative degradation is most common, and peracetic acid treatment leads to ring contraction to form 2,4-disubstituted imidazoles and their N-oxides (81H573). For example, 2-methyl-4-phenylpyrimidine (28) reacts in this way with peracetic acid, but with m-chloroperbenzoic acid in chloroform, pyrimidine N-oxides were formed as well (Scheme 12). Even pyrimidine itself gave the oxide in 48% yield under these latter conditions 2-methylpyrimidine gave 55% of the N-oxide (81H573). 

Thione groups can often be eliminated by oxidation probably the sulfinic acid is the intermediate. Sometimes the sulfinic acid can be isolated (e.g., 740 741), but more often it spontaneously loses SO2. In this way, thiazoline-2-thiones give thiazoles, l,2-dithiole-3-thiones 742 are converted into 1,2-dithiolylium salts 743, l,3-dithiole-2-thiones 744 into 1,3-dithiolylium salts 745, 1,5-disubstituted imidazole-2-thiones into imidazoles <2003JHC229>, and 3-mercapto-l,2,4-triazoles into the parent triazole <2006S156>. In the pyrazole series, 746 also loses an A-methyl group to yield 747. 

Examples exist of ring fission of purines to give 4,5-disubstituted imidazoles (Scheme 104) (78TL5007). The conversion of benzimidazoles into imidazoles has been discussed as an example of oxidation (Section 4.07.3.1). 

Pyrazine Al-oxides and 2,3-dihydropyrazines also rearrange photochem-ically into imidazoles. From 2,5-disubstituted pyrazine 1-oxides (73) two products, 2-acyl(or aroyl) 4-substituted imidazole (74) and 2,4-disubstituted imidazole (75), result. " " The reaction (Scheme 16) presumably takes place through two isomeric oxaziridine derivatives. 

Anodic oxidation of JV,iV-disubstituted trifluoroethanimidamide 45 in dry and in aqueous acetonitrile gave the imidazole 46 and quinoneimine 47 as the reaction products (Scheme 24). The constant current electrolysis on a glassy carbon anode and a platinum cathode was performed in an undivided cell [74]. 

When l-hydroxy-3-imidazoline 3-oxides (263) are treated with HCl they dehydrate forming imidazole 3-oxides (Scheme 153) (73CHE1175). Reduction of 4//-imidazole N-oxides with borohydride leads to either 1-hydroxy-imidazolines or -imidazolidines, depending on the position of the oxide function. Under the same conditions 4//-imidazole 1,3-dioxides give 1,3-dihydroxyimidazolidines (76CHE1280). The 4iT-imidazole AT-oxides are prepared by heating 5,5-disubstituted l-acyloxy-3-imidazoline 3-oxides in vacuo. 

Both pyrazine iV-oxides and 2,3-dihydropyrazines rearrange photochemically to imidazoles. Irradiation of the 2,5-disubstituted oxides (187) gives mixtures of the imidazole products (188, 189), probably through the intermediacy of oxaziridine intermediates (Scheme 109). 

Imidazoles normally undergo free-radical reactions at the 2-position. For example, homolytic free-radical alkylation of histidines and histamines yields 2,3-disubstituted histidines and histamines. In these reactions, the free radical was generated via silver-catalyzed oxidative decarboxylation of acids with peroxydisulfate 433 (Scheme 103) <2001BML1133>. 

Treatment of N-acylated a-aminonitriles 1077 with PPh3 and a carbon tetrahalide affords 2,4-disubstituted 5-halo-17/-imidazoles 1078 in good yields. A variety of alkyl and aryl substituents (R and R ) are tolerated. A possible mechanism involves the formation of a novel seven-membered ring intermediate and then elimination of triphenyl-phosphine oxide, as illustrated in Scheme 261 <20040L929>. 

Dichloroquinoline-5,8-dione is converted by peroxytrifluoroacetic acid into the N-oxide in low yield. This compound is also obtainable directly from 8-hydroxyquinoline with a mixture of concentrated hydrochloric and nitric acids (86JMC1329). The 6,7-dichloroquinone reacts also with imidazole to give the disubstituted product (72LA131). 

Thiazoles may also be intermediate in some other imidazole syntheses <87CJC282>. Dimroth rearrangement of 5-aminothiazoles ((255), (256)) gives hydantoin analogues <86BSBll29>. While 2,4-disubstituted thiazole A(-oxides are converted by aryl isocyanates into imidazoles, the 2,5-isomers are unreactive (Scheme 191) <82CPB1722>. 

IP s oxidation processes directly affecting the imidazole and pyridine rings were seldom observed. But oxidation of 1,3-dimethyl-IbP iodide and other salts of a similar structure by potassium ferrocyanide in alkaline medium at temperatures below 10 °C afforded 1,3-disubstituted IbP-2-one (68KG954) (Section IV.C.l). 

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