Imidazole IV-oxides

Adaptation of similar functionality to the synthesis of imidazole IV-oxides is illustrated by the fluoride ion-promoted cyclization of the trimethylsilyl ether of the oxime (30) derived from l-(dichloroacetylphenyl)aminopropanone (Scheme 15) (80AHC(27)24l). 

The reactions of a-aminooximes and a-dioximes with aldehydes to form imidazole iV-oxides are discussed with related synthetic methods in Section 4.08.1.2.2. 

A regiospecific synthesis of A -substituted (aminopyridinyl)imidazole 1286 started with ketone 1282 (cf. Section 4.02.9.2(i)). a-Oximination of ketone 1282 with isoamyl nitrite under basic condition provides oxime isomers 1283. Both as- and /ra t-oximes 1283 participate in the cyclization process when treated with l,3,5-trimethyl-l,3,5-triazinane, leading to imidazole iV-oxide 1284 that is then reduced with 2,2,4,4-treta-methyl-cyclobutane-l,3-dithione to give 1285 (Scheme 326) <2003JOC4527, 1999JME2180> (see also Section 4.02.9.3(i)). 

Many workers in recent years have been interested in the tautomeric equilibria pertaining to oxygenated imidazoles such as imidazolones, " " N-hydroxyimidazoles, and imidazole iV-oxides. The earlier results have been critically summarized. In the solid state l,2-dimethyl-5-phenylimidazol-4-one exists in the OH form, but insolubility prevented studies in solution. Theoretically l-methylimidazol-5-ones can exist in the forms 93-96 shown in Eq. (22). French workers ... 

The most common is the conversion of imidazolinones and benzimidazolinones into the halo compounds. Phosphoryl chloride transforms 4,5-diphenylimidazolin-2-one (126) into the 2-chloro compound, and the reaction is even more rapid with benzimidazolinones (66RCR122). The same reagent will convert imidazole iV-oxides into 2-chloroimidazoles (Scheme 59) (see Section 4.02.1.6.4). 

The solubility of imidazole in water is a function of its hydrophilic nature (equilibrium constant for transfer from water to vapor, determined by vapor pressure measurements log K vjw) = — 7.2). Potential electronic interactions between solvation sites (33) do not seem to be present. When imidazole is A -methylated its hydrophilicity only decreases by a factor of 8, hence its hydrophilie character is not exceptional <87JA463>. The calculated (using semiempirical methods) iV-shielding of imidazole is 3.93 ppm (cf. 4.6 ppm experimental value). For l-methylimidazole the observed shielding of N-1 decreases by 3.6 ppm and that of N-3 increases by 9.2 ppm on hydration compared with the calculated values (1.87, 10.72 ppm, respectively) <83OMR(2l)50l>. Imidazole iV-oxides are only sparingly soluble in nonpolar solvents, but more soluble in polar solvents. 

Scheme 69 Palladium-catalyzed and metal-free C-H/C-H cross-couplings of imidazole iV-oxides with indoles...

One of the most significant developmental advances in the Jacobsen-Katsuki epoxidation reaction was the discovery that certain additives can have a profound and often beneficial effect on the reaction. Katsuki first discovered that iV-oxides were particularly beneficial additives. Since then it has become clear that the addition of iV-oxides such as 4-phenylpyridine-iV-oxide (4-PPNO) often increases catalyst turnovers, improves enantioselectivity, diastereoselectivity, and epoxides yields. Other additives that have been found to be especially beneficial under certain conditions are imidazole and cinchona alkaloid derived salts vide infra). 

Dibenzo[/),/]thiepin-10(l 1H)-one (1) is an important synthon for the transformation of thiepins into other heterocycles. Oxidation with selenium(IV) oxide gives dibenzo[7>,/]thiepin-10,l 1-dionc (2), in 45% yield,38 which can be condensed with a series of benzaldchydes in the presence of ammonium acetate to provide the substituted 2-aryldibenzo[2,3 6,7]thiepino[4,5-t/]imidazoles 3, known to have anti-inflammatory properties.38... 

Oxidation of mono-iV -oxides 4H -imidazole (223) and (224) with Pb02 in methanol leads to the formation of stable a,a-dimethoxy-substituted nitroxyl radicals (271) and methoxy substituted imino nitroxyl radicals (INR) (272)-(274) (Scheme 2.101) (514). 

Photochemical hydroxyalkylation has been carried out with pyri-dines, quinolines, isoquinolines,acridine, pyridazines, pyrimidines, ethoxyquinolinium salts,and imidazoles. It also occurs with iV-oxides the mechanism of Scheme 13 has been suggested for pyridazine iV -oxide. ... 

The peracid oxidation of 2//-imidazoles to iV-oxides and Af,iV -dioxides has been discussed (Section II,E) both 92 and 99 under similar conditions give imidazolinones 124. ... 

A comparative study of the reduction of 4ff-imidazoles and their iV-oxides is shown in Scheme 33. ° Reduction stops at the imidazoline stage even with a large excess (2 1 mol ratio) of borohydride unless a 1-oxide group is present in this case it may proceed further to give an imidazolidine. 

Monocyclic oxadiazepines have not been isolated in reactions of this type but it has been proposed that the 1,2,6-system (508) is an intermediate in the formation of (509) from the pyrimidine IV-oxide (507) (69TL4899), and that the 1,2,5-systems (511) and (512) are intermediates in the formation of the imidazoles (513) and (514) from the pyrazine IV-oxide (510) (67TL1197). 

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). 

The N-hydroxy structure (26) was preferred123 to an iV-oxide representation on account of the amphoteric nature of the product and because the derived acetate formed a well-defined hydrochloride salt. Hydrogenation of these N-hydroxyimidazoles over Raney nickel gives imidazoles in 60-94% yields.122 The reaction has been adapted for the preparation of 4-mercaptoimidazoles, using an a-ketothionamide (27) with an aldimine.124... 

Of the substituted pyridines, the halogenated derivatives have been the most intensively studied.144,145 Treatment of 3,5-dichloropyridine A-oxide at 74° with 0.1 A NaOD led to exchange in three positions of the molecule, whereas with 3-chloropyridine iV-oxide relative rates of exchange were position 2>6>4>5. In l-methyl-4-pyridone, 1,3,5-trimethyl-4-pyridone, and 3,5-dibromo-l-methyl-4-pyridone, deuteration in basic D20 at 100° gives 2- and 6-substitution.146 With the poly-azaindenes (45) -(47) already discussed in the acid exchange section,141 base-catalyzed deuteration occurs in the positions indicated 45 3 and 5 46 2, 3, 5, and 6 and 47 2, 5, 6, and 7. In other isolated heterocycles some selectivity is observed in base-catalyzed exchange, e.g., certain imidazoles,147 thiazole,148 isothiazole,148 benzothiazole,149 and benzoxazole.149... 

As a striking exanq>le, photo-initiated chlorination (Scheme 21) of 3 mM (19) with 1.5 equiv. PhICk led to the 9-chloro derivative (20) in >98% yield with Ag this was converted to the A ">-alkene. Again the template-directed reaction overcomes the normal reactivity of the substrate, but at 21 mM (19) undirected reactions start to compete and some 6-chloro steroid is also formed. A pyridine iV-oxide template, that can use three-electron bonding to complex a chlorine to the oxygen atom, seems to be almost as effective. Furthermore, an imidazole template in compound (21) directs chlorination at C-9 with similar efficiency to the templates previously examined, and (21) is particularly easily prepared using carbonyldiimida le. 

Dry hydrogen chloride induces ring closure of PhCH=NC(CN)=C(R)SMe to chloroimidazoles, and N-(l-cyanoalkyl)alkylideneamine iV-oxides (26) can be converted by way of nucleophilic attack by thiophenol into imidazoles substituted at C-5 by thio-phenoxy (Scheme 13). This latter reaction is accelerated by small amounts of piperidine, but inhibited by temperatures above the melting point of the N oxide. The action of cyanide ion on similar nitrones gives cyanoimines which cyclize to imidazoles in 40-90% yield (80JCS(PD244). 

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). 

Glycosyl iV-oxides have also been prepared from imidazole precursors. Thus the ethoxy-methylidene derivatives (316) and hydroxylamine gave, presumably via the hydroxyaminomethylene derivatives, isopropylideneadenosine (and 8-methyladenosine) 1-oxides (317) and (318), respectively, in 35% overall yield (Scheme 123) (69CPB1128). Similarly (316) andmethoxyaminefumished9-(2,3-0-isopropylidene-j8-D-ribofuranosyl)-6-methoxyaminopurine (319). 

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. 

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