3- Substituted imidazole 1-oxide alkylation

The medium has no specific oxidative action towards the alkyl radicals, and in the presence of protonated base the major reaction is a substitution. Thus, imidazoles and 1-substituted imidazoles are alkylated exclusively at C-2, albeit in rather low yields. The use of isopropyl and r-butyl radicals gives improved yields (80-90%) but benzyl and allyl radicals tend to dimerize in preference. Benzimidazoles are also alkylated at C-2, and with isopropyl and t-butyl radicals yields of 50-80% can be achieved (80AHC(27)24l, 74AHC(16)123). 

Imidazole was converted by hydrogenation over platinum oxide in acetic anhydride to 1,3-diacetylimidazolidine in 80% yield, and benzimidazole similarly to 1,3-diacetylbenzimidazoline in 86% yield [480. While benzimidazole is very resistant to hydrogenation over platinum at 100° and over nickel at 200° and under high pressure, 2-alkyl- or 2-aryl-substituted imidazoles are reduced in the benzene ring rather easily. 2-Methylbenzimidazole was hydrogenated over platinum oxide in acetic acid at 80-90° to 2-methyl-... 

Substituted imidazole 1-oxides 228 can be prepared by N-oxidation of imidazoles 248, by N-alkylation of 1-hydroxyimidazoles 249, or by cycliza-tion using suitable starting materials derived from a 1,2-dicarbonyl compound, an aldehyde, an amine, and hydroxyamine. The substituents at the three first starting materials are transferred to the product and make control over the substituents in the imidazole 1-oxide 228 possible depending on the protocol used by the synthesis. The synthesis of 3-hydroxyimidazole 1-oxides is presented in Section 3.1.6. 

At-Alkylation of 1-hydroxyimidazoles 249 produces 3-substituted imidazole 1-oxides 228 (R=Aik) in low yields due to competing O-alkylation and dialkylation leading to 1-alkoxyimidazoles 250 and l-alkyl-3-alkyloxy-imidazolium salts 251, respectively (1970ZC211,1990S795) (Scheme 70). 

This issue was addressed taking into advance that butyloxycarbonyl (Boc)protection of 249 takes place regioselectively at the oxygen atom to give 252. Subsequent alkylation finds only N-3 accessible for attack (1990S795). Subsequent methanolysis and neutralization afforded the 3-substituted imidazole 1-oxide 228 (Scheme 71). 

Substituted imidazole 1-oxides 228 are predicted to be activated toward electrophilic aromatic substitution, nucleophilic aromatic substitution, and metallation as described in Section 1. Nevertheless little information about the reactivity of imidazole 1-oxides in these processes exists. The reason for this lack may be the high polarity of the imidazole 1-oxides, which makes it difficult to find suitable reaction solvents. Another obstacle is that no method for complete drying of imidazole 1-oxides exists and dry starting material is instrumental for successful metallation. Well documented and useful is the reaction of imidazole 1-oxide 228 with alkylation and acylation reagents, their function as 1,3-dipoles in cycloadditions, and their palladium-catalyzed direct arylation. 

Substituted imidazole 1-oxides 263 upon treatment with dimethyl or diethyl sulfate furnish l-alkoxy-3-subtituted imidazolium salts 283 that were converted to the tetrafluoroborate 283 (A- = BF4 ) or hexafluorophos-phates 283 (A = PF6-) by treatment with sodium tetrafluoroborate or hexa-fluorophosphate (2007ZN(A)295). The tetrafluoroborates 283 (A = BF4 ) reacted with cyanide ion to give 2-cyanoimidazoles 285 (1975JCS(P1)275). The reaction probably follows a mechanism similar to that suggested to be operative in the pyrazole series encompassing O-alkylation succeeded by nucleophilic addition and elimination of methanol (Scheme 85). 

Alkyl and fused aryl substituents (as in benzimidazoles) are oxidized by permanganate to carboxyl substituents. Oxidation of methylimidazoles with selenium dioxide is only useful in the case of benzimidazoles for the synthesis of imidazole aldehydes.426 The chemiluminescence of aryl-substituted imidazoles has been studied.427... 

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]. 

Radical substitution reactions include alkylations and arylations in the main. Nucleophilic radicals produced by the silver-catalyzed oxidative decarboxylation of carboxylic acids (by peroxydisulfate ion) attack proton-ated azoles at the most electron-deficient sites.Thus, imidazole and 1-alkylimidazoles are methylated exclusively at C-2 in rather low yields. The use of isopropyl and t-butyl radicals gives improved yields, but benzyl and acyl radicals tend to dimerize rather than substitute the... 

Although it is not easy to compare the electrochemical stabilities of different ILs, it is known, as described above, that the cations and anions of ILs have an impact on the electrochemical window. The cation species affect the reduction limit potential. l-Alkyl-3-methylimidazolium cations are easily reduced due to the presence of the hydrogen atom at the 2-position of the imidazole ring. When this position is substituted with an alkyl group, the reduchon stability is improved. The reduction stability of aliphatic quaternary ammonium and pyrrolium cations is higher than that of l-alkyl-3-methylimidazolium cations. The structure of the anion affects the oxidation potential. Some anions such as F2..3HF", N(CN)2, and C(CN)3 are easily oxidized, and other anions such as BF4, PFg, and N(CF3S02)2 have a relatively higher oxidation potential and present better oxidation stability. 

Alkyl radicals produced by oxidative decarboxylation of carboxylic acids are nucleophilic and attack protonated azoles at the most electron-deficient sites. Thus imidazole and 1-alkylimidazoles are alkylated exclusively at the 2-position (80AHC(27)241). Similarly, thiazoles are attacked in acidic media by methyl and propyl radicals to give 2-substituted derivatives in moderate yields, with smaller amounts of 5-substitution. These reactions have been reviewed (74AHC(i6)123) the mechanism involves an intermediate cr-complex. 

In relation to enzymic cytochrome P-450 oxidations, catalysis by iron porphyrins has inspired many recent studies.659 663 The use of C6F5IO as oxidant and Fe(TDCPP)Cl as catalyst has resulted in a major improvement in both the yields and the turnover numbers of the epoxidation of alkenes. 59 The Michaelis-Menten kinetic rate, the higher reactivity of alkyl-substituted alkenes compared to that of aryl-substituted alkenes, and the strong inhibition by norbornene in competitive epoxidations suggested that the mechanism shown in Scheme 13 is heterolytic and presumably involves the reversible formation of a four-mernbered Fev-oxametallacyclobutane intermediate.660 Picket-fence porphyrin (TPiVPP)FeCl-imidazole, 02 and [H2+colloidal Pt supported on polyvinylpyrrolidone)] act as an artificial P-450 system in the epoxidation of alkenes.663... 

---