Methylation of imidazoles

Norzooanemonin (161) was isolated in 1973 by Weinheimer et al. (227), from the Caribbean bark coral Pseudopterogorgia americana. These authors confirmed structure 161 by synthesis. Methylation of imidazole-4-carboxy-lic acid with dimethyl sulfate yielded 85% norzooanemonin, identical to the natural product. 

Specific preparation of each of the above isomers should theoretically be possible by methylation of imidazole-4-carboxylic acid in neutral and basic media. Methylation yields, however, are unlikely to be high, and the separation... 

Preparation of iV-Methylimidazole. Al-Methylimidazole (NMI) can be prepared via methylation of imidazole using various alkylating conditions. One early method utilized a solution of MesSOH, producing NMI in quantitative yield (eq 8). ... 

The basicities of the parent azole systems in water are shown in Table 1. When both heteroatoms are nitrogen, the mesomeric effect predominates when the heteroatoms are in the 1,3-positions, whereas the inductive effect predominates when they are in the 1,2-positions. The predominance of the mesomeric effect is illustrated by the pK value of imidazole (82 Z = NH), which is 7.0, whereas that of pyrazole (83 Z = NH) is 2.5 cf. pyridine, 5.2). An fV-methyl group is base-strengthening in imidazole, but base-weakening in pyrazole, probably because of steric hindrance to hydration. When the second heteroatom is oxygen or sulfur the inductive, base-weakening effect increases the pK of thiazole (82 Z = S) is 3.5 and that of isoxazole (83 Z = 0) is 1.3. 

In general, methyl groups in the 4- and 5-positions of imidazole, oxazole and thiazole do not undergo such deprotonation-mediated reactions, even when the ring is cationic. 

The same system of nomenclature can be used to differentiate tautomers of types 22 and 23, which would be named 4-methyl-IH-imid-azole and 4-methyl-3//-imidazole, respectively. 

This trend is also observed in the reactions with nitrogen- and carbon-centered nucleophiles (2001H425). Thus, the reaction of 109 with sodium indolyl in DMF affords methyl 2-(indol-l-yl)indole-3-carboxylate (188, 77%). In better yield, 2-(indol-l-yl)indole-3-carbaldehyde (189, 95%) is formed in the corresponding reaction (99H1157) of 115a (Scheme 28). Sodium imidazolyl reacts with 109 in DMF at 60°C to afford methyl 2-(imidazol-l-yl)indole-3-carboxylate (190,28%), methyl indole-3-carboxylate (191,11 %), and unreacted 109 (36%). In contrast, under the same conditions, 110 and 115a provide higher yields of methyl 2-(imidazol-... 

This mechanism does not require a decision as to the question of whether the association of imidazole occurs through hydrogen bonding or by ionization. - However, if the methylation with diazomethane is considered together with methylations with dimethyl sulfate, dimethyl sulfate and alkali, and methyl iodide and the silver derivative of the imidazole, then such a comparison is best done using the hydrogen-bonded association model. 

Hardacre et al. have developed a procedure for the synthesis of deuterated imidazoles and imidazolium salts [65]. The procedure involves the platinum- or palladium-catalyzed deuterium exchange of 1-methyl-d -imidazole with D2O to give 1-methylimidazole-d , followed by treatment with a deuterated alkyl halide. 

On the other hand, the fragmentation of pyramine obtained from (2 -l3C)AIRs indicated clearly that C-2, in the ribose part, was the precursor of carbon C-7 of the methyl on C-2 of the pyrimidine ring (Scheme 29). This result was confirmed by an experiment with a sample of AIRs labeled with l4C on C-l, C-2, C-3, on the ribose, and C-5 on the imidazole, with an approximate distribution of 1, 1, 3, 3. This precursor produced pyramine with the methyl group almost as radioactive as C-l or C-2, and much less than C-3 of AIRs. Because of the incorporation of C-5 of imidazole into C-4 of pyramine, and the comparable activities of C-3 and C-5 in the precursor AIRs, the specific activity of pyramine... 

Further improvements in activity of the ruthenium carbene complexes were achieved by incorporation of methyl groups in 3,4-position of imidazol-2-ylidene moiety. Introduction of sulfur in the trara-position to the N-heterocyclic carbene leads to increased stability of the resulting ruthenium complexes. The synthesis and the first applications of these new rathenium complexes are described herein. 

An interesting synthesis of a nucleoside carbonic ester was conducted in excellent yield by reaction with 1 -methyl-3 - [2-(p-nitropheny l)ethoxycarbony 1]-imidazolium chloride (for an analogous introduction of the npeoc-protecting group, see also Section 3.10.1) [2393 as mentioned in Section 3.1.8, methylation of the imidazole unit increases significantly the reaction rate. 

The l-acyl-3-methylimidazole-2-thiones are easily obtained either from bis-l-methyl-2-imidazole disulfide, a carboxylic acid, and triphenylphosphine, or from 2-mercapto-l-methylimidazole and a carboxylic acid chloride in the presence of triethylamine.[32 ... 

For this reason the regioselective methylation of various 4-substituted 1-acetyl-imidazoles was studied.1[2] While reaction with l-acetyl-4-phenylimidazole furnished the isomers l-methyl-5-phenylimidazole and l-methyl-4-phenylimidazole in a ratio of 93 7, reaction with l-acetyl-4-methylimidazole produced an isomer ratio of 86 14. 

The central piperazine core of 396 has been synthesized from reaction of 2-bromobenzofuran-3-one 394 and l-methyl-l//-imidazole-2-carboxamide 395 in acetonitrile at elevated temperatures (Equation 106) <1999H(50)259>. 

US patent 6,734,308, Crystal forms of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-ethynyl-phenyl)-l-methyl-lH-quinolin-2-one, 2,3,-dihydroxy-butanedioate salts and method of production [108]. The invention relates to crystal forms of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-meth-yl]-4-(3-ethynyl-phenyl)-1 -methyl-lH-quinolin-2-one, 2,3-dihydroxy butanedioate salts, and to pharmaceutical compositions containing the above compound, methods of treating hyperproliferative diseases, such as cancers, in mammals, especially humans by administering the above compound, and to methods of preparing the crystal forms of the above compound and related compounds. 

A basic ionic liquid, l-methyl-3-butylimidazolium hydroxide ([bmIm]OH) and l-butyl-3-methyl-methylimidazolium tetrafluoroborate ([bmim]BF4), has been introduced as a catalyst and reaction medium for the Markovnikov addition of imidazoles 116 to vinyl esters 115 under mild conditions to give imidazoesters 117 <06JOC3991 06TL1555>. A series of (nitroimidazolyl)succinic esters and diacids were prepared from the Michael-type addition of the nitroimidazole to the a,P-unsaturated ester <06S3859>. 

In a recent study, another method for microwave-assisted heterocycle synthesis leading to a small set of imidazole derivatives has been reported [54], These pharmaceutically important scaffolds were synthesized utilizing polymer-bound 3-N,N-(dimethylamino)isocyanoacrylate. This polymer support was easily prepared by treatment of [4-(bromomethyl)phenoxy]methyl polystyrene with a twofold excess of the appropriate isocyanoacrylate potassium salt in N,N-dimethylformamide (Scheme 7.37). The obtained intermediate was subsequently treated with N,N-di-methylformamide diethyl acetal (DMFDEA) in a mixture of tetrahydrofuran and ethanol to generate the desired polymer-bound substrate. 

Since Plieger et al. (171) were able to obtain a crystal structure for [Be(H20)2( 1-methyl-lH-imidazol-3-ium-4,5-dicarboxylate)]+, we compared the calculated and measured bond lengths and found satisfactory agreement between experimental and calculated structures. However, there is a clear influence of the strong hydrogen-bonding network in the X-ray structure. 

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