Imidazole alkylation reactions

Imidazole, 4-acetyl-5-methyl-2-phenyl-synthesis, 5, 475 Imidazole, 1-acyl-reactions, 5, 452 rearrangement, 5, 379 Imidazole, 2-acyl-synthesis, 5, 392, 402, 408 Imidazole, 4-acyl-synthesis, 5, 468 Imidazole, C-acyl-UV spectra, 5, 356 Imidazole, N-acyl-hydrolysis rate constant, 5, 350 reactions, 5, 451-453 synthesis, 5, 54, 390-393 Imidazole, alkenyl-oxidation, 5, 437 polymerization, 5, 437 Imidazole, 1-alkoxycarbonyl-decarboxylation, 5, 453 Imidazole, 2-alkoxy-l-methyl-reactions, 5, 102 thermal rearrangement, 5, 443 Imidazole, 4-alkoxymethyl-synthesis, 5, 480 Imidazole, alkyl-oxidation, 5, 430 synthesis, 5, 484 UV spectra, 5, 355 Imidazole, 1-alkyl-alkylation, 5, 73 bromination, 5, 398, 399 HNMR, 5, 353 synthesis, 5, 383 thermal rearrangement, 5, 363 Imidazole, 2-alkyl-reactions, 5, 88 synthesis, 5, 469... 

Whereas pyrrole was reported not to give N/H insertion by ketocarbenoids, such a reaction mode does occur with imidazole Copper-catalyzed decomposition of ethyl diazoacetate at 80 °C in the presence of imidazole gives ethyl imidazol- 1-ylacetate exclusively (93 %) small amounts of a C-alkylated imidazole were obtained additionally under purely thermal conditions 244). N/H insertion also takes place at benzimidazole 245 a). The reaction is thought to begin with formation of an N3-ylide, followed by N1 - C proton transfer leading to the formal N/H insertion product. Diazomalonic raters behave analogously however, they suffer complete or partial dealkoxycarbonylation under the reaction conditions 244) (Scheme 34). N-alkylation of imidazole and benzimidazole by the carbenoids derived from co-diazoacetophenone and 2-(diazoacetyl)naphthalene has also been reported 245 b>. 

This alkylation reaction can be applied to intramolecular alkylation affording cyclic products, as shown in Equations (19)-(21). The reaction of 2-vinylpyridines with 1,5- or 1,6-dienes results in the formation of five- or six-membered carbocycles with good efficiency.20,20a,20b In addition to pyridine functionality, oxozole and imidazole rings can be applied to this intramolecular cyclization. When the reaction is conducted in the presence of a monodentate chiral ferrocenylphosphine and [RhCl(coe)2]2, enantiomerically enriched carbocycles are obtained. A similar type of intramolecular cyclization is applied to TV-heterocycles. The microwave irradiation strongly... 

Reactions of Phosphonic and Phosphinic Acid Derivatives.—The reactions of phos-phonic and thiophosphonic amides and chlorides with carboxylic acid chlorides and amides have been discussed.101 Dialkyl alkylphosphonates and alkyl dialkylphos-phinates may be used for the iV-alkylation of imidazoles, triazoles, and pyrroles.105... 

The most common methods suitable for the synthesis of different azolium compounds will be discussed here. Two routes are particularly useful for the preparation of the imidazolium salts (1) substitution reactions at the nitrogen atoms of imidazole [25] and (2) multicomponent reactions for the generation of an Af,Af -substituted heterocycle which are particularly useful for the synthesis of imidazolium salts bearing aromatic, very bulky, or particularly reactive N,N -sub-stituents (Fig. 3a,b) [26]. Both methods offer the opportunity to produce unsym-metrically substituted imidazolium salts of type 1 either by stepwise alkylation of imidazole or by the synthesis of an W-arylated imidazole derivative followed by 77 -alkylation [27]. Nevertheless, the method of choice for the preparation of the imidazolium salts 1 is the 77,77 -substitution of imidazole. Several other methods for the preparation of imidazolium salts with previously unattainable substitution patterns have also been described [28, 29]. 

Electrophilic alkenes have been appended to imidazolium-type ILs for use in the Diels-Alder cycloaddition, 1,4-addition, Heck and Stetter reactions.Electrophilic alkenes containing Wang-type linkers were alkylated to imidazole followed by ion exchange and esterification giving the desired TSIL. Diels-Alder cycloaddition was carried out with 2,3-dimethylbutadiene and cyclopentadiene to give corresponding adducts. After washing with ether, transesterification resulted in cyclohexene derivatives. Scheme 29. 

Substituted imidazo[4,5-c]pyridin-2-ones such as compound (149) upon reaction with iodo-methane gave intractable mixtures rather than the desired product (150). To prepare compound (150) one must first /V-alkylate the imidazole (151) and subsequently annulate <93JMC1341>. 

A stereoselective synthesis of (+)-pilocarpine (7) starting from L-histidine (2) has been worked out by Noordam et al. (88 - 90). Use was made of the S configuration of the amino acid, which is the same as that of C-3 of the lactone ring in both (+)-pilocarpine and (+)-isopilocarpine. Furthermore, regioselective N-alkylation reactions of the imidazole nucleus of histidine had been developed by Beyerman et al. (29,91). Schemes 3 and 4 depict the different ways of the regioselective alkylations. For the synthesis of pilocarpine, the N7I-methylation has been performed via Nb-protection with the 4-nitrobenzenesulfonyl group, instead of the benzoyl group (29). 

There are numerous examples of quaternizing alkylations of imidazoles using such diverse reagents as alkyl, alkenyl or aralkyl halides, ethyl chloroacetate, phenacyl bromide or dimethyl sulfate. Since water is frequently held very tenaciously by imidazole quaternary salts the compounds are often best prepared in anhydrous conditions (e.g. dry benzene solvent in a dry nitrogen atmosphere) even though the reaction is commonly slower in non-polar solvents. 

Imidazole alkylations can be carried out under a variety of reaction conditions. For conventional iV-alkylations which are unlikely to be complicated in terms of regiochemistry, it is preferable to alkylate the imidazole anion (an Se2cB process). Such reactions are faster, higher yielding and less prone to azole salt formation than those in neutral conditions. The anion is generated best by the use of sodium in ethanol or liquid ammonia, with sodium or potassium hydroxide or carbonate, or by use of sodium hydride in dry DMF [3]. Addition of the alkylating agent to the deprotonated substrate completes the reaction. 

Although a number of such radical reactions are known, few promise much synthetic potential, Examples include the 2-phenylation of imidazole and benzimidazole by benzoyl peroxide, but both products are more readily obtained by other routes. Homolytic alkylations of imidazole and benzimidazole also occur at C-2, but usually give indifferent yields [10]. A potentially useful reaction is the synthesis of 2- and 4-trifluoromethylimidazoles from imidazoles and photochemically generated trifluoromethyl radicals. 1-Substituted imidazoles are largely substituted at C-5 in these reactions benzimidazole reacts initially at the 4-position [11-14]. 

However, the following are examples of direct electrophilic alkylation of imidazole. A two-step synthesis of marine natural product ageladine A 271 started from the commercially available histamine 269 and the pyrrole-2-carbox-aldehyde 268. The entire skeleton of the alkaloid was built in one step via a Pictet-Spengler type condensation. The reaction was accelerated by Lewis acid scandium triflate, although the reaction did proceed without a catalyst but at a slower pace (Scheme 68) <20060L4083>. 

Since N-acylation is a reversible process, it has allowed the regiospecific alkylation of imidazoles to give the sterically less-favored derivative, i.e., the 1,5-disubstituted derivative (e.g., 109 Scheme 22). ° The sequence followed is (1) acylation (2) alkylation (often with oxonium reagents) and (3) deacylation with alcohol, water, or base. The N-acylation of 2-substituted imidazoles using ethyl chloroformate, triethylamine, and acetonitrile gives JV-alkoxycarbonylimidazoles ° which can lose carbon dioxide to give the JV-alkyl derivatives. The reaction is of limited use in the synthesis of asymmetrically substituted imidazoles since, whereas 2-ethyl-4-methylimidazole gave >95% of l-carbethoxy-2-ethyl-4-methylimidazole, the subsequent decarboxylation afforded a 3 1 mixture of 1,2-diethyl-4-methyl and l,2-diethyl-5-methyl compounds. 

In 2009, Roelfes and co-workers reported the catalytic AFC alkylation reaction with olefins in water mediated by a DNA-based catalyst. The DNA-based catalyst is self-assembled by combining a Cu" complex with salmon testes DNA (st-DNA), which is inexpensive and readily available. With 4,4 -dimethyl-2,2 -bipyridine (dmbpy) as the ligand, 30 mol% (0.3 mM) of [Cu(dmbpy)(N02)2] (Cu-dmbpy) and 1.4 mg mL of st-DNA (2 mM in base pairs) were found to be the optimal reaction conditions for the AFC reaction of indoles with o,p-unsaturated 2-acyl imidazoles 98. The AFC products 99 were obtained in good yields and enantioselectivity (Table 6.11). Particularly noteworthy was that with 0.15 mol% catalyst, good yields and high ee values (up to 93 /o) were also obtained for various a,p-unsaturated 2-acyl imidazoles 98 and indoles. 

This concept was applied to the intramolecular alkylation of imidazole and benzimidazole derivatives (Scheme 19.86) [121]. Preliminary results showed that while the Wilkinson catalyst was effective for this transformation, standard ruthenium catalysts were unreactive. Further screening using [RhCl(coe)2]2 as the rhodium source with various phosphine ligands revealed that electron-rich ligands such as PCyj yielded the best results. As the reaction was found to be more efficient in the presence of the Lewis or Bronsted acid, an optimized protocol was devised through the use of [HPCyjKQ] imder microwave irradiation [122]. Mechanistic studies showed that the reaction is zero order in substrate and first order in catalyst. 

Comparative kinetic studies using PEGs as PTCs for the alkylation of imidazole by alkyl halides showed that reaction follows pseudo-first-order kinetics. 

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