Imidazoles Michael reactions

N-Unsubstituted pyrazoles and imidazoles add to unsaturated compounds in Michael reactions, for example acetylenecarboxylic esters and acrylonitrile readily form the expected addition products. Styrene oxide gives rise, for example, to 1-styrylimidazoles (76JCS(P1)545). Benzimidazole reacts with formaldehyde and secondary amines in the Mannich reaction to give 1-aminomethyl products. 

The mechanism of this reaction was hrst described by Breslow as early as 1958 [4], Subsequently, the natural enzyme thiamine, found in yeast, was replaced by related nucleophiles like thiazole [5,6], triazole [7] and imidazole [8], Reactions that follow this mechanism include the very important Stetter reaction (the benzoin condensation of aliphatic aldehydes), the Michael-Stetter reaction (a variant of the Stetter reaction where the aldehyde reacts with an a,P-unsaturated ketone) [1], transesteriflcations [9] or the acylation of alcohols [9,10], All four reactions are carbene catalysed nucleophilic acylation processes. 

Michael reaction Catalyzed by HfCU, indoles and pyrroles undergo Michael reactions with enones at C-3, and C-2/C-5, respectively. The reaction of pyrazole and imidazole takes place at an N-atom. 

Many reagents have been described to catalyze the Michael reaction but they are very substrate selective. An alternative method, which can be applied to a number of substrates of different natures, was developed. Thus, bismuth nitrate was used to catalyze the Michael reaction of various organic compounds with moderate to low nucleophilicity (amines, carbamates, indoles, imidazoles, and thiols) with unsaturated ketones. This procedure was proved to be very general, simple, and high yielding [27]. 

Boiani M, Gonzalez M (2005) Imidazole and benzimidazole derivatives as chemotherapeutic agents. Mini Rev Med Chem 5(4) 409 24. doi 10.2174/1389557053544047 Boncel S, Mqczka M, Walczak KZ (2010) Michael versus retro-Michael reaction in the regioselective synthesis of N-1 and N-3 uracil adducts. Tetrahedron 66(43) 8450-8457. doi 10. 1016/j.tet.2010.08.059... 

Davis introduced some complimentary strategies for the synthesis of functional ionic liquids, by the inclusion of functional group (FG) to the cationic skeleton, in his review (Davis, 2004). The called "task-specific ionic liquids" have been synthesized, for example, by N-alkylation of alkyl halides covalently linked to FG with appropriate Lewis bases (e.g., imidazole, amine, phosphine, and sulfide Scheme 2a), accompanied by the anion metathesis to realize ionic liquids. One of other strategies is to use Michael reaction of alkyl vinyl ketones linked to FG with tertiary cations, as in Scheme 2b (Wasserscheid et al., 2003). It is noteworthy that this facile one-pot reaction dispenses with the need for a further anion metathesis step and are free from haUde-containing by-product. 

Imidazole, 2-ethyl-1 -(o-nitrophenyl)-cyclization, S, 431 Imidazole, 4-ethyl-2-phenyl-oxidation, S, 405 Imidazole, ethynyl-Michael addition, S, 437 Imidazole, 4-ethynyl-2-phenyl-synthesis, S, 494 Imidazole, 1-formyl-reactions, S, 452 Imidazole, 2-formyl-mass spectra, S, 360 Imidazole, 4-formyl-synthesis, S, 475-476 Imidazole, 2-formyl-1,5-dimethyl-mass spectra, S, 360 3-oxide... 

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 2002, Leadbeater and Torenius reported the base-catalyzed Michael addition of methyl acrylate to imidazole using ionic liquid-doped toluene as a reaction medium (Scheme 6.133 a) [190], A 75% product yield was obtained after 5 min of microwave irradiation at 200 °C employing equimolar amounts of Michael acceptor/donor and triethylamine base. As for the Diels-Alder reaction studied by the same group (see Scheme 6.91), l-(2-propyl)-3-methylimidazolium hexafluorophosphate (pmimPF6) was the ionic liquid utilized (see Table 4.3). Related microwave-promoted Michael additions studied by Jennings and coworkers involving indoles as heterocyclic amines are shown in Schemes 6.133 b [230] and 6.133 c [268], Here, either lithium bis(trimethylsilyl)amide (LiHMDS) or potassium tert-butoxide (KOtBu) was em-... 

The microwave activation of Michael additions in the preparation of N-substituted imidazoles afforded excellent yields in very short reaction times under mild reaction conditions, Scheme 10.9. Basic clays (Li+, Cs+) exchanged montmorillonites were found to be very active and selective catalysts for the Michael addition of imidazole and ethyl acrylate [54]. 

The hthium ylide generated from methyl (2,2-dimethylpropylideneamino)ace-tate and LiBr/DBU reacts with an a,p-unsamrated ester bearing a perhydropyr-rolo[l,2-c]imidazole chiral auxiliary at the p-position at —78°C in THF to give a quantitative yield of the Michael adduct as a single diastereomer (Scheme 11.25) (112). When the reaction is performed at room temperature, the diastereoselectivity decreases to 95 5 and some epimerization is observed. Accordingly, epimerization is not a serious problem as long as the reaction temperature is kept at or below -78 °C. 

Some Michael additions of unsaturated reagents to imidazoles involve the neutral species of the heterocycles, but others may be reactions of the anion. Fluoride ion catalyzed addition of 2-methyl-4-nitroimidazole (113) to a suitable Michael acceptor gives almost quantitative yields of the 1-substituted 4-nitroisomers (114) (90JOC3702,91JCR(S)35o). 

Imidazole, l,2,5-trimethyl-4-nitro-mass spectra, 5, 359 Imidazole, 1-trimethylsilyl-reactions, 5, 454 with acid chlorides, 5, 391 Imidazole, 1-trimethylstannyl-reactions, 5, 454 Imidazole, 2,4,5-trinitro-reactions, 5, 98 synthesis, 5, 395 Imidazole, 1,2,4-triphenyl-UV spectra, 5, 356 Imidazole, 1,2,5-triphenyl-UV spectra, 5, 356 Imidazole, 2,4,5-triphenyl-chemiluminescence, 5, 381, 406 irradiation, 5, 433 oxidation, 5, 376, 406 photochemical addition reactions, 5, 421 synthesis, 5, 467, 483 UV spectra, 5, 356, 357 Imidazole, 1-trityl-rearrangement, 5, 377 Imidazole, vinyl-Michael addition, 5, 437 polymers, 1, 281 Imidazole, 1-vinyl-reactions, 5, 450 thermal rearrangement, 5, 450 Imidazole, 2-vinyl-oxidation, 5, 437 Imidazole, l-(D-xylofuranosyl)-synthesis, 5, 491 277-Imidazole, 2,2-dialkyl-rearrangement, 5, 422 277-Imidazole, 4,5-dicyano-2,2-dimethyl-synthesis, 5, 472... 

Vinyl and ethynyl groups attached to an imidazole ring can be catalytically reduced to the saturated (or less unsaturated) species and cleaved by oxidation. The corresponding 4-carbaldehyde is formed in 71% yield when l-methyl-2,5-diphenyl-4-styrylimidazole is oxidized with osmium tetroxide. However, they may not react like aliphatic alkenes and alkynes not all addition reactions occur normally, Michael additions are known, and the compounds can act as dienophiles in DielsAlder reactions (e.g., Scheme 132). 

Benzotriazole was found to be an efficient ligand for the Cu(I) iodide-catalyzed N-arylation of imidazoles with aryl and heteroaryl halides <07TL4207>. The first enantioselective conjugate addition reaction of I //-benzotriazole with a variety of enones catalyzed by a cinchona alkaloid thiourea affords Michael adducts in good yields with moderate to good enantioselectivities has been reported <07S2576>. 

Regioselective Michael addition of imidazole to levoglucosenone 475 is effectively catalyzed by cathodic electrolysis. The electrochemical conditions are milder and provide higher yields as compared to the base-catalyzed reactions (Scheme 110) <1996JOC8786>. 

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