Friedel 2-acyl imidazoles

A chiral Sc-pybox catalyst from Sc(OTf)3 catalyzes a highly enantioselective Michael-type indole Friedel-Crafts reactions with a variety of )3-substitnfed a, -unsaturated acyl phosphonates and -substituted a,j8-unsaturated 2-acyl imidazoles (Scheme 2). The acyl phosphonate products were efficiently ttansformed into the corresponding esters and amides, whereas the acyl imidazole prodncts were converted to more diverse functionalities snch as esters, amides, carboxyhc acids, ketones, and aldehydes. A nuld and efficient cleavage protocol for the diversification of the 2-acyl imidazole prodncts ntihzing methylating conditions was also developed. 

Later, this catalytic system was successfully applied to the Friedel-Crafts alkylation of various a,P-unsaturated 2-acyl imidazoles with indole derivatives [152]. The corresponding products were obtained in moderate to excellent yields with moderate to excellent enantioselectivities, the best selectivity being displayed with... 

Evans and coworkers [44] expanded the scope of enanti-oselective Friedel-Crafts alkylation of indoles 122 through the utilization of a series of p-snbstituted a,p-unsaturated phosphonates 123 and a,p-nnsaturated 2-acyl imidazoles 124 (Scheme 10.25). The active catalyst was proposed to be the respective complex of these enones in a bidentate fashion with bis(oxazolinyl)pyridine-scandium(III) triflate 125. Generally, this asymmetric addition reaction was found to be... 

DNA can be used to induce chirality in Friedel-Crafts alkylation in water. Boersma et al. [115] first explored the enantioselective alkylation of indoles, using Cu-dmbpy/st-DNA as catalyst A variety of indoles reacted with 2-acyl imidazole, achieving moderate ee s, and full conversions in 10 h, as shown in Scheme 6.23. The small variation in the ee values indicates that substitution at the indole does not have a significant influence on the enantioselection. Recently, Li s group demonstrated the same reaction with a human telomeric G-quadruplex (G4DNA) metalloenzyme assembled with G4DNA and Cu ions. The enantioselectivity (up to 75% ee) was found to vary with the conformation and the sequence of G4DNA [116]. 

The synthesis of a pyrrole segment common to netropsin and distamycin is shown in Scheme 2ji°l Friedel-Crafts acylation of 1-methylpyrrole (1) followed by nitration at C4 provides 3 in 54% yield. After a haloform reaction, hydrogenolysis, N-protection with B0C2O, and saponification, the pyrrolecarboxylic derivative acid 7 was obtained in 30% overall yield from 3. This monomer is readily chain-extended to the pyrrole-imidazole derivative 9 (Scheme 3)J10 Furthermore, solid-phase synthesis with this and related pyrrole-containing building blocks leads to polyamides that have recently been used in the recognition of a 16 base-pair sequence in the minor groove of DNA.1" ... 

Electrophilic substitution of nitro and sulfonic acid groups occurs in strongly acid media and involves attack on the conjugate acid of imidazole—a system exhibiting pronounced deactivation. Electron density calculations294,296 297 predict the experimentally found substitution at positions 4 and 5. Acylation under Friedel-Crafts conditions does not occur in imidazoles. 

As the imidazole nucleus does not undergo Friedel-Crafts acylation, ketone substituents must be introduced indirectly, either before the ring is formed34,41,210,275,435 or by modification of existing substituents.210 Roe210 prepared 2-acetylimidazole (92) by oxidation of l-(imidazol-2 -yl)ethanol (91) with chromic oxide in pyridine. The acyl-substituted imidazoles have distinctive infrared and ultraviolet... 

Ordinarily, direct Friedel-Crafts alkylation and acylation do not take place on imidazoles due to deactivation of imidazole ring after coordination to a Lewis acid catalyst (CHEC-II(1996)). Most alkylations and acylations of imidazoles have been realized via quenching of an imidazole lithium derivative with a corresponding electrophile (CHEC-II(19%)). 

One of these was synthesized by the Friedel-Crafts acylation of o)-chloroacid chloride(26) (0.1 mole) and AICI3 (0.15 mole) with Bio-beads SXl, SX2, SX12 and SM2 (0.1 mole) in 200 ml of nitrobenzene for 2 hours at 5 C. The resin was washed with acetic acid, 61 HCl dioxane (1 1), H20-dioxane (1 1), dioxane, CH2CI2 and MeOH. The resin was dried under vacuo at 45°C and treated with the sodium derivative of imidazole in DMF. 

Friedel-Crafts acylations are unknown for the azoles, clearly because of interaction between the basic nitrogen and the Lewis-acid catalyst. It is, however, possible to 2-aroylate 1-alkyl-imidazoles " or indeed imidazole itself by reaction with the acid chloride in the presence of triethylamine, the substitution proceeding via an iV-acyl-imidazolium ylide. Trifluoroacetylation of iV-substituted imidazoles, and some oxazoles and thiazoles, also produces 2-substituted products in good yields. In the reverse sense, 2-acyl-substituents can be cleaved by methanolysis, the mechanism again involving an imidazolium ylide. ... 

While Friedel-Crafts acylations do not occur readily with imidazoles, quatemization can lead to 2-acylimidazoles. The reaction of iV-phenyl imidazole with benzoyl chloride and EtsN in MeCN provides first the N-... 

Reactions of the imidazole carbon atoms occur easily under basic or neutral conditions however, once protonated, electrophilic substitution is slowed. For example, Friedel-Crafts type alkylations and acylations do not readily occur under protic or Lewis acid conditions, which has led to die development of syntheses of imidazoles that more readily allow the desired carbon alkylated or acylated products. Nitration and halogenations of both 7V-un-substituted and A-substituted imidazoles take place with preferential addition to the 4- or 4- and 5-positions. ... 

Direct C-acylation of imidazole and pyrazoles in Friedel-Crafts reactions were previously unknown and it was predicted that this is not possible at all. It was previously necessary to rely on other more expensive methods of preparation. This direct acylation in the gas phase has been made possible by zeolite catalysts [15]. For example, if a mixture of 2-methylimidazole and acetic acid or acetic anhydride is reacted at 400 °C over a pentasil zeolite, the result is a conversion of 63 % and a selectivity of 85 % for 2-methyl-4-acetylimidazole. 

Aryltrifluoromethyl ketones are prepared by reaction of an aryl-lithium with a,a,a-trifluoro-N,N-dimethylacetamide. 2-Acyloxypyridines and N-acylimidazoles, " in conjunction with trifluoroacetic acid, acylate arenes in good yield without the need for a classical Friedel-Crafts catalyst or a preformed mixed anhydride. However, imidazole in trifluoroacetic anhydride is reported to form 2-aryl-Af,JV -diacyl-4-imidazolines with arenes reactive towards electrophilic attack. These adducts are readily hydrolysed by sodium hydroxide to the corresponding aldehyde [equation (14)]. This sequence may offer advantages over the Vilsmeier method of formylation, in that the aldehyde is introduced in a protected form. 

Pyridine itself can be reacted with olefins and carbon monoxide in the presence of a catalytic amount of Ru3(CO)i2 to give a-acylated pyridines (eq 8)T A number of olefins react with the pyridine to afford the corresponding linear p)ridyl ketones as the major products. The ruthenium-catalyzed carbonylation of 1,2-disubstituted imidazoles with olefins and carbon monoxide provides C-C bond formation at the 4-position (eq Various functional groups, e.g., ether, acetal, ester, imide, and nitrile are tolerant to the reaction conditions. The reaction of 1-methylpyrazole under similar carbonylation conditions gives 3-pyrazolyl ketones (eq 10). This result is in contrast to the Friedel-Crafts acylation of a pyrazole ring, which yields 4-pyrazolyl ketones. ... 

---