Imidazoles reaction with chloroform

Non-linear kinetics have been reported for aminolysis of sulfamate esters RNHSO2ONP (Np=/7-N02C6H4) in chloroform. The first-order rate constants obs for reaction with imidazoles (primarily) under pseudo-first-order conditions display saturation curvature with increasing amine concentration, according to the expression... 

As alternatives to 4-nitrophenyl chloroformate, carbonyl diimidazole [100-102] or di-A-succinimidyl carbonate [103,104] can be used to convert polymeric alcohols into alkoxycarbonylating reagents suitable for the preparation of support-bound carbamates. Polystyrene-bound alkoxycarbonyl imidazole is less reactive than the corresponding 4-nitrophenyl carbonate, and sometimes requires heating to undergo reaction with amines. Additional activation of these imidazolides can be achieved by N-methylation (Entry 9, Table 14.7). 

Reaction of imidazole with chloroformates in the presence of triethyl-amine produces 2-carboxylates (78S675). 

Methylimidazole (51) with chloroform in the vapor phase gave, among other products, 2-chloro-3-methylpyrazine (52) (550°C, flow system 17%) n other such reactions with imidazole, methylimidazoles, and methylimidazo-... 

When 3,4-disubstituted 4-aminoisoxazolin-5(4Af)-ones (9) are hydrogenated, and then subsequently recyclized, high yields of imidazoles (10) are obtained (Scheme 6.1.4). The starting materials can be readily made from isoxazolin-5(4Af)-ones by sequential bromination, reaction with sodium azide and conversion of azide into amino by reaction with hydrobromic acid in acetic acid. The amines are then converted into formamidine or acetamidine derivatives with DMF or dimethylacetamide under reflux in phosphoryl chloride-chloroform. Yields at this stage are 50-93%. Catalytic... 

Imidazole (6.8 g, 0.1 mol) is dissolved in DMSO (50 ml), and 1 cq. of powdered potassium hydroxide is added. When this has dissolved, the solution is cooled to 0°C, and benzenesulfonyl chloride (17.7 g, 0.1 mol) is added during 30min. The reaction mixture is then poured into water (l(X)ml) and extracted with chloroform (3 x 50ml). The organic extracts are washed with water, dried and evaporated to give a yellow oil, which usually solidifies on evacuation (12.4 g, 60%). Recrystallization from chloroform-hexane gives the pure product (8.2 g, 40%), m.p. 78°C. 

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. 

The reaction of chloroform with imidazoles > benzimidazoles and secondary amines (especially alicyclic amines) in the presence of alkoxides or hydroxides, as well as the reaction of chlorodifluoro-methane with sodium N-alkyl-iV-arylamides furnishes trisaminomethanes (525) and (526) (Scheme 95), respectively. Aziridine transforms fluorodialkyl sulfide (527) to the orthoamide (528 equation... 

A completely different picture emerges when nucleophilic attack on the carbonyl carbon is examined. The nucleophilic order follows the basicity order more closely as demonstrated by reactions of p-nitrophenyl acetate with anilines, pyridines, imidazoles, oxyanions, etc. (25, 26). The same is true for reactions with ethyl chloroformate (27). 

Comparing the formation of chloroformate 3 with triphosgene and of oxycarbonyl imidazole 4 with GDI, respectively, as activated intermediates for the preparation of carbamates at 7-0-taxol shows that, under similar reaction conditions, CDI yields better results than triphosgene [6] (see Section 4.2.1). 

Azoles containing a free NH group react comparatively readily with acyl halides. N-Acyl-pyrazoles, -imidazoles, etc. can be prepared by reaction sequences of either type (66) -> (67) or type (70)->(71) or (72). Such reactions have been carried out with benzoyl halides, sulfonyl halides, isocyanates, isothiocyanates and chloroformates. Reactions occur under Schotten-Baumann conditions or in inert solvents. When two isomeric products could result, only the thermodynamically stable one is usually obtained because the acylation reactions are reversible and the products interconvert readily. Thus benzotriazole forms 1-acyl derivatives (99) which preserve the Kekule resonance of the benzene ring and are therefore more stable than the isomeric 2-acyl derivatives. Acylation of pyrazoles also usually gives the more stable isomer as the sole product (66AHCi6)347). The imidazole-catalyzed hydrolysis of esters can be classified as an electrophilic attack on the multiply bonded imidazole nitrogen. 

The imidazole nucleus is often found in biologically active molecules,3 and a large variety of methods have been employed for their synthesis.4 We recently needed to develop a more viable process for the preparation of kilogram quantities of 2,4-disubstituted imidazoles. The condensation of amidines, which are readily accessible from nitriles,5 with a-halo ketones has become a widely used method for the synthesis of 2,4-disubstituted imidazoles. A literature survey indicated that chloroform was the most commonly used solvent for this reaction.6 In addition to the use of a toxic solvent, yields of the reaction varied from poor to moderate, and column chromatography was often required for product isolation. Use of other solvents such as alcohols,7 DMF,8 and acetonitrile9 have also been utilized in this reaction, but yields are also frequently been reported as poor. 

A V -Carbonyldiimidazole (CDI) is prepared in a convenient and safe procedure from phosgene and imidazole as a non-toxic crystalline compound (m.p. 116-118 °C).[5],[6] It reacts almost quantitatively at room temperature or by short and moderate heating with an equimolar quantity of a carboxylic acid in tetrahydrofuran, chloroform, or similar inert solvents within a few minutes to give the corresponding carboxylic acid imidazolide, which is formed under release of carbon dioxide, together with one equivalent of readily separable and recyclable imidazole.Thus, this reaction leads under very mild conditions to the activation of a carboxylic acid appropriate for transacylation onto a nucleophile with an alcohol to an ester, with an amino compound to an amide or peptide, etc. 

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