Imidazolide, amide formation

A special case of amide formation was observed in the reaction of a furan-2-carboxylic acid with two moles of CDI and subsequent conversion with amines, hi this reaction, besides formation of the imidazolide, addition of imidazole also takes places.1-1411... 

Since formamide is a weak nucleophile, the use of imidazole or 4-dimethylaminopyridine (DMAP) is necessary for acyl transfer to formamide via an activated amide (imidazolide) or acylpyridinium ion. As Scheme 22 illustrates, the reaction starts with the oxidative addition of aryl bromide 152 to Pd(0) species, followed by CO insertion to form acyl-Pd complex 154. Imidazole receives the aroyl group to form imidazolide 155 and liberates HPdBr species. Then, imidazolide 155 reacts with formamide to form imide 156. Finally, decarbonylation of imide 156 gives amide 157. In fact, the formations of imidazolide intermediate 155 and imide 156 as well as the subsequent slow transformation of imide 156 to amide 157 by releasing CO were observed. This mechanism can accommodate the CO pressure variations observed during the first few hours of aminocarbonylation. When the reaction temperature (120 °C) was reached, a fast drop of pressure occurred. This corresponds to the formation of the intermediary imide 156. Then, the increase of pressure after 3 h of reaction was observed. This phenomenon corresponds to the release of CO from imide 156 to form amide 157. ... 

This synthesis also gives a small glimpse at the chemistry of heterocyclic compounds. Most active compounds in today s pharmaceuticals or agrochemicals include heterocycles, as well as most vitamins and natural products. The chemistry of heterocycles is thus very important and lectures or textbooks should be consulted.6 Formation of amide bonds also plays a large role in this problem. It was demonstrated that the strong amide bond can be formed from an amine and a carboxylic acid only after the acid has been activated. This can be done by transformation into the carboxylic halide or imidazolide or by application of an activating agent developed for peptide synthesis. 

Alcoholysis of amides is possible, although it is usually difficult. It has been most common with the imidazolide type of amides (e.g., 100). For other amides, an activating agent is usually necessary before the alcohol will replace the NR2 unit. Dimethylformamide, however, reacted with primary alcohols in the presence of 2,4,6-trichloro-l,3,5-pyrazine (cyanuric acid) to give the corresponding formate ester. Treatment of an amide with triflic anhydride (CF3SO2OSO2CF3) in the... 

Dehydrohalogenation of amide chlorides affords a-chloroenamines, which undergo cycloaddition with IV-diphenylmethylaldimines to furnish azetidinium salts (303 equation 161). From these salts the diphe-nylmethyl group can be removed by hydrogenation, subsequent deprotonation yields 2-amino-1-aze-tines. The addition of primary or secondary amines to nitrilium salts gives rise to formation of amidinium salts and amidines respectively, e.g. (304 equation 162). In a similar reaction from copper(I) imidazolide, r-butyl bromide and nitriles amidines (305 equation 163) were prepared. ... 

One potential explanation for the slow reaction in the pilot plant was that the CO2 released in the imidazolide formation step was not removed completely from the reactor in the pilot plant prior to addition of diamine 8. This lingering CO2 conld have reacted with the amine to form the carbamate salt, thns slowing the amidation reaction. 

PROBLEM 17.37 In Section 17.7b, we saw how dicyclohexyl-carbodiimide (DCC) could be used as a dehydrating agent for the formation of amides from carboxylic acids and amines. Another reagent that can be used to good effect is the phosgene derivative A(A -carbonyldiimidazole (CDI). Carboxylic acids and CDI react under mild conditions to form imidazolides, 1, which then easily react with amines to give amides. Propose mechanisms for the formation of 1 from carboxylic acids and CDI, and for the formation of amides from 1 and amines. 

---