Imidazolides with amines

In the context of synthesis and exchange reactions of biodegradable drug-binding matrices, starch trisuccinic acid was loaded via imidazolides with amines such as n-butylamine, morpholine, 4-aminobenzoic acid, or 3,4-dihydroxyphenylalanine to prepare the respective amides in high yields [160] an example is presented below. 

Imidazolides can also be activated by N-alkylation with methyl triflate.116 Imidazolides react with alcohols on heating to give esters and react at room temperature with amines to give amides. Imidazolides are particularly appropriate for acylation of acid-sensitive materials. 

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... 

Spin-labeled phosphoramidates are synthesized analogously by the reaction of phosphoric imidazolides with primary or secondary amines[189] or amino acid esters.11883... 

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). 

The formation of a phosphorimidazolide intermediate provides better reactivity toward amine nucleophiles than the EDC phosphodiester intermediate if EDC is used without added imidazole. The EDC phosphodiester intermediate also is shorter-lived in aqueous conditions due to hydrolysis than the imidazolide. Although EDC alone will create nucleotide phosphoramidate conjugates with amine-containing molecules (Shabarova, 1988), the result of forming the secondary phosphorimidazolide-activated species is increased derivatization yield over that of carbodiimide-only reactions. 

Like the mixed carbonic anhydride (intermediate A from Problem 7(a)), the intermediate imidazolide (intermediate C) is an activated carboxy group that can react with amines to form amides. The addition-elimination mechanism, illustrated below using arrow pushing, involves addition of an amine followed by elimination of imidazole. 

Acyl imidazolides can be used as activated acids they are very frequently used to prepare 3-keto esters from acids. It has recently been found that carbon dioxide dramatically increases the rate of reaction of the acyl imidazolide with an amine (see Vaidyanathan, R. Kalthod, V. G. Ngo, D. R Manley, J. M. Lapekas, S. P. J. Org. Chem. 2004, 69, 2565-2568). 

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. 

Photosensitive functions are in many cases also heat sensitive, so the preparation of photosensitive polyimides needs smooth conditions for the condensations and imidization reactions. Some chemical reactants, which can be used for polyamide preparation, have been patented for the synthesis of polyimides and polyimide precursors. For example, chemical imidization takes place at room temperature by using phosphonic derivative of a thiabenzothiazoline.102 A mixture of N -hydroxybenzotriazole and dicyclohexylcarbodiimide allows the room temperature condensation of diacid di(photosensitive) ester with a diamine.103 Dimethyl-2-chloro-imidazolinium chloride (Fig. 5.25) has been patented for the cyclization of a maleamic acid in toluene at 90°C.104 The chemistry of imidazolide has been recently investigated for the synthesis of polyimide precursor.105 As shown in Fig. 5.26, a secondary amine reacts with a dianhydride giving meta- and para-diamide diacid. The carbonyldiimidazole... 

Amides are conveniently prepared by the azolide method, usually in two steps first by reaction of the free carboxylic acid at room temperature with CDI in a 1 1 molar ratio under elimination of C02 the carboxylic acid imidazolide is formed after C02 evolution has ceased an equimolar amount of amine is then added.[1]... 

For the preparation of sterically crowded amides amino magnesium salts have been recommended for the reaction with imidazolides in order to increase the nucleophilicity of the amine moiety. Amino magnesium salts are prepared from the appropriate amines and ethyl magnesium bromide in tetrahydrofuran [90]... 

For the preparation of poly(methacrylamide), the poly(methacrylic acid) is converted with CDI into a polymer imidazolide, which reacts with an amine to give the corresponding polyamide [156M157]... 

Polyamides can also be prepared by the reaction of polyamines with azolides, as shown by the following reaction of nucleosil—300 (7 NH2), a spherical silica derivatized with propyl amine, with lecithin imidazolide 1623... 

Aminolyses of the imidazolides of aromatic sulfonic acids require prolonged heating with a primary amine at temperatures above 100 °C in a sealed tube to generate sulfonamides in good yield. 

The imidazolides required for these reactions can be prepared from sulfonyl chlor-ides[1] or sulfonic anhydrides[2] and imidazole, or by treatment of the corresponding sulfonic acid with CDI,[1] ImSOIm,[3] or ImS02Im[3] (see Section 10.1.1). However, for the synthesis of sulfonamides it is more convenient to employ a one-pot reaction starting from the free sulfonic acid, CDI or ImSOIm, and the appropriate amine [1]... 

The inductive effect of the imidazole substituents on the transphosphorylation of alcohols and amines with the following spin-labeled phosphoric imidazolides is discussed in reference [190]. 

The effect upon the transphosphorylation reaction with alcohols and amines of electron-releasing (CH3) and electron-withdrawing (Cl, N02) groups in the benzene ring of phosphoric imidazolides has been studied as well.[191]... 

Phenols can be converted with trifluoromethylsulfonic imidazolide in the presence of sodium hydride into the corresponding trifluoromethylsulfonates, which react with potassium amide/ammonia to give aromatic amines. 15]... 

In a recently published report by MacMillan s group [121] on the enantioselective synthesis of pyrroloindoline and furanoindoline natural products such as (-)-flustramine B 2-219 [122], enantiopure amines 2-215 were used as organocatalysts to promote a domino Michael addition/cyclization sequence (Scheme 2.51). As substrates, the substituted tryptamine 2-214 and a, 3-unsaturated aldehydes were used. Reaction of 2-214 and acrolein in the presence of 2-215 probably leads to the intermediate 2-216, which cyclizes to give the pyrroloindole moiety 2-217 with subsequent hydrolysis of the enamine moiety and reconstitution of the imidazolid-inone catalyst. After reduction of the aldehyde functionality in 2-217 with NaBH4 the flustramine precursor 2-218 was isolated in very good 90 % ee and 78 % yield. 

BSA possesses a total of 59 lysine e-amine groups (with only 30—35 of these typically available for derivatization), 1 free cysteine sulfhydryl (with 17 disulfides buried within its three-dimensional structure), 19 tyrosine phenolate residues, and 17 histidine imidazolides. The presence of numerous carboxylate groups gives BSA its net negative charge (pi 5.1). 

The reactivity of amines and imidazolide anions with aryl 4-toluenesulfonates (310) in 80% aqueous DMSO has been studied and Bronstcd [lmlc values of ca 0.7 and ca 1.0, respectively, were found.284 The points for botii die amines and die imidazolides can all be accommodated on die same Bronsted plot. S—O rather than C—O cleavage occurs in the reaction, hi a useful aside to tiiis work die authors have shown that plots of pKA data in water are linear witii tiiose in DMSO or 80% DMSO and tiiese can be used to obtain unknown pA, values. The same Ukrainian group has obtained deviations from Bronsted plots for the reaction of (310) witii highly basic nucleophiles such as imidazoles and arenesulfonamides. The /Jnuc value goes from 0.79 for pA/<11 to 0-0.1 for pKa>11.0.285... 

In this context, it is worthwhile to note that the use of alcohols in catalytic hydrogenations may lead to related aldehydes or ketones which in turn are capable of producing stable imidazolid-4-one derivatives with the N-terminal amine group.Moreover, when carrying out hydrogenations in an alcohol, oxygen has to be removed meticulously from the system to avoid as a serious side reaction N-alkylation via aldehyde and related imine derivatives which has been observed to occur readily, particularly with methanol as the solvent.f l An additional inconvenience observed when air is not rigorously excluded, is the formation of palladium complexes with the peptides. 

For reactions carried out in homogeneous solution or under solid-phase conditions the use of Fmoc amino acid chlorides is limited by the competition between their aminolysis and the formation of the less reactive oxazol-5(4//)-ones in the presence of tertiary amines, which are essential components of such reaction systems. To improve the results under these conditions a hindered base, e.g. 2,6-di-/er/-butylpyridine, can be used as a hydrogen chloride acceptor since conversion to oxazol-5(4//)-one is slow with such bases. Although shown to be advantageous in certain cases, Fmoc amino acid chlorides are used in homogeneous solution synthesis only in particular cases. They react efficiently in the presence of pyridine with weak nucleophiles such as imine 2P l (Scheme 2) where other activated species such as an active ester, anhydride, acyl fluoride, and acyl imidazolide fail. 

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