Acyl imidazolide

These carbon nucleophiles react with acyl chlorides220 or acyl imidazolides.221 The initial products decarboxylate readily so the isolated products are (3-ketoesters. 

Acyl imidazolides are more reactive than esters but not as reactive as acyl halides. Entry 7 is an example of formation of a (3-ketoesters by reaction of magnesium enolate monoalkyl malonate ester by an imidazolide. Acyl imidazolides also are used for acylation of ester enolates and nitromethane anion, as illustrated by Entries 8, 9, and 10. (V-Methoxy-lV-methylamides are also useful for acylation of ester enolates. 

To complete the synthesis of finasteride, carboxylic acid 17 in lOml(gTHF)"1 was activated with CDI (1.02equiv) to form the acyl imidazolide 18 (Scheme 3.11). Without isolation, the acyl imidazolide was reacted with 4.6equiv of t-BuNHMgBr heating to reflux in THF for 18h to give finasteride in 98% yield [9]. 

Scheme 3.11 Preparation of finasteride from carboxylic acid 16 via the acyl imidazolide.

There were several problems to address in developing the conversion of the unsaturated acyl imidazolide 18 to these ketones. The acetylacetonate ligand was found to add to 18 leading to more than 2% of a by-product, believed to be 59 (Figure 3.7), which proved difficult to remove. The reaction also consumes far more organomagnesium reagent than should be necessary 5 equiv are required for complete conversion (the theoretical is 2.0). Also, the reaction provided best results when carried out at low temperature (-35 °C). 

Acyl imidazolides are more reactive than esters but not as reactive as acyl halides. /1-K.cto esters are formed by reaction of magnesium salts of monoalkyl esters of malonic acid with imidazolides. 

Acyl imidazolides have also been used for acylation of ester enolates and nitromethane anion, as illustrated by entries 9 and 10 in Scheme 2.14. 

Among the alternative polymerization schemes, the approach involving acyl imidazolides is quite unique. Although, imidazolides are generally sufficiently... 

The 6th rank in terms of acylation reactivity that is attributed to the acyl imidazolides in Table 6.1 (entry 10) is also plausible. In the acyl imidazolides, the free electron pair of the acylated N atom is essentially unavailable for stabilization of the C=0 double bond by resonance because it is part of the -electron sextet, which makes the imidazole ring an aromatic compound. This is why acyl imidazolides, in contrast to normal amides (entry 2 in Table 6.1) can act as acylating agents. Nevertheless, acyl imidazolides do not have the same acylation capacity as acylpyridinium salts because the aromatic stabilization of five-mem-bered aromatic compounds—and thus of imidazole—is considerably smaller than that of six-membered aromatic systems (e. g., pyridine). This means that the resonance form of the acyl imidazolides printed red in Table 6.1 contributes to the stabilization of the C=0 double bond. For a similar reason, there is no resonance stabilization of the C=0 double bond in N-acylpyridinium salts in the corresponding resonance form, the aromatic sextet of the pyridine would be destroyed in exchange for a much less stable quinoid structure. 

A rapid method for esterification using a mild agent was described by Ko and Royer [37], A substrate containing a carboxyl group reacts with N,N -carbonyldiimidazole, and the acyl imidazolide produced in this way is decomposed with alcohol and the appropriate ester is produced (Scheme 4.9). The reaction proceeds very rapidly even at room temperature and is completed within several minutes. In the course of this procedure no transesterification of the esters occurs, e.g., triglycerides or cholesteryl esters. The method... 

The C17S mutant reacts cleanly with a number of thiol-specific agents, e.g. p-nitrophenyldisulphide, and a number of saturated and functionalised acyl residues can be cleanly added to the protein via the corresponding acyl imidazolides. In all cases the extent of fidelity of acylation can be monitored by ESMS. ... 

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. 

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). 

Several procedures required for the preparation of porphyrins with labile side chains have already been referred to above or in the earlier article, for example, the conversion of acetoxyethyl or aminoethyl groups (introduced at the pyrrole stage) into vinyl groups. The preparation of porphyrin 3-keto esters has now been improved by the use of imidazolides (rather than acid chlorides) in condensations with magnesium methyl hydrogen malonate. The porphyrin acyl imidazolides have also been converted into acrylic esters by the sequence porCo-imidazole - -CH2OH — CHO - CH = CHC02Me. Alternatively the porphyrin ketoesters may be reduced with borohydride to hydroxyesters and dehydrated to acrylic esters. ... 

Overall, this coupling substrate showed the greatest flexibility in the coupling of arene heterocycles with a wide variety of 3-substituted (Ri-substituted) A - Pr-substituted a,P-unsaturated 2-acylimidazoles. The resulting acyl imidazolides could be converted in straightforward fashion to either aldehyde, ketone, acid, ester, or amide moieties using a one-pot two- or three-reaction sequence (not shown in scheme). ... 

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