Acylation 1,1 -Carbonyldiimidazole

Methyl acetoacetate, 60 p-(Tolylsulfinyl)methyllithium, 115 Intramolecular acylation 1,1 -Carbonyldiimidazole, 66 of organometallic reagents to form carbonyl compounds... 

The benzoic acid moiety common to many of the benzamides is prepared in straightforward manner from the methyl ether of p-aminosalicylic acid 141. Acylation on nitrogen (142) followed by chlorination gives intermediate 143 benzoic acid 144 is then obtained by removal of the acetyl group. Condensation of this acid with an aminopiperidine could be achieved by means of the mixed anhydride (prepared by reaction with ethyl chlonoformate), which affords clebopride (145). Reaction with 3-aminoquinuclidine (146) of the intermediate prepared from acid 144 with carbonyldiimidazole affords zacopride (147) [36]. 

To set the stage for the crucial carbene insertion reaction, the acetic acid side chain in 32 must be homologated. To this end, treatment of 32 with 1,l -carbonyldiimidazole furnishes imidazo-lide 33, a competent acylating agent, which subsequently reacts with the conjugate base of Meldrum s acid (34) to give 35. Solvolysis of this substance with para-nitrobenzyl alcohol in acetonitrile at reflux provides /Mceto ester 36 after loss of one molecule of ace-... 

In addition to acyl halides and acid anhydrides, there are a number of milder and more selective acylating agents that can be readily prepared from carboxylic acids. Imidazolides, the (V-acyl derivatives of imidazole, are examples.115 Imidazolides are isolable substances and can be prepared directly from the carboxylic acid by reaction with carbonyldiimidazole. 

FIGURE 6.10 The side chain of histidine is readily acylated (A) by activated residues. The imidazolide produced is an activated species similar to the intermediate generated by reaction (B) of a carboxylic acid with coupling reagent carbonyldiimidazole. (Staab, 1956). Imida-zolides acylate amino and hydroxyl groups. Isomerization of histidyl during activation results from abstraction (C) of the a-proton by the 7t-nitrogen. 

Macor has developed what appears to be a quite general method for the acylation (protection) of the indole nitrogen using l,r-carbonyldiimidazole (CDI) in the presence of DMAP. Reaction of substituted indoles 98 with CDI presumably occurs to form the imidazolyl amide of indole 99 which upon treatment in situ with either amines, alcohols or thiols affords the desired indole-1-carboxamides, -1-carboxylates, or 1-thiocarboxylates derivatives 100, respectively. 

Carbonyldiimidazole does certainly stand out as one of the most remarkable reagents for peptide coupling. Carboxylic acids react readily with this reagent to yield acyl imidazoles which in turn couple with the amino group of a peptide to produce a new acyl-nitrogen linkage with very little racemization. Reaction of the acylimidazolide with other nucleophiles can lead to a variety of carbonyl derivatives (62AG(E)35l). 

An essentially neutral process for C-acylation relies on the reaction of imidazolides (542) with the magnesium salt (543) of a malonic acid half thiol ester (Scheme 119) (79AG(E)72>. The method requires slight modification when applied to an w-hydroxycarboxylic acid since a primary hydroxyl reacts with carbonyldiimidazole. The use of malonic acid half thiol esters in this fashion patterns the scheme proposed for carbon-carbon bond formation in the biosynthesis of fatty acids. 

In addition to moving the sulfonyl chloride earlier in the synthesis, the commercial route also uses an acyl imidazole to form a key amide bond (13.77 — 13.79) instead of an acid chloride (13.67 — 13.70, Scheme 13.12). Carbonyldiimidazole (13.76) is an expensive reagent, but the use of acyl imidazole 13.77 gives many advantages. The yields of the amide-forming reaction are higher, and solvent requirements are greatly simplified. The overall... 

Amino acylations.1 This salt is far more reactive, particularly for O-acylation, than N,N -carbonyldiimidazole. Thus it effects esterification of N-Cbz protected amino acids with even hindered alcohols such as /-menthol in 98% yield without need of a base and, consequently, free from racemization. It also can effect coupling of amino acids in high yields and without racemization. 

Recently, Melillo et al.t applied this Meldrum s acid method with some modifications to the synthesis of thienamycin. A carboxylic acid was treated with carbonyldiimidazole, followed by treatment with Meldrum s acid to give an acyl Meldrum s acid, which was converted to a 0-keto p-nitrobenzyl ester by refluxing in acetonitrile containing p-nitrobenzyl alcohol. ... 

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... 

When intermediate 81 is formed from indole 80 and l,l -carbonyldiimidazole (GDI) using DMAP to promote indole nitrogen acylation in acetonitrile at reflux, it is reasonably stable, observed by TLC, but not isolated. Treatment of intermediate 81 in situ with amines, alcohols, or thiols afforded the desired derivatives 82. During the reaction of indoles with GDI, some carbonyl diindole 83 was formed. In many cases this material could be isolated and characterized. In an alternative approach, alcohols reacted with GDI stoichiometrically to form an unstable intermediate carbamate species 84, which could in turn be reacted with indoles to form the desired indole-1-carboxylates 82. This new methodology for the formation of compound 82 proved to be useful in one of the approaches for the synthesis of novel Serotonergics. 

The ideas for delocalization of nitrogen lone pair electron density into an aromatic or heteroaromatic system were pursued through reduction of acylated pyrazoles and imidazoles to aldehydes in high yield. 3,5-Dimethyl-A -acylpyrazoles are easy to prepare and afford 77-96% yields of aldehydes with LiAlH4 in diethyl ether at 0 Further examples of this reaction have appeared.Although these later publications commented unfavorably on the ability of LiAlH4 to reduce acyl imidazoles to aldehydes (low yields), other workers have demonstrated that yields of 60-80% could be attained at temperatures of -20 to 4-20 °C in diethyl ether.It was considered that the earlier failure may have been caused by the presence of impurities in the acyl imidazoles. The latter are easy to prepare from the parent carboxylic acid and A jV -carbonyldiimidazole. 

This method was introduced by Staab and is suitable for the acylation of primary, secondary and tertiary alcohols. First the carboxylic acid is converted into the imidf lide (42) with carbonyldiimidazole (41), and then the alcohol is added together with a catalytic amount of strong base (alkoxide). The ester is formed at room temperature within a few hours (equation 17). If functional groups in the acid or alcohol prevent the use of base, the imidazolide and the alcohol have to be heated to 70 °C for 1-2 h. 

P-Keto esters (8, 313). Complete details are available for use of acyl derivatives of Meldrum s acid as precursors to fi-keto esters.1 A modification of this procedure has been used in a synthesis of thienamycin.2 The carboxylic acid group is activated by reaction with carbonyldiimidazole, and 4-dimethylaminopyridine is used as... 

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