2- Acylimidazoles, addition

A similar approach uses the potassium enolate and achieves acylation with anhydrides or acylimidazoles in addition to acid chlorides (80TL2773). 

Simple bis(oxazoline) ligands, especially azabis(oxazolines), can catalyse the addition of indoles to benzylidene malonates in up to 99% ee, provided that excess of the chiral ligand is avoided.166 The paradigm followed in many asymmetric catalytic reactions that an excess of the chiral ligand with respect to the metal should improve enantioselectivity because the background reaction catalysed by a free metal is suppressed, was shown not to be applicable here,166 which might call for revisiting some of the many copper(II)-bis(oxazoline)-catalysed processes known. Enantioselective additions of pyrroles and indoles to ,/9-unsaturated 2-acylimidazoles catalysed by the bis(oxazolinyl)pyridine-scandium(III) triflate complex have been accomplished.167... 

In aprotic media a l-(acyloxycarbonyl)imidazole such as 16 is formed primarily which reacts to the acylimidazole and carbon dioxide. Imidazole now serves as a good leaving group and so the previously synthesized amine 6 could be added and the desired amide was formed via the usual addition elimination mechanism. One of the advantages of using this more expensive way of activation is the possibility to run the nitro reduction, acid activation and acylation in the same solvent (ethyl acetate) thus all three reactions could be telescoped into a single step during production. 

The conjugate addition of carbonyl anions catalysed by thiazolium salts (via umpol-ung) that is fully operative under neutral aqueous conditions has been accomplished. The combination of a-keto carboxylates (157) and thiazolium-derived zwitterions (e.g. 160) in a buffered protic environment (pH 7.2) generates reactive carbonyl anions that readily undergo conjugate additions to substituted o /3-unsaturated 2-acylimidazoles (158) to produce (159). The scope of the reaction has been examined and found to accommodate various a-keto carboxylates and /3-aryl-substituted unsaturated 2-acylimidazoles. The optimum precatalyst for this process is the commercially available thiazolium salt (160), a simple analogue of thiamine diphosphate. In this process, no benzoin products from carbonyl anion dimerization were observed. The resulting 1,4-dicarbonyl compounds (159) can be efficiently converted into esters and amides by way of activation of the A-methylimidazole ring via alkylation.181... 

The acylimidazoles (Table 6.1, entry 10) and the A-acylpyridinium salts (entry 12) occupy additional leading positions with respect to their acylation rates. In the acylimidazoles 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 17-electron sextet, which makes the imidazole ring an aromatic compound. For a similar reason there is no resonance stabilization of the C=0 double bond in A-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. 

Reactions leading to AC-acylimidazoles have excited considerable interest in recent years in view of the importance of AC-acylimidazoles in certain biological processes. In addition... 

In nucleophilic catalysis the catalytic properties are a result of the intermediate formation of a 1-acylimidazole (Scheme 27). When the ester has a good leaving group, e.g. p-nitrophenyl acetate, the effective catalyst is the imidazole neutral molecule which increases in effectiveness as the basic pKa of the heterocycle increases. Where, however, the ester has a poor leaving group, e.g. p-cresol acetate, the imidazole anion becomes involved and general base catalysis predominates. Thus, for imidazoles with pjK"a 4 catalysis by the anion is the main reaction. Imidazole is a much more effective nucleophile than other amines in this type of reaction since it is a tertiary amine with little steric hindrance, and it is able to delocalize the positive charge which results from the nucleophilic addition to... 

The major classes of carbonyl compounds include aldehydes, ketones, carboxamides, esters, carboxylic acids and anhydrides, and carbonyl halides (acyl halides). These groups differ in the identity of the substituent X on the carbonyl group. At this point we concentrate on these examples, but a number of other carbonyl derivatives have important roles in synthetic and/or biological reactions. These other compounds include acyl cyanides, acyl azides, A-acylimidazoles, 0-aryl esters, and thioesters. The carbonyl compounds are arranged below in the order of the increasing reactivity toward nucleophilic addition. 

Esters from Carboxylic Acids. Reaction of equimolar amounts of carboxylic acid, alcohol, and (1) in an inert solvent (e.g. THF, benzene, or chloroform) results in ester formation (eq 2). Since alcoholysis of the intermediate acylimidazole is relatively slow, the reaction mixture must be heated at 60-70 °C for some time. However, addition of a catalytic amount of a base such as Sodium Amide to convert the alcohol to the alkoxide, or a... 

As is the case in esterification reactions, the presence of unreacted (1) can cause problems since the amine reacts with this as quickly as it does with the acylimidazole, forming urea byproducts that can be difficult to separate. Use of exactly one equivalent of (1) is difficult due to its moisture sensitivity, and also because of the tendency of some peptides or amino acids to form hydrates. Paul and Anderson solved this problem by use of an excess of (1) to form the acylimidazole, then cooling to —5 °C and adding a small amount of water to destroy the unreacted (1) before addition of the amine. ... 

A soln. of N-trifluoroacetylimidazole in dry tetrahydrofuran added at 0° to a soln. of N-carbohenzoxy-L-proline and p-nitrophenol in the same solvent, kept an additional hr. at 0°, then stirred 4 hrs. at room temp. N-carbobenzoxy-L-proline p-nitrophenyl ester. Y 78.5%. — In general, the use of 1-acylimidazoles seems less satisfactory then available alternatives, but may be useful in some specific instances. F. e. s. H. D. Law, Soc. 1965, 3897. 

True catalysis of esterolysis, (as opposed to rapid acyl transfer and formation of a stable intermediate) requires a second rapid step in which the acyl group is transferred to water or to an oxygen nucleophile. This has presented micellar histidines and imidazoles with a second role, in experiments first carried out separately by Tagaki, Moss, and Tonellato. In the simplest experimenta mixture of (49) with myristoylhistidine (72) reacts with p-nitrophenyl acetate first by nucleophilic attack of imidazole and then transfer of the acyl group to (49) in a rapid step. In the bifunctional surfactant (73) this process was shown to be intermolecular (but presumably intramicellar). The acylimidazole can be observed spectroscopically when the substrate is p-nitrophenyl hexanoate. Similar conclusions are recorded in a study by Tonellato, who additionally... 

Stetter and Lorenz reported in 1985 that a thiazolylidine catalyst could promote the addition of a-ketoacid derivatives (17) to activated olefins (18) with loss of CO2 to give 1,4-diketones (19)7 The reaction has been called biomimetic because of its resemblance to the family of biochemical transformations effected by thiamine diphosphate-dependent enzymes acting on pyruvate While the original report was limited to alkyl vinyl ketones, more recent work by Scheldt and co-workers has greatly expanded the scope of this reaction by employing a, 3-unsaturated 2-acylimidazoles as the activated olefin component. ... 

Yoshida et aL recendy reported the direct synthesis of branched alkenylbo-rons via a-selective hydroboration of terminal alkynes employing (pin)B-B(dan) (where dan = 1,8-diaminonaphthalene) in the presence of 2 mol% [(SIPr)CuCl] 212,6 mol% KOt-Bu and MeOH (3 equiv.). Given that the scope of the alkynes is broad, the method was extended to the synthesis of Bexarotene and LG100268, which are used to treat T-cell lymphoma and as retinoid X receptor. In a different study by the same group, 208 catalyzed the selective addition of alkyl hydrob-oranes to imidazofyl-o,p-unsaturated ketones at the Imposition. Interestingly, the 2-acylimidazole moiety could be replaced by esters or amides. ... 

---