Acylation process

This reaction must be distinguished from the Claisen condensation, which is an acylation process (see discussion before Section 111,151). 

One of the most actively investigated aspects of enamine chemistry has been the acylation process (i). Initial intensive studies by Hiinig (373-375) showed the ease of preparing a variety of 9-diketones and particularly the synthetic potential of acylated cyclic ketones as intermediates in the preparation of aliphatic keto acids, keto dicarboxylic acids and diketo dicarboxylic acids (376-378). 

Acidic chloroaluminate ionic liquids have already been described as both solvents and catalysts for reactions conventionally catalyzed by AICI3, such as catalytic Friedel-Crafts alkylation [35] or stoichiometric Friedel-Crafts acylation [36], in Section 5.1. In a very similar manner, Lewis-acidic transition metal complexes can form complex anions by reaction with organic halide salts. Seddon and co-workers, for example, patented a Friedel-Crafts acylation process based on an acidic chloro-ferrate ionic liquid catalyst [37]. 

This reaction is completely analogous to other acylation processes, such as the formation of the acetyl derivative from dimethylamine acetate. The only difference is, that since the C=0 double bond of acetic acid is less reactive than the N=0 double bond of nitrous acid, a higher temperature is required in the former case. 

A cobalt catalysed carbonylation reaction converts A-substituted 1-aza-1,3-dienes into A-allylacetamides by a reductive acylation process [31]. Acetamides are byproducts of the reaction. In contrast, Schiff bases undergo a double A,C-acetylation under the same conditions producing a-acetamido ketones and A,A-disubstituted acetamides [32],... 

Miller also explored the ASD of glycerol derivatives through an enantioselective acylation process which relies on the use of a pentapeptide-catalyst which incorporates an A-terminal nucleophilic 3-(l-imidazolyl)-(5)-alanine residue [171], Most recently, Miller has probed in detail the role of dihedral angle restriction within a peptide-based catalyst for ferf-alcohol KR [172], site selective acylation of erythromycin A [173], and site selective catalysis of phenyl thionoformate transfer in polyols to allow regioselective Barton-McCombie deoxygenation [174],... 

Orsat, B. Wirz, B. Bishof, S. (1999) A continuous lipase-catalyzed acylation process for the large-scale production of vitamin A precursors. Chimia, 53, 579-84. 

The influence of catalysts (AICI3 and SnCU) acid chlorides, and solvents (dichloroethane, nitromethane) in the acylation of methyl 2-methyl-4/f-thieno[3,2- ]pyrrole-5-carboxylate 75 was studied. Conditions for the regioselective acylation processes were found and four types of compounds 76a-f, 77a-e, and 78 were obtained. 

Enamines are the stable products of a similar reaction between secondary amines (such as pyrrolidine or morpholine) and aldehydes and ketones.218 These vinylamines are reactive reagents of value in synthesis they function as specific enol equivalents of carbonyl compounds, readily undergoing alkylation and acylation processes (e.g. Section 5.9.2, p. 632). 

Aryl alkyl ketones are readily prepared by the Friedel-Crafts acylation process (see Section 6.11.1, p. 1006) and their Clemmensen reduction constitutes a more efficient procedure for the preparation of monoalkylbenzenes than the alternative direct Friedel-Crafts alkylation reaction (see below). Alternatively aldehydes and ketones may be reduced to the corresponding hydrocarbon by the Wolff-Kishner method which involves heating the corresponding hydrazone or semicarbazone with potassium hydroxide or with sodium ethoxide solution. 

Friedel-Crafts-type acylation processes (Expts 6.121 to 6.125). 

The course consists of the acyl process (—OR process) and deacyl process, and (II) is called Michaelis complex. The formation of the Michaelis complex which is the predominant process of substrate selection serves the catalysis with high efficiency. Although it depends on pH a drastic decrease in activation entropy in this process shows that the free energy barrier of the Michaelis complex formation is entropic (2). The magnitude of the decrease is so large that it can not be explained by a decrease of the freedom due to a steric fit of the enzyme and the substrate, therefore changes in conformation of the enzyme and in structure of water molecules at the binding should be taken into account (4). 

Grohe K. The importance of the cycloar-acylation process for the synthesis of modern fluoroquinolones. /. prakt. Chem., 1993, 335, 397-409. 

Compound 25 (Fig. 18.9), a prodrug of 9-P-D-arabinofuranosyl guanine (26), was developed for the potential treatment of leukemia. Compound 24 is poorly soluble in water and its synthesis by conventional techniques is difficult. An enzymatic demethoxylation process was developed using adenosine deaminase (Mahmoudian et al., 1999, 2001). Compound 25 was enzymatically prepared from 6-methoxyguanine (27) and ara-uracil (28) using uridine phosphorylase and purine nucleotide phosphorylase. Each protein was cloned and overexpressed in independent Escherichia coli strains. Fermentation conditions were optimized for production of both enzymes and a co-immobilized enzyme preparation was used in the biotransformation process at 200 g/L substrate input. Enzyme was recovered at the end of the reaction by filtration and reused in several cycles. A more water soluble 5 -acetate ester of compound 26 was subsequently prepared by an enzymatic acylation process using immobilized Candida antarctica lipase in 1,4-dioxane (100 g/L substrate) with vinyl acetate as the acyl donor (Krenitsky et al., 1992). 

Aromatic ketones are important intermediates in the production of fine chemicals and pharmaceuticals1,2. Thus, the anti-rheumatic Naproxen is produced by the Friedel-Crafts acetylation of 2-methoxynaphthalene into 2-acetyl-6-methoxynaphthalene and subsequent Willgerodt-Kindler reaction. Commercial acylation processes involve over-stoechiometric amounts of metal chlorides (e g. AICI3) as catalysts and acid chlorides as acylating agents, which results in a substantial formation of by-products and in corrosion problems. This is why the substitution of these corrosive catalysts by solid acid catalysts and of acid chlorides by anhydrides or acids is particularly desirable. 

Acylation processes are often carried out in batch reactors by using acid metal chlorides such as AICI3 as catalysts and acid chlorides as acylating agents. The use of this type of catalysts generates serious environmental problems. Indeed, because the arylketone forms a 1 1 molar adduct with the catalyst, more than stoichiometric... 

Recently, the asymmetric variants of the Stetter [114-118], crossed-benzoin [114, 117-120], and transeslerification [121] reactions have attracted great interest as asymmetric nucleophilic acylation processes. A prerequisite for asynunetric catalysis is the availability of a chiral catalyst. Introduction of chirahty into the thiamin framewoik follows the same principles as that for the related imidazoUum systems, mainly the introduction of a chiral centre next to the nitrogen atom of the thiazole ring [117]. 

The mechanism of this reaction was hrst described by Breslow as early as 1958 [4], Subsequently, the natural enzyme thiamine, found in yeast, was replaced by related nucleophiles like thiazole [5,6], triazole [7] and imidazole [8], Reactions that follow this mechanism include the very important Stetter reaction (the benzoin condensation of aliphatic aldehydes), the Michael-Stetter reaction (a variant of the Stetter reaction where the aldehyde reacts with an a,P-unsaturated ketone) [1], transesteriflcations [9] or the acylation of alcohols [9,10], All four reactions are carbene catalysed nucleophilic acylation processes. 

Note NHC can be used as organocatalysts in carbene catalysed nucleophilic acylation processes. 

Note The benzoin condensation is a carbene catalysed nucleophilic acylation process. 

Khurgin et al. (1977) measured the chymotrypsin-catalyzed breakdown of the amide substrate A -succinyl-L-phenylalanine-/>-nitroaniline at low hydration levels. For this substrate the acylation process is rate limiting. Figure 28 shows the extent of reaction for 1 1 enzyme-substrate mixtures, of nominal pH 7.5, reacted for 5—7 days. The intent of the experiments was to define the critical water concentration at which activity could first be detected. This was determined as the intercept of the linear region of the response with the abscissa. For chymotrypsin with no added buffer, the critical hydration level was at relative humidity 0.48, which corresponds to 0.12 A (Luescher-Mattli and Ruegg, 1982a). The reaction grows explosively (Fig. 28) above this hydration level. Addition of 0.57 g of sodium acetate per g of chymotrypsin reduced the critical hydration level by about half. This may reflect the hydration of the the salt, rather than a specific effect on the enzyme. 

In contrast to the sparse use of acids, aroyl chlorides, no doubt because of their availability and greater reactivity, have been widely used to provide 8-arylpurines via intermediate aroylamidopyrimidines. These can Usually be prepared by reaction of the appropriate diaminopyrimidine with the aroyl chloride in aqueous alkali. The intermediate amides may be cyclized by heating the free pyrimidine or, on occasions, its sodium salt, and in some cases, especially with methylated pyrimidines, spontaneous cydization can occur during the acylation process. 

While there is evidence from IR investigations for the formation of traces of oxazol-5(4//)-one by treatment of Fmoc-protected amino acid fluorides, e.g. Fmoc-Val-F, with DIPEA, this reaction is not rapid enough to compete with the acylation process. In contrast to Fmoc amino acid chlorides, the related fluorides can be used in homogeneous systems with tertiary amines as efficient agents in peptide synthesis. 

Some 1- and 2-hydroxyalkanephosphonates have been successfully resolved by a CALB (Candida antarctica lipase B)-catalysed acylation process to give both (R)- and (S)-isomers with high enantiomeric excess (in most cases with 95% ee). (S)-Naproxen and (S)-Ibuprofen chloride are convenient chemical derivatizing agents for the determination of the enantiomeric excess of hydroxy and aminophosphonates by PMR. . New phosphorylating agents, 3-phosphoro-2(-N-cyanoimino)-thiazolidine derivatives (3-phosphoro-NCTS) (316), can be used as a stable alternative to phosphorochloridates. Phosphoryla... 

Mukaiyama has shown that in cases where lactonization was not possible, oxothioates can be used in the acylation process with selective addition only to the thiol ester (equations 19 and 20). ... 

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