Acylation mixed anhydrides

It is known that certain Friedel-Crafts acylations of reactive aromatics may proceed with a small amount of catalyst or even, to some extent, with no catalyst at all.41 Effective catalysts are Fe, FeCl3, ZnCl2, iodine, and hydroiodic acid. However, satisfactory yields are usually obtained with activated and polynuclear aromatics, and heterocycles. The mixed anhydrides acyl triflates are also powerful acylating agents without catalyst.34... 

When carboxylic acids are treated with trifluoroacetic anhydride, mixed anhydrides (acyl trifluoroacetates) are formed. These compounds are useful acylating agents. What is the product of the reaction of an alcohol with acyl trifluoroacetate ... 

The role of the metal ion in ester hydrolysis catalysed by CPA has been examined with both Zn +- and Co +-substituted enzymes. When the terminal carboxyl of the substrate is electrostatically linked to argenine-145 and the aromatic side-chain lies in a hydrophobic pocket, the only residues close enough to the substrate to enter catalysis are glutamate-270, tyrosine-248, the metal ion, and its associated water. Low-temperature studies aid the elucidation of the mechanism. Between - 25 and - 45 °C in ethylene glycol-water mixtures two kinetically discrete processes are detected, the slower of which corresponds to the catalytic rate constant. The faster reaction is interpreted as deacylation of a mixed anhydride acyl-enzyme intermediate formed by nucleophilic attack by glutamate-270 on the substrate (Scheme 6). Differences in the acidity dependences of the catalytic rate constant with the metal ions Zn + (p STa 6.1) and Co +-(pATa 4.9) suggest that ionization of the metal-bound water molecule occurs and is involved in the decay of the anhydride. The catalytic rate constant shows an isotope effect in DgO. 

The 7 glutamyl phosphate formed m this step is a mixed anhydride of glutamic acid and phosphoric acid It is activated toward nucleophilic acyl substitution and gives glutamine when attacked by ammonia... 

Fluorosulfuric acid [7789-21-17, HSO F, is a colodess-to-light yellow liquid that fumes strongly in moist air and has a sharp odor. It may be regarded as a mixed anhydride of sulfuric and hydrofluoric acids. Fluorosulfuric acid was first identified and characterized in 1892 (1). It is a strong acid and is employed as a catalyst and chemical reagent in a number of chemical processes, such as alkylation (qv), acylation, polymerization, sulfonation, isomerization, and production of organic fluorosulfates (see Friedel-CRAFTSreactions). 

AijAT-dicyclohexylcarhodiimide (DCC) also leads to essentially quantitative conversion of amic acids to isoimides, rather than imides (30,31). Combinations of trifluoroacetic anhydride—triethjlarnine and ethyl chi oroform a te—triethyl amine also result in high yields of isoimides (30). A kinetic study on model compounds has revealed that isoimides and imides are formed via a mixed anhydride intermediate (12) that is formed by the acylation of the carboxylic group of amic acid (8). 

Carboxylic acids react with trifluoroacetic anhydride to give mixed anhydrides that are especially useful for the acylation of hindered alcohols and phenols ... 

The active acylating agent may be the protonated mixed anhydride, or, alternatively, the anhydride m dissociate to the acylium and trifluoroacetate ions ... 

In an interesting analogy to the penicillin series, acylation of 7-ACA with the phenylglycine moiety affords a compound with oral activity. Thus, phenylglycine is first protected as the carbo tertiary butyloxy derivative (45). Reaction of this with isobutyloxy chloroformate affords the mixed anhydride (46). Condensation of that with 7-ACA gives the intermediate, 47. Treatment with either trifluoroacetic or formic acid provides the free amine cephaloglycin (48). ... 

Nucleophilic aromatic substitution of the anion from ary lace ton itrile 113 on the dichloroni-trobenzene 114 results in replacement of the para halogen and formation of 115. Reduction of the nitro group gives the corresponding aniline (116). Acylation of the amine with 3,5-diiodoacetylsa-licylic acid 117 by means of the mixed anhydride formed by use of ethyl chloroformate, gives, after alkaline hydroly.sis, the anthelmintic agent closantel (118) [28]. 

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]. 

Somewhat milder oxidative conditions lead to loss of but one carbon. Periodic acid cleavage of the side chain in 65, leads to the so-called etio acid (66). Reaction with propionic anhydride leads to acylation of the 17-hydroxyl group (67). Possibilities for neighboring group participation severely limit the methods available for activating the acid for esterification. Best results seemed to have been obtained by use of a mixed anhydride from treatment with diphenyl chloro-... 

To set the stage for the crucial aza-Robinson annulation, a reaction in which the nucleophilic character of the newly introduced thiolactam function is expected to play an important role, it is necessary to manipulate the methyl propionate side chain in 19. To this end, alkaline hydrolysis of the methyl ester in 19, followed by treatment of the resulting carboxylic acid with isobutyl chlorofor-mate, provides a mixed anhydride. The latter substance is a reactive acylating agent that combines smoothly with diazomethane to give diazo ketone 12 (77 % overall yield from 19). 

Kinetic resolution of the racemic aziridine-2-carboxylate 82 (Scheme 3.26) was reported by Iqbal and co-workers [74], When 82 was allowed to react with N-cinna-moyl-L-proline (81) under mixed anhydride coupling conditions, the N-acyl azir-idine 83 was obtained in optically pure form along with aziridine 84. 

It is proposed that the boric acid reacts with the carboxylic acid to form a mixed anhydride as the actual acylating agent.913 Upon reaction with an amine, this intermediate forms the desired carboxamide and regenerates the catalytically active boric acid. 

Even though formic anhydride is not a stable compound (see p. 714), amines can be formylated with the mixed anhydride of acetic and formic acids (HCOO-COMe) °°° or with a mixture of formic acid and acetic anhydride. Acetamides are not formed with these reagents. Secondary amines can be acylated in the presence of a primary amine by conversion to their salts and addition of 18-crown-6. ° The crown ether complexes the primary ammonium salt, preventing its acylation, while the secondary ammonium salts, which do not fit easily into the cavity, are free to be acylated. 

These reactions are most important for the preparation of acyl fluorides. " Acyl chlorides and anhydrides can be converted to acyl fluorides by treatment with polyhydrogen fluoride-pyridine solution" or with liquid HF at — 10°C. Formyl fluoride, which is a stable compound, was prepared by the latter procedure from the mixed anhydride of formic and acetic acids. Acyl fluorides can also be obtained by reaction of acyl chlorides with KF in acetic acid or with DAST. Carboxylic esters and anhydrides can be converted to acyl halides other than fluorides by the inorganic acid halides mentioned in 10-77, as well as with PhsPXa (X = Cl or but this is seldom done. Halide exchange can be carried out in a... 

A. Acylation with acyl halides and mixed anhydrides 1a O O... 

Use of 2,4,6-trichlorobenzoyl chloride, Et3N, and DMAP, known as the Yamaguchi method,128 is frequently used to effect macrolactonization. The reaction is believed to involve formation of the mixed anhydride with the aroyl chloride, which then forms an acyl pyridinium ion on reaction with DMAP.129... 

Carboxylic acids can also be activated by the formation of mixed anhydrides with various phosphoric acid derivatives. Diphenyl phosphoryl azide, for example, is an effective reagent for conversion of amines to amides.140 The proposed mechanism involves formation of the acyl azide as a reactive intermediate. 

Highly reactive mixed anhydrides can also promote acylation. Phenylacetic acid reacts with alkenes to give 2-tetralones in TFAA-H3P04.55 This reaction involves an intramolecular Friedel-Crafts alkylation subsequent to the acylation. 

The acyl azide intermediates are prepared either by reaction of sodium azide with a reactive acylating agent or by diazotization of an acyl hydrazide. An especially convenient version of the former process is treatment of the carboxylic acid with ethyl chloroformate to form a mixed anhydride, which then reacts with azide ion.265... 

Section A of Scheme 10.15 contains a number of examples of Curtius rearrangements. Entry 1 is an example carried out in a nonnucleophilic solvent, permitting isolation of the isocyanate. Entries 2 and 3 involve isolation of the amine after hydrolysis of the isocyanate. In Entry 2, the dihydrazide intermediate is isolated as a solid and diazotized in aqueous solution, from which the amine is isolated as the dihydrochloride. Entry 3 is an example of the mixed anhydride procedure (see p. 948). The first stage of the reaction is carried out in acetone and the thermolysis of the acyl azide is done in refluxing toluene. The crude isocyanate is then hydrolyzed in acidic water. Entry 4 is a reaction that demonstrates the retention of configuration during rearrangement. 

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