Trifluoroacetic anhydrides, mixed, acylating

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 ... 

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 ... 

Scheme 11.4 shows some other representative Friedel-Crafts acylation reactions. Entries 1 and 2 show typical Friedel-Crafts acylation reactions using A1C13. Entries 3 and 4 are similar, but include some functionality in the acylating reagents. Entry 5 involves formation of a mixed trifluoroacetic anhydride, followed by acylation in 85% H3PO4. The reaction was conducted on a kilogram scale and provides a starting material for the synthesis of tamoxifen. Entry 6 illustrates the use of bismuth triflate as... 

In mixed trifluoroacetic anhydrides, the strong electron-withdrawing tri-fluoroacetyl group polarizes the bonds to the anhydride oxygen in such a way that it tends to split to acylium cation and trifluoroacetate anion [/0/. Generally, the products of the reaction of hydroxy compounds with acyl trifluoroacetates are esters of carboxylic acids and trifluoroacetic acid, because the acyl carbonyl is better fit for a nucleophilic attack than the carbonyl next to the trifluoromethyl group [707]. 

Although the 2,3-dimethyl and 3,4-dimethyl ethers of L-rhamnose were known, the 2,4-dimethyl ether had not been synthesized prior to its preparation through a trifluoroacetyl intermediate. - The synthesis started from methyl 2,3-0-isopropylidene-a-L-rhamnopyranoside this was methylated and the acetal group removed, to give methyl 4-0-methyl-a-L-rhamnopyranoside (6). Conversion to the 2,3-bis(trifluoroacetate) (7) was readily achieved with trifluoroacetic anhydride in the presence of sodium trifluoroacetate. As expected, the trifluoroacetate (7) was completely de-acylated by treatment with alcohol, regenerating (6) this process was complete after 25 min. at room temperature. The procedure for selective de-esterification was based on the observation that, if excess carbon tetrachloride (6 vol.) is present, very little methanolysis occurs. By use of a mixed methanol-carbon tetrachloride solvent (65 35 vol./vol.), the meth-... 

Jacobi s synthesis of ( )-paniculide-A involves an intramolecular Diels-Alder reaction of the alkynic ketone (31). This compound was prepared in >90% yield (Scheme 9) by acylation of a lithium alkynide with the A7-methoxy-A7-methylamide (30). Addition of the anion to other derivatives related to (30) such as an acid chloride, a trifluoroacetic mixed anhydride, an acyl imidazole, S-(2-pyridyl) thiolates and a mixed carbonic anhydride (from ethyl chloroformate) led to either bis-addition or to proton abstraction. Notice should be made of the stability exhibited by the A7-methoxy-A7-methylamide group while the oxa-zole moiety was being introduced. ... 

The fact that, in the reaction formulated above, anisole yields the acetyl and not the trifluoroacetyl derivative means that the mixed anhydride is a more reactive acylating agent than trifluoroacetic anhydride. However, the pure anhydride alone is capable of effecting acylation. It reacts with azulene (blue) in carbon tetrachloride without catalyst at room temperature to give 1-trifluoroacetylazulene (red) in high yield. "... 

Henne and Tedder " report interesting, if low-yield, acylations of olefins and acetylenes. A mixture of cyclohexene, acetic acid, and trifluoroacetic anhydride warms up to about 37° with formation of the ester (1), formally the product of di-tion of the mixed ynhydride and regarded us resulting from attack by CH )C=0... 

Anhydrides may also be employed instead of an acid chloride. The mixed anhydride of acetic and formic acid reacts with 1-iV-morpholinocyclohexene to give 2-hydro-xymethylenecyclohexanone . Acylation of isobutyraldehyde enamines with trichloroacetic anhydride in tetrahydrofuran at room temperature gives the a-trichloromethyl-j5-trichloroacetyl adduct . This occurs by initial ) -acylation to give the acyl iminium trichloroacetate, followed by decarboxylation and nucleophilic addition of the tri-chloromethyl anion to the iminium group. Trifluoroacetic anhydride under the same conditions just gave the -trifluoroacetyl derivative . 

Acylations with carboxylic acids and anhydrides have been carried out with sulfuric acid as both solvent and catalyst, the reactive acylating agents from acyl halides probably being haloacyloxonium ions. Trifluoroacetic anhydride offers a rather milder reagent for reactions of carboxylic acids, with mixed anhydrides being likely intermediates. However, polyphosphoric acid remains the most widely used dehydrating agent for acylations by carboxylic acids. 

We have already considered the use of mixed anhydrides and so in this section we shall be concerned with homocarboxylic anhydrides. The use of anhydrides constitutes the most frequently reported method after the use of an acyl chloride and aluminum chloride. Anhydrides from monocarboxylic acids yield ketones, and cyclic anhydrides derived from dicarboxylic acids afford keto acids. Very nucleophilic aromatic compounds react with trifluoroacetic anhydride in the absence of a catalyst. The confirmation of aromatic character invariably involves establishing reactivity towards a range of electrophiles. Trifluoroacetic anhydride reacts with homoazulene in the presence of an excess of triethylamine to afford 1-tri-fluoroacetylhomoazulene in 91-95% yield. The preparations of 3-aroylpropanoic acids from succinic anhydride and 4-aroylbutanoic acids from glutaric anhydride have been known for many years. Maleic anhydride can be used in a similar way to prepare 3-aroylacrylic acids. We will now concentrate our attention on more recent examples. 

An efficient and ecofriendly procedure for the small-scale acylation of ferrocene with carboxylic acids is based on the in situ production of the mixed carboxylic-triflic anhydride (Table 4.15 see also Chapter 3). The reaction is simply performed by adsorbing ferrocene on the surface of activated alumina (preheated at 150°C for 3 h) and adding a mixture of carboxylic acid and trifluoroacetic anhydride (TFAA) at room temperature for a selected time. Products 40 are recovered in 55%-98% yield simply by elution with diethyl ether. 

B.ii. Synthetic Approaches to Macrocyclic Lactones. There are many examples of biologically important, naturally occurring lactones. A variety of cyclization techniques have been developed, but all are based on the idea that the carbonyl end of an cu-substituted acid is activated to facilitate attack by or at the other functionalized end. Trifluoroacetic anhydride, for example, was used to convert 220 to 222 in 31% yield.xhe initially formed mixed anhydride (221) activated the carbonyl to attack by the hydroxyl moiety, leading to 222 in the Taub et al. synthesis of zearalenone. An alternative synthetic route required a macrocyclization reaction but it involved Friedel-Crafts acylation (sec. 12.4.D). Cyclization has also been observed using a mixture of trifluoroacetic acid and trifluoroacetic anhydride. ... 

The regioselective acylation of aromatic ethers with carboxylic acids (aromatic ether/carboxylic acid ratio =1) can be pafonned with an equimolecular mixture of trifluoroacetic anhydride adsorbed on the surface of alumina without any solvent [77]. The process can be applied, with nearly quantitative yields, to anisole and the three isomeric dimethoxybenzenes by using carboxylic acids. The authors outline that in the case of anisole, the acylation selectively occurs at the para position to the methoxy group. The reaction requires a large amount of alumina and trifluoroacetic anhydride, and consequently, it can only be appUed at the laboratory scale. The intervention of a mixed carboxyhc acidArifluoroacetic acid mixed anhydride intermediate is presumed. 

Aryltrifluoromethyl ketones are prepared by reaction of an aryl-lithium with a,a,a-trifluoro-N,N-dimethylacetamide. 2-Acyloxypyridines and N-acylimidazoles, " in conjunction with trifluoroacetic acid, acylate arenes in good yield without the need for a classical Friedel-Crafts catalyst or a preformed mixed anhydride. However, imidazole in trifluoroacetic anhydride is reported to form 2-aryl-Af,JV -diacyl-4-imidazolines with arenes reactive towards electrophilic attack. These adducts are readily hydrolysed by sodium hydroxide to the corresponding aldehyde [equation (14)]. This sequence may offer advantages over the Vilsmeier method of formylation, in that the aldehyde is introduced in a protected form. 

Activated Esters. Mixed anhydrides may be prepared by reaction of carboxylic acids with trifluoroacetic anhydride. The method has been used widely as a means of activating carboxyl groups to nucleophilic attack. The method has also been highly useful in Friedel-Crafts acylation of arenes (eqs 1 and 2). Sulfonic acids are also activated to nucleophilic attack substituted sulfones result. Intramolecular Friedel-Crafts reactions are also facilitated, but only for formation of six-membered rings. ... 

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). ... 

Mixed anhydrides with trifluoroacetic acid are particularly reactive acylating agents.48 For example, Entry 5 in Scheme 11.4 shows the use of a mixed anhydride in the course of synthesis of the anticancer agent tamoxifen. 

Electron-rich aromatic compounds such as durene, p-dimethoxybenzene, mesitylene, anisole, thiophene, and fluorene can be benzoylated or acetylated by the corresponding Af-acylimidazole in trifluoroacetic acid to give the corresponding benzophenone or acetophenone derivative in good yield (Method A). As the actual acylating agent, a mixed anhydride of trifluoroacetic acid and benzoic acid has been proposed 1973... 

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