Anhydrides mixed, with trifluoroacetic acid

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. 

Azotomycin is anticancer antibiotic produced by Streptomyces ambofaciens. Total sythesis of it from y-benzyl-N-tert-butyloxycarbonyl-L-glutamic acid (y-OBzi-N-Boc-L-Glu) has been accomplished in nine steps. The mixed carbonic anhydride method was chosen for peptide bond formation. Commerically available y-OBzi-N-Boc-L-Glu was esterified with ethereal diazomethane, deprotected with trifluoroacetic acid-methylene chloride (1 1), and converted to hydrochloride y-benzyl-L-glutamic acid a-methyl ester (y-OBzi-L-Glu-a-OMe HCI) by treatment with dry hydrogen chloride in ethyl ether, MP 129°-135°C (dec.) [a]D25= + 13.3° (CHCI3). 

The addition of alcohols to nitrilium salts gives rise to formation of alkoxymethyleneiminium salts, which react with bases to yield imido esters (231 Scheme 33). - By deprotonation of carboxylic acid amides ambident anions are formed, which can be alkylated in the presence of silver ions to give imido esters, e.g. (232). " Secondary amides react with trifluoroacetic acid anhydride or trifluorosulfonic acid anhydride to give mixed anhydrides of imidic acids (233). ... 

Peptide synthesis. The reagent has been used successfully for the N-protection of amino acids the bulky 1-adamantyloxycarbonyl group is removed by solvolysis with trifluoroacetic acid. The reagent was used also in the mixed-anhydride method of peptide synthesis, but considerable racemization was noted. 

Another y-hydrazide derivative of MTX was prepared by Rosowsky and Forsch [333] from a-t-butyl MTX by a mixed anhydride activation of the y-carboxyl group (/-BuOCOCl-Et3N) followed by addition of biotin hydrazide and treatment with trifluoroacetic acid (room temperature, 10 min) to obtain the biotinyl derivative (VIII.228). The overall yield for the coupling and deprotection steps was approximately 30%. 

Muller and others (1975) described the preparation of 3-fluoromethyl-3-cephem esters and their corresponding acids. The deacetyl-2-cephem benzhydryl ester (218) was treated with 2-chloro-l,l,2-trifluorotriethyl-amine, and after chromatography 3-fluoromethyl-2-cephem ester (219) was isolated in 36% yield as a crystalline substance. Oxidation of 219 with m-chloroperbenzoic acid yielded the sulfoxide (220) which was subsequently reduced to 3-fluoromethyl-3-cephem ester 221. Treatment of 221 with PCls-pyridine at -5 to - 10 C resulted in side-chain cleavage and isolation of the nucleus (221, R = H) in 74% yield. Reacylation of 221 with the mixed anhydride, made from (V-BOC-D-phenylglycine and isobutylchloroformate, provided 222 from which the crystalline acid (223) was prepared by treatment with trifluoroacetic acid in anisole. The acid displayed only low antibacterial activity in vitro and in vivo, because it is unstable in aqueous solution. 

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. 

The synthesis of BIRT-377 (1) is outlined in Scheme 4. The commercially available (D)-iV-Boc-alanine (13) reacted with 3,5-dichloroaniline via a mixed anhydride intermediate (i-BuOCOCl, iV-methylmorpholine, -10 °C to rt, THF) to give amide 14. Deprotection of the crude amide 14 with trifluoroacetic acid in dichloromethane afforded amino iV aryl amide 15 in 92% yield over two steps. This crude product was pure enough to carry on for next step without any purification. 

At Smith Kline French a general approach to cephalosporin and penicillin nuclear analogs was developed that utilizes a monocyclic /3-lactam (59) with the correct cis stereochemistry as a key intermediate. This is prepared by reaction of the mixed anhydride of azidoacetic acid and trifluoroacetic acid with imine (58) followed by oxidative removal of the dimethoxybenzyl group. This product could be further elaborated to intermediate (60) which, on reaction with a -bromoketones, provides isocephalosporins (61). These nuclear analogs displayed antibacterial properties similar to cephalosporins (b-79MI51000). 

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

Initial nitration of pyrazole derivatives with nitric acid in acetic or trifluoroacetic anhydrides leads to A-nitropyrazoles, which rearrange to the C-nitrated product on stirring in concentrated sulfuric acid at subambient temperature. This N -> C nitro group rearrangement often occurs in situ when pyrazoles are nitrated with mixed acid. 

The acylation of dibenzofuran is carried out under the usual Friedel-Crafts conditions with an acid chloride or an acid anhydride in the presence of aluminum chloride. Dibenzofuran on treatment with 2-trifluoromethane-sulfonyloxypyridine and benzoic acid in boiling trifluoroacetic acid produces the 2-benzoyl derivative in 75% yield. The species responsible for benzoyla-tion is probably a mixed anhydride of trifluoromethanesulfonic acid and benzoic acid. Dibenzofuran on treatment with 2-benzoyloxypyridine and trifluoroacetic acid also produces the 2-benzoyl compound (21%). The kinetics of the acetylation of dibenzofuran with acetyl chloride and aluminum chloride in nitroethane at 25"C have been studied. Only the 2-acetyl compound was detected by the methods used. The rate obtained is in general agreement with the studies mentioned previously. The rate of acetylation of diphenyl ether relative to toluene was 138 (+ 16), whereas that of dibenzofuran was 5.9 ( 0.3). In contrast, the benzoylation of dibenzofuran with benzoyl chloride in the presence of aluminum chloride in nitrobenzene at... 

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