Trifluoroacetic Anhydride activated esters

As with trifluoroacetic anhydride, activation of dimethyl sulfoxide with thionyl chloride must be carried out at low temperatures as the reaction is highly exothenmic. Besides the higher yields, a further advantage of thionyl chloride to activate dimethyl sulfoxide over anhydrides is the lack of Pummerer rearrangement products or of esters formed as by-products (as long as Ae reactions are carried out below -60 C). This is amply demonstrated by the oxidation of (-)-bomeol which proceeds in an excellent 99% yield (equation 12). ... 

The alternative method for making activated esters is base-catalyzed transesterification. Fmoc-amino acids are esterified in excellent yields by reaction with pentafluorophenyl trifluoroacetate at 40°C in the presence of pyridine (Figure 7.13). A mixed anhydride is formed initially, and the anhydride is then attacked by the pentafluorophenoxy anion that is generated by the pyridine. Succinimido, chlorophe-nyl, and nitrophenyl esters were made by this method when it was introduced decades ago. A unique variant of this approach is the use of mixed carbonates that contain an isopropenyl group [Cf C CfyO-COjR]. These react with hydroxy compounds in the presence of triethylamine or 4-dimethylaminopyridine (see Section 4.19) to give the esters and acetone.30 35... 

Optically active 4-alkoxycarbonyl-3-hydroxycyclohexanones (formed in highly enantio- and diastereoselective organocatalytic asymmetric domino Michael aldol reaction of / -keto esters and a,/ -unsaturated ketones) are transformed into corresponding chiral oxepanones under the action of urea-hydrogen peroxide and trifluoroacetic anhydride <2004AGE1272>. 

Carboxylic acids on the outer surface of SAMs may also be activated as symmetric anhydrides by action of trifluoroacetic anhydride as dehydrating agent57 The most common active esters are A-hydroxysuccinimidyl esters (NHS esters). They are usually prepared by reacting the carboxyl-terminated SAMs with... 

Although many oxidizing reagents remove the chromium tricarbonyl group, benzylic alcohols can be oxidized to benzaldehydes using dimethyl sulfoxide with acetic anhydride, trifluoroacetic anhydride, or sulfurtrioxide with minimal decomplexation. Asymmetric oxidation of aUcylthio-substituted complexes can be achieved using titanium tetraisopropoxide and an optically active tartrate ester (Scheme 108). Dimethyloxirane can also be used to oxidize sulfides to sulfoxides. 

Water was found to decrease the rates of polymerisation, but not to inhibit the process. Moreover, the four corresponding carbinols were successfully polymerised by trifluoroacetic anhydride. These reactions went throu a dehydration stage, and since polymerisation occurred even with about 50 times more carbinol than anhydride it was again proved that excess of water did not impede the polymerisation of these monomers by trifluoroacetic acid. It was concluded that two types of active species coexist in these systems, one sensitive to moisture (carbenium ions ) and one insensitive to it (ester ). 

Other than those of the carboxylic type for example, a mixture of p-toluene-sulfonic acid and triduoroacetic anhydride forms sulfones by reaction with suitably activated aromatic compounds. By the same technique, the hexa-nitrate esters of o-mannitol and D-glucitol were obtained by use of solutions of fuming nitric acid in trifluoroacetic anhydride at 0°. The probable reaction mechanisms of these and other examples of the conversion of oxy acids into reactive entities have been briefly considered. ... 

Prepared in quantitative yield by refluxing p-nitrophenol with trifluoroacetic anhydride, the reagent reacts rapidly with a carbobenzoxyamino acid at room Icmperature to give the p-nitrophenyl ester. The reaction with a carbobenzoxy peptide is slower and requires heat or a long reaction period. p-Nitrophenyl trichloro-ncetate is active only in refluxing pyridine and gives p-nitrophenyl esters in poor yield. 

Similar simple reactions can be carried out in solution. Terminal hydroxy groups can be esterified with trifluoroacetic anhydride or glutaric anhydride , although the reaction in the latter case is probably incomplete. Amino groups in the monolayer of cysteamine were reported to react with active esters, such as JV-hydroxysuccinimide (equation 8) . No characterization of the resultant monolayer was, however, given. Cysteamine mono-layers were also acylated with terephthaloyl chloride and an isocyanate derivative . ... 

Deblocking with HCl in acetic acid or with trifluoroacetic acid can leave, even after thorough washing, small amounts of acetic acid or trifluoroacetic acid attached to the peptidyl-resin. The carboxyl groups of these acids are activated in the next coupling step, certainly by carbodiimides, but potentially also by symmetrical anhydrides or active esters... 

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. ... 

Reaction of the imidazole (7-4) with the benzofuran derivative (6-7) leads to the displacement of the benzylic halogen and the formation of the alkylation product (8-1). Treatment of that intermediate with trifluoroacetic acid breaks open the urethane to afford the corresponding free amine. This is allowed to react with ttiflic anhydride to afford the trifluoromethyl sulfonamide (8-2). The ester group on the imdidazole is then saponified, and the newly formed acid is reacted with carbonyl diimidazole. Reaction with ammonia converts the activated carboxyl group to the amide. There is thus obtained the angiotensin antagonist saprisartan (8-3) [6]. 

NHS trifluoroacetate is an amazing reagent. Not only does is activate the carboxylic acid through a mixed anhydride to form an ester under mild conditions, but the NHS leaving group is also the nucleophile that forms an ester that is both stable enough to work with, yet easily reactive when it needs to be. Perfect ... 

In more recent work involving a series of alkyl, aralkyl and arylamides of MTX and AMT [316], MeAPA was condensed with a-benzyl L-glutamic acid y-3,4-methylenedioxyanilide by the diethyl phosphorocyanidate coupling procedure to obtain the ester amide (VIII. 195). The benzyl ester group in (VIII.195) was then removed with NaOH to form (VIII.196) in 64% overall yield. Further reaction of (VIII.196) with boron tris(trifluoroacetate) in tri-fluoroacetic acid at 0 °C for 15 min afforded MTX y-(3,4-dihydroxyanilide) ((VIII.197) 79% yield). AMT y-amides (VIII.198)-(VIII.205) were prepared via the blocked intermediates (VIII.206)-(VIII.213), which were generated from FmAPA by the modified mixed anhydride route (four activation cycles ... 

To evaluate the effects on biological activity of variations in structure of the ester moiety, several semisynthetic esters of maytansinol were prepared. The propionate (230), bromoacetate (231), crotonate (232), and trifluoroacetate (233) esters of maytansinol (229) were made by procedures involving either anhydride-pyridine (230-232) or anhydride-acid (233) treatment. Fig. (58). TTie esters 228, and 230-232 were found to show antileukemic activity comparable to those of the naturally occurring substituted alanyl esters. The trifluoroacetate ester 233 showed no antileukemic activity, possibly because of ready solvolysis in vivo to inactive maytansides. 

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