Trifluoroacetyl group esters

Trifluoroacetamides are more stable toward nucleophiles than the corresponding esters and are easily formed from trifluoroacetic anhydride and the amine. The trifluoroacetyl group (Tfac) is slowly cleaved by aqueous or methanolic HQ, NH, or Ba(OH)2 solutions as well as by NaBHj in methanol (M.L. Wolfrom, 1967). 

In 1992, Legros and Fiaud found palladium-catalyzed benzyiic alkylation of naphthylmethyl and 1-naphthylethyl esters 103 with sodium dimethyl malonate 104 in dimethylformamide (DMF) to give the corresponding benzyiic alkylated products 105 in high yields (Equation (41)). " When trifluoroacetyl group is used as a leaving group of the ester partner, catalytic alkylation proceeds quite smoothly even at room temperature. In this reaction system, no reaction occurs with benzyiic acetates. 

Heck cyclization with concomitant deprotection of the trifluoroacetyl group to form the indoleacetic methyl ester 68. Compound 68 was hydrolyzed and then treated with PCI5 followed by dimethylamine to give the amide 69, which was reduced with LiAlHi to afford almotriptan (5). 

The trifluoroacetyl group, which is extremely labile towards hydrolysis, may be readily removed under mild conditions from carbohydrate mixed-esters. Thus, treatment of an acetone solution of methyl... 

Several factors affect the volatility and stability of a peptide derivative, not least of these being the number and nature of the constituent amino acids. Heterocyclic and aromatic amino acids reduce volatility while those containing sulphur tend to decrease the thermal stability. Small naturally occurring peptides which are not derived from proteins often contain only aliphatic amino acids which lack functional groups in the side chains. Peptides of this type of up to about ten amino acids, after conversion to suitable derivatives, are amenable to analysis by mass spectrometry, e.g. [164]. A variety of derivatives has been reported and include N-trifluoroacetyl peptide esters [136,165], N-acetyl peptide esters [166-168], aromatic N-acyl peptide esters [169-172], and per-methylated N-acyl peptides [173]. The principal modes of the electron impact induced fragmentation of these peptide derivatives are well established and have been summarised in recent reviews [174,175]. Although the spectra of the permethylated derivatives [176] are perhaps the simplest and easiest to interpret and are now frequently used, the N-acyl peptide esters have been widely and successfully employed. 

Compounds carrying a trifluoroacetyl group, for example trifluoromethyl ketones and esters of trifluoroacetic acid, can be converted into the corresponding trimethylsilyl difluoroenol ethers [27] or into trimethylsilyldifluoroacetic acid esters [28] by reduction with magnesium metal in the presence of Me SiCl (Scheme 2.195). These readily accessible species are synthetically very useful as nucleophilic difluoromethylene equivalents. The same type of chemistry [29] can also be extended to trifluoromethyl imines [30]. 

When trifluoroacetic anhydride was used for the Pummerer rearrangement of phenylboronate ester 465, the 1-O-trifluoroacetyl derivative 469 was formed rapidly and could be used in situ for further reactions. The 1-O-trifluoroacetyl group could be replaced by bromide which, in turn, was exploited for glycoside synthesis. 

At about the same time, in 1963, it was reported that simple iV-acetyl-peptides (Heyns and Griitzmacher [29]) or iV-trifluoroacetyl peptide esters (F. Weygand et al. [30]) are cleaved under electron impact at the peptide bonds, giving rise mainly to ions corresponding to N-terminal parts of the chain. If such fission occurs at each peptide bond, a series of ions are formed all having the same N-acyl group. This is equal to a stepwise degradation of the chain from its carboxyl end (Fig. 13). 

Consecutive treatment of pyrrolidine-2-methanol compounds with trifluoroacetic anhydride and then with triethylamine has been reported to result in a rearrangement that produces ring-expanded 3-hydroxypiperidines as their trifluoroacetyl esters. Following hydrolysis of the trifluoroacetyl group with sodium hydroxide, the 3-hydroxypiperidines were isolated in good yields and with excellent enantiomeric excess. 

A second group of analytical methods requires preliminary acid hydrolysis. This is conducted in 7 M HCl at 95 to 9TC for 4 h (73) or in 1 M HCl at 80°C for 3 h (23). The hydrolysis product p-alanine has been analyzed after its conversion to the corresponding Ar-trifluoroacetyl methyl ester or jv-trifluoro-acetyl butyl ester. Derivatization of p-alanine is a two-step procedure. The compound is converted first to its methyl or butyl ester using alcoholic HCl and then to its AT-trifluoroacetate by the use of trifluoroacetic acid anhydride. The resulting derivative is analyzed using a polar stationary phase (23). 

Figure 6. Schematic outlining the steps to produce a multifunctional surface with parallel reactivity. The aminomethyl group only reacts with the ester, and the trifluoroacetyl group only reacts with the hydrazide. (Reproducedfrom reference 56 with permission. Copyright 2006 Wiley Interscience)...

Shorter peptides obtained by partial acid hydrolysis were separated by ion-exchange chromatography and studied by El mass spectrometry of their N-trifluoroacetyl methyl esters and the reduction products obtained after hot treatment with LiAlD4. Consequently, structure (54) was proposed for the A21978 C antibiotics, each member of the group differing from the others only by the structure of the fatty acyl moieties (125). 

A tertiary radical can be formed by elimination during AF of ter/-butyl methyl and ethyl ethers thus, isolation of the respective perfluoro-/erf-butyl ethers, e.g. 1, occurs in only 36 and 42% yield.28 Significant quantities of perfluoro(2-methylpropane) (2) are also isolated. The longer alkyl chains (ethyl and larger) appear to be slightly less prone to scission than the methyl group. Apparently, carbonyl fluoride is more readily eliminated than trifluoroacetyl fluoride, a phenomenon observed during AF of esters.29 Elimination becomes most serious in the special class of polyethers called ortho esters, e.g. 3-5.30 Cyclic ortho esters, acetals and ketals are much less affected than acyclics. 

The naturally occurring amino acids are very polar, and cannot be separated as the free compounds by GC at a temperature below decomposition. If the polar groups in the molecule are chemically modified to produce a more volatile derivative a suitable temperature is then possible. Weinstein (25) reviews all the various derivatives which may be formed from amino acids and the GC conditions necessary to separate them. In actual practice only three derivatives are in popular use. These include the N-heptafluorobutyryl n-propyl ester derivatives, the N-trimethyl-silyl ether derivatives, and the n-trifluoroacetyl n-butyl ester derivatives. 

---