Trifluoroacetylation heterocycles

Reaction of the thia-amino acid 392 with trifluoroacetic anhydride gave the 2,2,2-trifluoro-l-[7-(trifluoromethyl)-l//-pyrrolo[l,2-c]-[l,3]thiazol-6-yl] ethanone pyrrole 395. The formation of the pyrrole can be rationalized by a sequence involving trifluoroacetylation of the enamine 392 affording dione 393 followed by loss of water and carbon dioxide to give the aromatic product 395. These decarboxylations afford fluorinated derivatives of heterocyclic skeletons known to exhibit interesting biological activity (Scheme 58) <2000T7267>. 

Hojo et al. [218,308,309] described the trifluoroacetylation of alkenes activated by heteroatom donors such as vinyl ethers and ketene acetals (Eq. 116) the reaction occurs under mild conditions and can be used to prepare bis(trifluoro-acetyl) products from highly activated derivatives [310]. The main use of the products appears to be in the synthesis of trifluoromethyl heterocycles both... 

The C-acyl heterocycles do not generally form hydrates under acidic or alkaline conditions unless the five-membered ring is also substituted with a second electron-withdrawing group or, as with the trifluoroacetyl and trichloroacetyl derivatives, the carbonyl group is activated to nucleophilic attack. Such activated substituents also undergo the normal reactions with aqueous sodium hydroxide, sodium alkoxide and with amines to give the appropriate... 

Some acyl halides are reactive enough to effect Friedel-Crafts acylation on the neutral heterocycles without a catalyst. For pyrrole such reactions are known, for example, with trifluoroacetyl chloride and trichloroacetyl chloride. Indole reacts smoothly in cold ether with oxalyl chloride and on heating with acetic anhydride. Some examples of these types of acylation are collected in Table 10. 

Thiophene is far more reactive than benzene in electrophilic substitution reactions. Reaction with bromine in acetic acid has been calculated to be 1.76 x 109 times faster than with benzene (72IJS(C)(7)6l). This comparison should, of course, be treated with circumspection in view of the fact that the experimental conditions are not really comparable. Benzene in the absence of catalysts is scarcely attacked by bromine in acetic acid. More pertinent is the reactivity sequence for this bromination among five-membered aromatic heterocycles, the relative rates being in the order 1 (thiophene) and 120 (furan) or, for trifluoroacetylation, 1 (thiophene), 140 (furan), 5.3 xlO7 (pyrrole) (B-72MI31300, 72IJS(C)(7)6l). Among the five-membered heteroaromatics, thiophene is definitely the least reactive. 

From the synthetic viewpoint, a particularly interesting trifluoroacetylation reaction of simple vinyl ethers was reported first by Hojo et al in 1976 [73] The scope and limitation of this particular reaction were elaborated intensively, the reaction proved to be of general applicability with practically no restrictions on substituents of the vinyl ether moiety 9] (equation 34) This general validity is particularly beneficial because a trifluoroacetylated vinyl ether is the synthetic equivalent of a specifically protected tnfluoromethyl-substituted 1,3-dicarbonyl compound 19], thus the reaction provides access to a broad spectrum of variously substituted synthetic building blocks with selective reactivities on each carbon acceptor (a) and donor (d) center (equation 35) Obviously, such building blocks can react as heterodiene systems m cycloaddition reactions [< 74] or can be treated with a wide variety ot 1,2 or 1 3-dinucleophihc species to give any desired tnfluoromethyl-substituted carbocychc or heterocyclic system [8 75] Treatment of simple vinyl ethers with an excess of trifluoroacetic anhydride at elevated temperature leads to doubly acylated products [76] Comparable acylation reactions occur with vinyl thioethers [73], and the mesoiomc l,3-oxathiol-4-ones show, at least in a formal sense, similar behavior [77] (equation 36)... 

The effect of substituents on the reactivity of heterocyclic nuclei is broadly similar to that on benzene. Thus, meta-directing groups such as methoxycarbonyl and nitro are deactivating. The effects of strongly activating groups such as amino and hydroxy are difficult to assess since simple amino compounds are unstable, and hydroxy compounds exist in an alternative tautomeric form. Comparison of the rates of formylation and trifluoroacetylation of the parent heterocycle and its 2-methyl derivative indicates the following order of sensitivity to substituent effects furan > tellurophene > selenophene thiophene. 

Dihydroartemisinin or trifluoroacetyl dihydroartemisinin reacted with aromatic amines or heterocycles, such as triazole and benzotriazole, in the presence of acidic catalyst to afford its iV-glycosides, which were more active in vivo than qinghaosu (Scheme 5-12). ... 

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. 

Ono, M, Saotome, C, Akita, H, Total syntheses of A-fluoroacetyl-L-daunosamine, A-trifluoroacetyl-L-acosamine, A-benzoyl-D-acosamine, and A-benzoyl-D-ristosamine from an achiral precursor, methyl sorbate. Heterocycles, 45, 1257-1261, 1997. 

Dimer formation was also reported for the photolysis of the germanium heterocycle [Eq. (31)] (23) but not for tellurophene. Lack of reactivity in this latter compound was ascribed to aromaticity of the heterocycle. Tellurophene also undergoes electrophilic substitution at the a position in formylation, acetylation, and trifluoroacetylation reactions (121). 

These substitutions are facilitated by electron release from the heteroatom pyrroles are more reactive than furans, which are in turn more reactive than thiophenes. Quantitative comparisons of the relative reactivities of the three heterocycles vary from electrophile to electrophile, but for trifluoroacetylation, for example, the pyrrole furan thiophene ratio is 5 x 10 1.5 x 10 I " in formylation, furan is 12 times more reactive than thiophene, and for acetylation, the value is 9.3. In hydrogen exchange (deuteriodeproton-ation), the partial rate factors for the a and p positions of A-methylpyrrole are 3.9 x 10 ° and 2.0 x 10 ° respectively for this same process, the values for furan are 1.6 x 10 and 3.2 x l(f and for thiophene, 3.9 X 10 and 1.0 x 10 respectively, and in a study of thiophene, a P ratios ranging from 100 1 to 1000 1 were found for different electrophiles. Relative substrate reactivity parallels positional selectivity i.e. the a P ratio decreases in the order furan > thiophene > pyrrole. ° Nice illustrations of these relative reactivities are found in acylations of compounds containing two different systems linked together. ... 

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