Trifluoroacetic acid-catalyzed

Under certain conditions, the trifluoroacetic acid catalyzed reduction of ketones can result in reductive esterification to form the trifluoroacetate of the alcohol. These reactions are usually accompanied by the formation of side products, which can include the alcohol, alkenes resulting from dehydration, ethers, and methylene compounds from over-reduction.68,70,207,208,313,386 These mixtures may be converted into alcohol products if hydrolysis is employed as part of the reaction workup. An example is the reduction of cyclohexanone to cyclohexanol in 74% yield when treated with a two-fold excess of both trifluoroacetic acid and triethylsilane for 24 hours at 55° and followed by hydrolytic workup (Eq. 205).203... 

Liquid-phase fluorination of methyl-substituted benzene derivatives depends strongly on the structure and concentration of the substrate, its molar ratio to xenon difluoride and the catalyst used (Scheme 32). HF-catalyzed fluorination of 1,2,4,5-tetramethylbenzene with an equimolar amount of xenon difluoride gave a small amount of 1,4-difluoro product, while reaction with two equivalents of xenon difluoride also gave the demethylated product l-fluoro-2,4,5-trimethylbenzene, which was also formed by HF-catalyzed fluorination of 1,3,4-trimethylbenzene34. In contrast, trifluoroacetic acid catalyzed fluorination is much more complex, and forms the four products l-(trifluoromethyl)-2,3,5,6-tetrametylbenzene, 2,4,5-trimethylbenzyl trifluoroacetate, l-fluoro-2,3,5,6-tetramethyl-benzene and l-(trifluoromethyl)-2,3,4,5-tetramethylbenzene, the distribution depending on the amount of trifluoroacetic acid used. Similar results were also observed in the fluorination of 1,2,3-trimethylbenzene and 1,3,5-trimethylbenzene34. 

A trifluoroacetic acid-catalyzed PictetSpengler reaction between the N,N-disubstituted aniline 93 and aromatic or aliphatic aldehydes afforded fused 1,4-benzodiazepines 94 in high yields after stirring at reflux in acetonitrile for 1648 h (Scheme 49). Electron-deficient aromatic aldehydes provided the best yields of 94, attributed to facile imine formation, while ketones were uniformly unreactive <2006T2563, CHEC-III(13.06.9.1.8)212>. 

Another readily available and potentially useful chiral reagent that has received very little attention is T-butyloxycarbonyl-L-leucine-N-hyroxy-succinimide ester, [12]. This reagent was used to acylate the amino group of the chiral drug y-vinyl- v-aminobutyric acid, followed by trifluoroacetic acid-catalyzed removal of the t-butyloxycarbonyl group (63). The dia-stereomeric derivatives were resolved on a C8 column, with an a value as... 

The bis(phenylthio)carbanion can be condensed with a ketone yielding an intermediate bis(phenylthio)alcohol.33 Trifluoroacetic acid catalyzed hydrolysis generates an alkylated carbonyl compound without the utilization of an alkyl halide. 

In another approach, Officer et al. prepared a series of dyads where oligothiophenes were attached to the porphyrin unit through a- (2.150) and -linkages (2.151) (Chart 1.31) [246]. Dyads 2.150 were synthesized by condensation of 2-formyloligothiophenes with pyrrole by trifluoroacetic acid-catalyzed reaction followed by oxidation using / -chloranil. Condensation of 3 -formyl-2,2 5, 2"-terthiophene with pyrrole using a Lewis acid as catalyst gave 2.151 in 30 % yield. 

As with bimolecular cycloaddition, the intramolecular Diels-Alder reaction can be catalyzed by Lewis acid [127-129]. In one case, it was reported that trifluoroacetic acid catalyzed cycloaddition [130]. 

The in situ-generated iminium could also be exploited as hydride acceptor, via which inert C(sp )-H bond could be functionalized to C-N bond efficiently. Seidel et al. reported a trifluoroacetic acid-catalyzed cascade [1,6]-hydride transfer/cy-clization of 77 to synthesize 7,8,9-trisubstituted dihydropurine derivatives 78 (Scheme 27) [73]. TFA plays two roles in this process (1) promotion of imine formation and (2) protonation of imine for acceleration of the hydride shift process. Meth-Cohn and Volochnyuk et al. reported similar reactions in 1967 [71] and 2007, respectively [72]. 

CH2CI2 mixture was carried out at room temperature to afford quantitatively the compound benzimidazoles 19. The proposed mechanism of this TFA-catalyzed ring closure reaction of immobilized diamine 12 was initiated by the reaction of trimethylorthoformate exclusively with aniline funcationality (Fig. 12). The resulting intermediate-imine was reacted with a secondary amine with further elimination of methanol to afford the desired benzimidazole 19. The possible trifluoroacetic acid catalyzed mechanism is shown in Fig. 12. 

Condensation of the vinylogous carbamate (40) with acetaldehyde and isocyanic acid afforded the pyrimidine derivative (41) which was converted to the urea derivative (42) by Curtius rearrangement in 65% overall yield. Treatment of (42) with acetic acid at 50° afforded exclusively the desired product (39), whereas treatment with trifluoroacetic acid gave a mixture of (39) and stereoisomer (43). The stereochemistry was established by comparing the coupling constants involving H-5 and H-6 with those of saxitoxin (1). Different cyclization mechanisms were suggested for the acetic acid and trifluoroacetic acid catalyzed cyclization to account for the different stereochemistry of the products. 

Harwood, L.M. Trifluoroacetic Acid-Catalyzed Claisen Rearrangement of 5-Ally-loxy-2-hydroxybenzoic Acid and Esters An Effident Synthesis of Mellein. Chem. Commun. 1982, 1120. 

Figure 3.5 Trifluoroacetic acid-catalyzed exchange labeling of gossypo ...

The following acid-catalyzed cyclizations leading to steroid hormone precursors exemplify some important facts an acetylenic bond is less nucleophilic than an olelinic bond acetylenic bonds tend to form cyclopentane rather than cyclohexane derivatives, if there is a choice in proton-catalyzed olefin cyclizations the thermodynamically most stable Irons connection of cyclohexane rings is obtained selectively electroneutral nucleophilic agents such as ethylene carbonate can be used to terminate the cationic cyclization process forming stable enol derivatives which can be hydrolyzed to carbonyl compounds without this nucleophile and with trifluoroacetic acid the corresponding enol ester may be obtained (M.B. Gravestock, 1978, A,B P.E. Peterson, 1969). 

Many carbamates have been used as protective groups. They are arranged in this chapter in order of increasing complexity of stmcture. The most useful compounds do not necessarily have the simplest stmctures, but are /-butyl (BOC), readily cleaved by acidic hydrolysis benzyl (Cbz or Z), cleaved by catalytic hy-drogenolysis 2,4-dichlorobenzyl, stable to the acid-catalyzed hydrolysis of benzyl and /-butyl carbamates 2-(biphenylyl)isopropyl, cleaved more easily than /-butyl carbamate by dilute acetic acid 9-fluorenylmethyl, cleaved by /3-elimination with base isonicotinyl, cleaved by reduction with zinc in acetic acid 1-adamantyl, readily cleaved by trifluoroacetic acid and ally], readily cleaved by Pd-catalyzed isomerisation. 

Alkynes react when heated with trifluoroacetic acid to give addition products. Mixtures of syn and anti addition products are obtained. Similar addition reactions occur with trifluoromethanesulfonic acid. These reactions are analogous to acid-catalyzed hydration and proceed through a vinyl cation intermediate. 

Accordingly, cyclic nitronates can be a useful synthetic equivalent of functionalized nitrile oxides, while reaction examples are quite limited. Thus, 2-isoxazoline N-oxide and 5,6-dihydro-4H-l,2-oxazine N-oxide, as five- and six-membered cyclic nitronates, were generated in-situ by dehydroiodination of 3-iodo-l-nitropropane and 4-iodo-l-nitrobutane with triethylamine and trapped with monosubstituted alkenes to give 5-substituted 3-(2-hydroxyethyl)isoxazolines and 2-phenylperhydro-l,2-oxazino[2,3-fe]isoxazole, respectively (Scheme 7.26) [72b]. Upon treatment with a catalytic amount of trifluoroacetic acid, the perhydro-l,2-oxazino[2,3-fe]isoxazole was quantitatively converted into the corresponding 2-isoxazoline. Since a method for catalyzed enantioselective nitrone cycloadditions was established and cyclic nitronates should behave like cyclic nitrones in reactivity, there would be a good chance to attain catalyzed enantioselective formation of 2-isoxazolines via nitronate cycloadditions. 

The aromatization of the oxepin structure can be accompanied by other acid-catalyzed reactions such as the hydrolysis of ketals. Dimethyl 11 -oxo-6-oxabicyclo[5.4.0]undeca-l (7),2,4-triene-2,3-dicarboxylate ethylene ketal reacts in the presence of trifluoroacetic acid to give the tetralone system 3.133... 

Further attempts to effect a one-step synthesis of the hasubanan skeleton via acid-catalyzed cyclization of urethane 28 and unsaturated amides 31 and 32 were explored, using trifluoroacetic acid (TFA) (Scheme 1). Treatment of... 

The formation of stable disulfonium dications from certain bis-sulfides provided an impetus for re-evaluating the mechanisms of some old reactions. The isomerization of sulfoxide 124, using trifluoroacetic acid, involved an acid-catalyzed migration of an oxygen atom from a sulfoxide to sulfide (see Equation 36). This was one of the first examples in which an intermediate formation of an S-S dication was proposed. Recently, such a dication 125 was detected in a non-nucleophilic medium such as sulfuric acid <1995HAC145>. 

Acid-catalyzed migration of an oxygen atom from a sulfoxide to sulfide is one of the first examples where an intermediate formation of a S-S dication was proposed.26 Recently, such intermediates were observed by physical methods. Kinetic studies suggested that an intramolecularly formed S-S dication 54 was involved in isomerization of sulfoxide 53 to 55 under influence of trifluoroacetic acid (Scheme 18).82... 

The oxaspirocyclization was applied to the synthesis of theaspirone and vitispirane (equations 26 and 27)59. Under slightly modified reaction conditions where water is employed as the major solvent, palladium-catalyzed 1,4-oxidation of 64 afforded 65. Alcohol 65 was oxidized to theaspirone, which was obtained as a 1 1 isomeric mixture of cis and trans isomers. When the analogous reaction was performed at a lower pH by the use of trifluoroacetic acid, vitispirane was formed in high yield, again as a 1 1 isomeric mixture of stereoisomers. 

Besides these results, we registered with interest the first example of a Pd-bi-nap-catalyzed hydrogenation of a fluorinated a-imino ester in the presence of trifluoroacetic acid in fluorinated alcohols (with ee-values up to 91%, but very low TON and TOF) [42]. 

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