Thallium(III) Trifluoroacetate1

Tl(OCOCF3)3

[23586-53-0]  · C6F9O6Tl  · Thallium(III) Trifluoroacetate  · (MW 543.44)

(oxidizing agent; thallating agent; Lewis acid; reagent for dethioacetalization)

Alternate Name: TTFA.

Physical Data: mp 100 °C (dec).

Solubility: sol water, organic solvents.

Form Supplied in: moist white crystals, hygroscopic; widely available. Drying: decomposes on heating.

Preparative Method: readily prepared by refluxing a suspension of thallium(III) oxide with Trifluoroacetic Acid (TFA).2

Handling, Storage, and Precautions: water sensitive solid. All thallium compounds are extremely toxic to inhalation, skin contact, and ingestion. Toxicity is cumulative. Extreme caution should be used when handling these materials. Use in a fume hood.

Thallation.

Thallium trifluoroacetate is the most versatile of all the thallium reagents. It has seen extensive utility in a variety of organic transformations.1 The solution of TTFA in TFA is a potent thallating reagent. Aromatic compounds react with TTFA to provide thallated aromatics (eq 1). As is the case with other electrophilic aromatic substitution reactions, thallation is most efficient with electron-rich aromatics. Other methods are now available for the preparation of thallated aromatics using TTFA.3 Generally, the thallated intermediates are not isolated, but are transformed to a variety of compounds in a subsequent reaction with nucleophiles.

Thallation of substituted aromatics with TTFA is highly regioselective, depending on the nature of the substituent and reaction conditions. The reaction is reversible, requires a moderately large activation energy, and has large steric constraints. The electrophilic character of TTFA can be increased by the addition of Lewis acids such as Boron Trifluoride or Antimony(V) Fluoride.4 Thallation of substituted aromatics (nonheteroatom substituents) under kinetic control (short reaction times) yields the para-thallated product, illustrating the steric requirements of the reaction. The meta-thallated product can be obtained by conducting the reaction in refluxing TFA (eq 2).5

Thallation of aromatics possessing heteroatom-containing substituents (CO2R, CO2H, OR, CH2OH, etc.) shows a different type of regioselectivity, providing the ortho-thallated product (eq 3).6 This selectivity has been rationalized as intramolecular delivery of the thallium electrophile. The monothallated species generally deactivates the ring toward further thallation.

Anisole can be polythallated using excess TTFA in TFA (eq 4).7 The thallated intermediate can be converted to the corresponding iodo compound on treatment with Sodium Iodide.

Electrophilic thallations are not restricted to aromatic compounds. Heterocyclic compounds, such as thiophenes, furans, and indoles, undergo thallations cleanly.8 These thallated intermediates can also be treated with nucleophiles to provide substituted heterocycles.

ipso-Displacements.

The thallated aromatics are useful in the preparation of a variety of substituted compounds. The reaction involves treatment of the thallated intermediates with nucleophiles, alkenes, arenes, and cations.1 The introduction of the nucleophile takes place with very high selectivity: the nucleophile occupies the same position as the thallium (ipso substitution) (eq 5) (see Phenylthallium Bis(trifluoroacetate) for examples).

Preparation of aryl fluorides from thallated aromatics has been attempted by several researchers with mixed results.9 Only Taylor et al.9b have been successful, using the three-step method (including the preparation of the arylthallium bis(trifluoroacetate)) shown in eq 6. While Taylor's method is less complicated than the Balz-Schiemann method of preparing fluoride compounds, it is limited to those aromatic substrates that do not contain electron-withdrawing groups, or oxygen or nitrogen functionality.

Phenols are also readily accessed via this methodology. Arylthallium bis(trifluoroacetate) salts can be oxidized in a single step to phenols, as shown in eq 7.10 An interesting alternative which combines both boron and thallium chemistry has been developed whereby the arylthallium compound is treated with diborane to provide the arylboronic acid.11 Oxidation of the boronic acid under standard conditions (eq 8) yields the phenol.

Thallation of substituted arenes provides entry into indoles under notably mild conditions (eqs 9 and 10).12,13

Silyl enol ethers have been treated with tolylthallium bis(trifluoroacetate) to generate the novel a-metallo ketones shown in eq 11.14 These compounds are enolate equivalents in titanium-mediated aldol condensations.

Oxidations.

TTFA is a very useful oxidant. Simple alkenes undergo oxidation when treated with thallium(III) salts. The reaction proceeds by an initial oxythallation of the alkene followed by dethallation to give the oxidation product and thallium(I). The intermediate thallium(III) salts are not generally isolated. The oxidation products are glycols, their mono- and diesters, aldehydes, ketones, and epoxides, and the reaction generally involves the migration of a substituent. The product distribution is dependent on reaction conditions and the nature of the thallium(III) salt. An illustration of the use of TTFA in alkene oxidation is shown in eq 12.15 The reagent of choice for alkene oxidations is, however, Thallium(III) Nitrate.

Acyclic conjugated dienes react with TTFA to provide 1,2-diacetoxyalkenes in low yields.16 This is in contrast to Thallium(III) Acetate, which provides both 1,2- and 1,4-addition products.17 On the other hand, reaction of cyclic dienes with TTFA provides both the 1,2- and 1,4-addition products with cis stereochemistry (eq 13). Oxidation of nonconjugated dienes with TTFA is also possible. An example of this methodology in the transannular cyclization of 1,5-cyclooctadiene is shown in eq 14.18

Efficient routes have been developed for the preparation of p-quinones from a variety of aromatic substrates.19 For example, substituted 4-t-butylphenols can be converted to quinones in good yields (eq 15). Similarly, hydroquinones, 4-aminophenols, and 4-halophenols can be converted to p-quinones in good yields (eq 16).

Thallated aromatics also undergo oxidation with Trifluoroperacetic Acid to provide quinones (eq 17). The reaction proceeds with the migration of an R group or by elimination of hydrogen halide (R1 = halogen).20

Methoxy-substituted phenylpropanoic acids undergo oxidation with 2 equiv TTFA to provide p-quinones (eq 18).21 The reaction involves a one-electron oxidation to form a radical cation, followed by trapping of the intermediate with the carboxyl group and subsequent oxidation to the quinone by the second equivalent of TTFA.

TTFA has found extensive utility in intramolecular oxidative phenolic coupling reactions and has been elegantly used in the synthesis of many natural products. This coupling strategy, which mimics the biosynthesis of these natural products, provides a laboratory analog of this important reaction. In these reactions, TTFA functions as a two-electron oxidant. The ortho-para coupling strategy in the synthesis of a precursor for racemic oxocrinine is shown in eq 19.22

The major problems associated with this type of coupling reaction are regioselectivity, oxidation of other functional groups, and low yields. A solution to the above problems has been presented in the synthesis of narwedine by the use of a palladacycle to direct the mode of cyclization and to protect the oxidizable functional groups (eq 20).23 The reaction furnishes a 51% yield of narwedine.

Oxidative dimerization reactions of cinnamic acids have been explored. The reaction proceeds in the presence of Boron Trifluoride Etherate to provide fused bislactones (eq 21).24

TTFA can be effectively used for both inter- and intramolecular biaryl coupling reactions (Ullmann-type couplings). An example of an intermolecular coupling reaction is illustrated in eq 22.25 (for similar biaryl coupling reactions with TTFA and palladium catalysis, see Thallium(III) Trifluoroacetate--Palladium(II) Acetate). The details of the various reaction conditions for this coupling reaction have been determined.25 The coupling reactions work well with moderately electron-rich aryls and poorly with electron-poor aryls. Modification of the reaction conditions for coupling of highly electron-rich aryls has also been reported.26

Intramolecular biaryl coupling reactions using TTFA also proceed in a facile fashion. An example of this methodology in the synthesis of the aporphine alkaloid ocoteine is shown in eq 23.27 TTFA is a superior reagent to Vanadyl Trifluoride in this type of coupling, since the latter reagent generally gives O-demethylated compounds.

An interesting example of the biaryl coupling reaction in the synthesis of macrocyclic lactones has been reported (eq 24).28 Other examples of oxidative biaryl coupling reactions include the synthesis of lignan natural products.29

Miscellaneous.

Aromatic compounds are allylated using allylsilanes and TTFA.30 Allylsilanes are converted to allyl ethers,31 N-allyl amides,32 and allyl nitrates33 on treatment with TTFA and the appropriate nucleophile. The soft Lewis acid properties of TTFA can be effectively applied in the deprotection reactions of sulfur-containing compounds. Thioacetals can be deprotected to form the corresponding carbonyl compounds in high yields (eq 25).34

TTFA has also been used for the deprotection of sulfur protecting groups in cysteines and subsequently as an oxidant to yield cystines (eq 26).35 The reaction has been extended to intramolecular disulfide bond formation in cystine-containing peptides. The reaction employs very mild conditions and proceeds in high yields without the problems associated with other oxidants such as iodine.


1. (a) McKillop, A. PAC 1975, 43, 463. (b) McKillop, A.; Taylor, E. C. In Comprehensive Organometallic Chemistry; Wilkinson, G., Ed.; Pergamon: Oxford, 1982; Vol. 7, p 465. (c) McKillop, A.; Taylor, E. C. ACR 1970, 3, 338. (d) McKillop, A.; Taylor, E. C. Chem. Br. 1973, 9, 4. (e) Uemura, S. In The Chemistry of the Metal-Carbon Bond; Hartley, F. R., Ed.; Wiley: Chichester, 1987; Vol. 4, Chapter 5.
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Mukund P. Sibi

North Dakota State University, Fargo, ND, USA

Nancy E. Carpenter

University of Minnesota, Morris, MN, USA



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