Trifluoromethanesulfonic Anhydride1

(CF3SO2)2O

[358-23-6]  · C2F6O5S2  · Trifluoromethanesulfonic Anhydride  · (MW 282.16)

(preparation of triflates;1 mild dehydrating reagent; promoter for coupling reactions in carbohydrates2)

Alternate Name: triflic anhydride.

Physical Data: bp 81-83 °C/745 mmHg; d 1.677 g cm-3; n20D 1.3210.

Solubility: sol dichloromethane; insol hydrocarbons.

Form Supplied in: colorless liquid in ampules. Once opened it should be immediately used.

Analysis of Reagent Purity: IR, NMR.

Preparative Methods: by distillation of Trifluoromethanesulfonic Acid with an excess of Phosphorus(V) Oxide.1

Purification: by redistillation with a small amount of P2O5. It is advisable to freshly distill the reagent from a small quantity of P2O5 before use.

Handling, Storage, and Precautions: the pure reagent is a colorless liquid that does not fume in air and is stable for a long period. It is not soluble in water and hydrolyzes only very slowly to triflic acid over several days at room temperature. Preferably stored under N2 in a stoppered flask.

Reaction with Alcohols and Phenols.

The reaction of alcohols and phenols with triflic anhydride (Tf2O) at ~0 °C in the presence of a base (usually Pyridine) in an inert solvent (usually dichloromethane) for 2-24 h affords the corresponding reactive trifluoromethanesulfonate esters (triflates).1 When triflic anhydride and pyridine are combined, the pyridinium salt forms immediately and normally precipitates out from the reaction mixture. Nevertheless, the salt is an effective esterifying agent, reacting with the added alcohol to give triflates in high yields (eq 1).3

Pyridine can become involved in nucleophilic substitution when very reactive triflates are being synthesized.2,3 One approach to minimize this disadvantage is to replace it with sterically hindered bases, such as 2,6-di-t-butyl-4-methylpyridine,3,4 2,4,6-trisubstituted pyrimidines,5 or nonnucleophilic aliphatic amines (usually N,N-diisobutyl-2,4-dimethyl-3-pentylamine). No salt formation appears to take place under these conditions. The triflic anhydride seems to be the direct triflating agent and the base only neutralizes the triflic acid formed. Numerous alkyl triflates have been prepared in the literature1b by the above method. Some recent examples of triflates prepared from alcohols are illustrated in eqs 2 and 3.6,7 As an exception, 2,6-dinitrobenzyl alcohol does not react with Tf2O although similar sulfonyl esters could be prepared.8

Alkyl triflates have come to be recognized as useful intermediates for the functionalization of organic substrates by nucleophilic substitution, e.g. in carbohydrate chemistry.9 Triflate is the best leaving group known1b next to the nonaflate and hence a large number of triflates, obtained in good yields by reaction of the corresponding alcohols (or alkoxides) with Tf2O, have been used to generate unstable or destabilized carbocations under solvolytic conditions.1b Some new typical examples are shown in (1)-(4).10-13

Alkyl triflates are known to be powerful reagents for the alkylation of aromatic compounds.1b,14 However, the reaction of alkyl triflates with heterocycles affords N-alkylation products.15

In an improved modification of the Ritter reaction, primary and secondary alcohols react with Tf2O in CH2Cl2 in the presence of a 2:1 excess of nitriles to give the corresponding amides in good yields (eq 4).16

Aryl triflates are prepared from phenols at 0 °C using pyridine as solvent.1b Sometimes it is useful to conduct the reaction in CH2Cl2 at -77 °C, as in the preparation of 3,5-di-t-butyl-4-hydroxyphenyl triflate (eq 5).17 Aryl triflates are synthetically transformed into several products of interest and applications in organic chemistry, by cross-coupling reactions with organometallics (eqs 5 and 6).18

Reaction of Tf2O with Amines.

The reaction of 1 equiv of Tf2O in CH2Cl2 and Et3N with amines (or their salts) affords trifluoromethanesulfonamides (triflamides) in good yields.19,20 If 2 equiv of Tf2O are used, triflimides are formed. The triflamides are soluble in alkali and readily alkylated to triflimides (eq 7).19,20

Triflamides can be deprotected reductively (Sodium-Ammonia) to yield the corresponding amines.21 This protocol has been employed in the facile two-step synthesis of aza macrocycles starting from trifluoromethanesulfonyl derivatives of linear tetramines (eq 8).22

Several triflamides (5-8)23 and O-triflylammonium salts24 have been used for the formation of vinyl triflates from regiospecifically generated metalloenolates or for preparing triflates from alcohols.

Reaction of Tf2O with Carbonyl Compounds.

The reaction of Tf2O with carbonyl compounds consists of the electrophilic attack of the anhydride on the carboxylic oxygen, resulting in the formation of triflyloxycarbenium ions as intermediates (eq 9). According to the nature of the carbonyl compound, the triflyloxycarbenium cations can eliminate a proton giving a vinyl triflate, undergo a rearrangement, or be trapped by the gegenion yielding gem-bistriflates (eq 9).

In the case of acyclic and monocyclic ketones, the reaction with Tf2O affords vinyl triflates in good yields. Several methods exist to realize this reaction.1b,25 For example, the reaction is carried out at room temperature in CH2Cl2 (or pentane) in the presence of 2,4-di-t-butyl-4-methylpyridine (DTBMP) (eq 10).4

Other bases such as pyridine,1b lutidine,1b Et3N,1b polymer-bound 2,6-di-t-butyl-4-methylpyridine,26 and 2,4,6-trialkyl-substituted pyrimidines27 were also used. The commercially available N,N-diisobutyl-2,4-dimethyl-3-pentylamine is a very convenient base to prepare the vinyl triflates.28 In the case of nonfunctionalized ketones, anhydrous Na2CO3 has been proved to be very successful.1b,25

The reaction of ketones with Tf2O is governed by Markovnikov's rule and results in the formation of the more substituted triflate as the major product. When the reaction of ketones27 and a-halo ketones29 with Tf2O is carried out in the presence of a nitrile, the intermediate trifloxy cation (eq 9) can be trapped, forming pyrimidines in good yields (eq 11).

The reaction of Tf2O with strained bicyclic ketones such as 2-norbornanone and nopinone takes place with Wagner-Meerwein rearrangement of the corresponding triflyloxy cations, forming bridgehead triflates in good yields (eq 12).30 These triflates are key compounds in the preparation of other bridgehead derivatives by substitution31 and of substituted cyclopentanes by fragmentation.32

In the reaction of Tf2O with norcaranones and spiro[2.5]octan-4-one, the cyclopropane ring undergoes fragmentation to give vinyl triflates (eqs 13 and 14).33

However, a cyclopropane ring is formed in the reaction of 5-methylnorborn-5-en-2-one with Tf2O under the same conditions (eq 15).34

When the ketone can accomplish neither the stereoelectronic conditions for the elimination of TfOH nor for a rearrangement, the reaction of ketones with Tf2O results in the formation of a gem-bistriflate (eqs 16 and 17).35

Sensitive ketones such as 3-pentyn-2-one also afford the corresponding vinyl triflate on treatment with Tf2O in the presence of a base (eq 18).36

Substituted cyclopropenones and tropones react with Tf2O with the formation of the corresponding dication ether salts (eq 19).37

Treatment of trifluoroacetyl ylides with Tf2O results in the formation of gem-bistriflates (eq 20).38

Reaction of Tf2O with Aldehydes.

The reaction of aliphatic aldehydes with Tf2O in the presence of 2,6-di-t-butyl-4-methylpyridine (DTBMP) in refluxing CH2Cl2 or ClCH2CH2Cl for 2 h affords the corresponding vinyl triflates as a mixture of (Z)- and (E)-isomers.4,39 When the reaction is carried out at 0 °C, gem-bistriflates are formed as products (eq 21).40 The gem-bistriflates result due to the trapping of the intermediate triflyloxycarbenium ion by the triflate anion. Primary vinyl triflates have been used extensively in the generation of alkylidene carbenes,41 and gem-bistriflates are interesting precursors for gem-dihaloalkanes42,43 and (E)-iodoalkenes.44

Reaction with Dicarbonyl Compounds.

1,3-Diketones can be reacted with an equimolar amount of Tf2O or in excess to furnish the corresponding vinyl triflates or dienyl triflates (eq 22).45 These triflates are transferred into monoketones, monoalcohols, alkanes, and unsaturated ketones by means of various reducing reagents.45

The reaction of 3-methylcyclopentane-1,2-dione with Tf2O/Et3N affords the vinyl triflate in 53% yield (eq 23).46 The reaction takes place probably through the enol form. The product was coupled with alkenylzinc compounds in the presence of a palladium catalyst.46

The reaction of b-keto esters47 with Tf2O in the presence of a base results in the formation of 2-carboxyvinyl triflates (eq 24). These substrates undergo nucleophilic substitution of the TfO- group (eq 24)47 and also coupling reactions.48

Reaction with Carboxylic Acids and Esters.

The reaction of carboxylic acids and esters with Tf2O takes place according to the scheme shown in eq 25.49

The trifluoromethanesulfonic carboxylic anhydrides are highly effective acylation agents, which react without catalysts even with deactivated aromatics to yield aryl ketones (eq 26).50

Alkyl arylacetates react with Tf2O to give a cation which in the presence of a nitrile affords isoquinoline derivatives via cyclization of the intermediate nitrilium cation (eq 27).50

Reaction of Tf2O with Amides.

The reaction of a 2-oxo-1,2-dihydroquinoline with Tf2O in the presence of pyridine affords the corresponding 2-quinoline triflate (eq 28).51

The reaction of tertiary amides with Tf2O gives a mixture of O-sulfonylated (major) and N-sulfonylated (minor) products. In the presence of collidine and an alkene, [2 + 2] cycloadducts are formed which hydrolyze to give cyclobutanones (eq 29).52

Treatment of DMF with Tf2O results in the formation of an imminium triflate, which formylates less active aromatics. It is a convenient variation of the Vilsmeier-Haack reaction (eq 30).53

The reaction of N-methylpyridone and substituted urea systems with Tf2O gives heteroatom-stabilized dicarbonium salts (eqs 31 and 32).37,54

Secondary amides can be converted to tetrazoles with Tf2O in the presence of Sodium Azide (eq 33).55

Other Applications.

Activated arenes can be converted to aryl triflones by Friedel-Crafts reaction with Tf2O using Aluminum Chloride as catalyst (eq 34).56

The reaction of Tf2O with Ph3PO in CH2Cl2 at 0 °C affords triphenylphosphine ditriflate, which can be used as an oxygen activator, and then to a diphosphonium salt (eq 35).57

The less stable dimethyl sulfide ditriflate, obtained from Tf2O and DMSO, has been used to oxidize alcohols (eq 36).58

Tetrahydropyran is not a suitable solvent in reactions involving Tf2O because it is cleaved, affording 1,5-bistrifloxypentane (eq 37).59

Diols react with Tf2O to yield the corresponding ditriflates; however, the reaction of 1,1,2,2-tetraphenyl-1,2-ethanediol with Tf2O takes place with rearrangement (eq 38).59

Vinylene 1,2-bistriflates are formed by the reaction of azobenzils with Tf2O (eq 39).60

The reaction of enolates, prepared from silyl enol ethers and Methyllithium, with Tf2O affords vinyl triflates (eq 40).61

The combination of equimolecular quantities of Iodosylbenzene and Tf2O generates PhI(OTf)2, a compound also formed by treatment of Zefiro's reagent with Tf2O. As shown in eq 41, this compound can be used to prepare para-disubstituted benzene derivatives in good yields.62

Tf2O is a suitable promoter for the stereoselective glucosidation of glycosyl acceptors using sulfoxides as donors.63

The reaction of Tf2O with a catalytic amount of Antimony(V) Fluoride at 25 °C produces trifluoromethyl triflate in 94% yield (eq 42).64

Useful application of Tf2O as dehydrating reagent is accounted by the synthesis of isocyanides from formamides and vinylformamides (eq 43).65

Reaction of enaminones with Tf2O in a 1:1 molar ratio affords 3-trifloxypropeniminium triflates by O-sulfonylation. From a cyclic enaminone, by using a 2:1 molar ratio, the corresponding bis(3-amino-2-propenylio) bistriflate is obtained (eq 44).66


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Antonio García Martínez, Lakshminarayanapuram R. Subramanian & Michael Hanack

Universität Tübingen, Germany



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