Methyl Trifluoromethanesulfonate

(R = CF3)

[333-27-7]  · C2H3F3O3S  · Methyl Trifluoromethanesulfonate  · (MW 164.12) (R = F)

[421-20-5]  · CH3FO3S  · Methyl Fluorosulfonate  · (MW 114.11)

(powerful methylating agents1,2)

Alternate Name: R = CF3, methyl triflate; R = F, Magic Methyl.

Physical Data: methyl triflate: bp 99 °C, mp -64 °C, d 1.50 g cm-3. Methyl fluorosulfonate: bp 92 °C, mp -92.5 °C, d 1.45 g cm-3.

Solubility: both reagents are miscible with all organic solvents, but react with many. They are only sl sol water, but hydrolyze rapidly as they dissolve. Useful inert solvents are CH2Cl2, SO2, sulfolane, nitromethane, Me2SO4, and Me3PO4.

Form Supplied in: methyl triflate (MeOTf) is available as a colorless liquid. Methyl fluorosulfonate (MeOSO2F) was formerly available as Magic MethylTM but has been withdrawn (see below).

Analysis of Reagent Purity: MeOTf gives a singlet in 1H NMR at d 4.18, with 13C absorption at d 61.60 and 119.32 (q), and a 19F shift of 75.4 ppm. MeOSO2F absorbs at d 4.19 in 1H NMR (JHF &AApprox; 0.4 Hz or less), with 13C absorption at d 62.45, and a 19F shift of -31.2 ppm. 33S and 17O NMR data have been reported for both compounds.9

Preparative Methods: both reagents are prepared3,4 by distilling an equimolar mixture of the corresponding acid with Dimethyl Sulfate in an all-glass apparatus with a short Vigreux column. They may be dried by standing over fused K2CO3 and redistillation. Trifluoromethanesulfonic Acid and Fluorosulfuric Acid are both available, and are comparably priced.

Handling, Storage, and Precautions: both reagents are extremely hazardous. All possible precautions should be taken to avoid inhalation or absorption through the skin. A fatality has occurred with MeOSO2F through inhalation of the vapors leading to pulmonary edema.5 Dexamethasone isonicotinate (Auxiloson® spray) has been recommended as a first aid in the treatment of such pulmonary irritation.5 The oral LD50 of MeOSO2F is 112 mg/kg in mice, and an LC50 for 1 h exposure for rats between 5 and 6 ppm has been reported; severe eye irritation was noted.6 It is very unlikely7 that MeOTf is less dangerous, but no data on toxicity have been reported. Both materials are extremely destructive to the tissue of the mucous membranes and upper respiratory tract, eyes, and skin. Inhalation may be fatal as a result of spasm, inflammation, and edema of the larynx and bronchi, chemical pneumonitis, and pulmonary edema. Use in a fume hood.

The reagents are stable in glass when dry, but storage of MeOSO2F in bottles with ground glass joints should be avoided as these slowly become fused. It is reported8 that MeOSO2F after storage over CaH2 for two weeks contained 17% Me2SO4.

General Reactivity.

MeOTf and MeOSO2F are two of the most powerful reagents for methylation and are more reactive by a factor of ~104 than Iodomethane and Me2SO4.1,2 The only reagents which are substantially more powerful are Methyl Fluoride-Antimony(V) Fluoride and related reagents10 and the dimethylhalonium ions; these reagents pose more severe handling problems. The reactivity of MeOTf and MeOSO2F is not effectively enhanced by addition of Lewis acids. Thus addition of Antimony(V) Chloride to MeOSO2F and Dimethyl Sulfone led to complexation of the sulfone rather than methylation;11 it is also reported that addition of SbCl5 leads to formation of MeCl.12

The qualitative reactivity of some methylating agents toward a range of functional groups is shown in tabular form (Table 1).1 Few quantitative data are available, but MeOTf and MeOSO2F are only a little less reactive than the trimethyloxonium ion, with the dimethoxycarbenium ion probably somewhat more reactive again. Substitution rates with various nucleophiles are reported to be in the order: Me3O+ > MeOTf > MeOSO2F > MeOClO3, with rate ratios of 109:23:8:6:1.0 for reaction with acetonitrile at 0 °C.13,14 Methyl perchlorate, an explosion hazard, therefore never offers a practical advantage. Our experience is that the relative rates for MeOTf and MeOSO2F rarely differ by more than a factor of 2-5.

It is noteworthy that neither MeOTf nor MeOSO2F shows any reactivity on their own in Friedel-Crafts methylation reactions even with highly reactive substrates (Me3O+ ion is similar). Reaction has been observed in the presence of protic or Lewis acids.15 Olah has recently suggested that this reactivity is associated with generation of superelectrophiles by further protonation.16 MeOSO2F has been reported to react as a methylsulfonylating agent towards phenol and anisole,17 but this alternative reactivity is usually not significant.

The alkylation reactions of MeOTf and MeOSO2F are discussed according to the atom alkylated. To avoid unnecessary repetition, reactions can be assumed to use MeOTf unless MeOSO2F is specified. Historically, MeOSO2F was mainly used up until about 1980, but MeOTf has since become the reagent of choice. In the great majority of cases these reagents can probably be used interchangeably.

Alkylation at Nitrogen.

Most amines react violently with MeOTf or MeOSO2F, and only those with severe steric hindrance or conjugated with strong electron-withdrawing groups really require the use of these reagents. Of derivatives with sp3 nitrogen, Diisopropylamine, N,2,2,6,6-pentamethylpiperidine, and 1,8-Bis(dimethylamino)naphthalene (Proton Sponge™) can all be quaternized by MeOSO2F, and N,N,2,6-tetramethylaniline reacts on heating.1 However, it has been reported that i-Pr3N does not react with MeOSO2F.19 2,6-Lutidine reacts exothermically with MeOSO2F at room temperature, and 2,6-dimethoxycarbonylpyridine can be quantitatively quaternized.1 A range of [n](2,6)-pyridinophanes have been methylated with MeOSO2F, with n as small as 6 (eq 1).20

2,6-Di-t-butylpyridine does not react at normal pressure, and this or 2,6-di-t-butyl-4-methylpyridine (synthesis21), are often used in applications which require base (see below). Note that 2,6-di-t-butylpyridine can be alkylated under high pressure with MeOSO2F to give >90% of the methylation product when water is carefully excluded.22

Simple imines, such as benzylideneaniline, react readily. The N-methylation of imine and amidine derivatives of amino acid esters, followed by hydrolysis, has been used as a method for the preparation of N-alkylated amino acids with minimal racemization.23 A convenient synthesis of N-methyl nitrones has been developed by alkylation of OTMS oximes with MeOTf, followed by treatment with fluoride ion.24

Besides the pyridine derivatives already mentioned, most heterocyclic nitrogens can be alkylated. Aspects of the quaternization of heteroaromatics have been recently reviewed.25 With respect to the limits of reactivity, it is interesting that dimethylation of 2-phenyl-4,6-dimethylpyrimidine could only be achieved with Trimethyloxonium Tetrafluoroborate; MeOSO2F only gave monoalkylation.26 2-Benzoylbenzothiazole can be N-alkylated with MeOSO2F (but not with MeI) and then acts as an active acylating agent.27 Formation of an N-methylindole from an N-ethoxycarbonylindole has been achieved with MeOSO2F.28

A number of alkylation products from MeOTf and heterocycles have been advocated as useful intermediates. Thus treatment of 2-substituted thiazoles with MeOTf in acetonitrile, followed by reduction of the salt formed with Sodium Borohydride/CuO in CH2Cl2, leads to aldehydes.29 1-(Benzenesulfonyl)-3-methylimidazolium and 1-(p-toluenesulfonyl)-3-methylimidazolium triflates have been proposed as efficient reagents for the preparation of aryl sulfonamides and aryl sulfonates.30 MeOTf alkylates 2,5-oxazoles to give salts which can be reduced by PhSiH3/CsF to give 4-oxazolines, and these provide a route to stabilized azomethine ylides.31

A novel synthesis of 2-aryl-4-piperidones by Mannich cyclization of imino acetals, initiated by methylation of the imine, has been described.32 MeOTf has been used in the generation of a munchnone for cycloaddition.33 Finally, methylation of 1-lithio-2-n-butyl-1,2-dihydropyridine with MeOTf gives 2-butyl-5-methylpyridine in 42% yield.34

Nitriles, with sp hybridized nitrogen, are unreactive to MeI or Me2SO4, but are readily methylated by MeOSO2F,1 MeOTf,35 or oxonium ions. Nitrilium salts have been shown to have a number of useful applications. The reduction of nitrilium salts by NaBH4 in alcohols leads first to iminoethers and subsequently to amines.36 Reduction of N-alkylnitrilium ions by organosilicon hydrides gives n-alkylaldimines, and thus provides a route to aldehydes from nitriles.37 Nitrilium triflate salts have been shown to be useful reagents for the synthesis of ketones and ketenimines by electrophilic substitution of reactive aromatics, and also provide good routes to amidinium, imidate, and thioimidate salts.35 Reaction with 2-amino alcohols gives oxazolidines.38 Synthesis of either 5-substituted 1-methyl-1H-tetrazoles or 3,5-disubstituted 1,4-dimethyltriazolium salts from N-methylnitrilium triflate salts can be controlled in reactions with (Me2N)2C=NH2+N3-.39 Reaction of nitrilium ions with alkyl azides gives 1,2,3-trisubstituted tetrazolium salts.40 These can be deprotonated to highly reactive 2-methylenetetrazoles.41

Amides are alkylated largely on oxygen, as expected (see below), although some N-alkylation can be seen by NMR.1 N-Alkylation is more apparent with carbamates (see the section on ambident nucleophiles). N,N-Dimethylmethanesulfonamides can be N-alkylated (MeOSO2F) to provide salts which are effective reagents for mesylation.42 N,N-Dimethylsulfamate esters react with MeOSO2F to give trimethylammoniumsulfate esters, which rapidly give methyl esters unless the O-group is aryl, showing that Me3N+SO3- is a very powerful leaving group.43 Me3N+SO2OPh reacts with nucleophiles at either the sulfur or a methyl carbon atom.44

Azo compounds, which do not react with methyl iodide, can be N-methylated by MeOSO2F.45

A steroidal oxaziridine was converted (MeOSO2F) to an oxaziridinium salt which showed oxidizing properties.46

Alkylation at Oxygen.

Most neutral functionalities with lone pairs on oxygen are not alkylated by MeI or Me2SO4 but do react with MeOTf or MeOSO2F, although not all such reactions are preparatively useful.1,2 Ethers react reversibly, and the ultimate product depends on the conditions. Thus good yields of the oxonium ion can be obtained from reaction of THF with stoichiometric amounts of MeOTf, but the use of catalytic amounts leads to polymerization. Cationic ring opening polymerization, initiated by MeOTf and MeOSO2F among other reagents, has been extensively investigated and recently reviewed.47

Reaction of MeOSO2F with 2-methoxyethyl carboxylates gives 2-alkyl-1,3-dioxolanium ions.1 The reaction of these ions with trialkylalkynylborate anions provides versatile and direct routes to (Z)-a,b-unsaturated ketones (eq 2). Specifically protected 1,3-diketones and other ketonic species can also be prepared from the intermediates.48

Almost all carbonyl functions can be methylated. Enolizable aldehydes and ketones usually lead to complex mixtures, probably because of deprotonation to enol ethers, followed by reaction of these with the electrophilic species in the reaction mixture. Nonenolizable aldehydes and ketones give methoxycarbenium ions cleanly, and the relative thermodynamic stabilities of these have been assessed via pairwise equilibrations.49 Most esters only generate low equilibrium concentrations of dialkoxycarbenium ions, but lactones are readily alkylated.1

Amides, carbamates, and ureas are rapidly alkylated, usually on carbonyl oxygen (see the section on ambident nucleophiles). Alkylation of amides with MeOT5f in CH2Cl2 followed by reduction of the salts provides a route for the selective reduction of amides; esters, nitriles, acetals, and double bonds are left unaffected by this procedure.50 Alkylation of isoindolin-1-ones and subsequent deprotonation can provide routes to methoxyisoindoles.51

Alcohols can be converted to methyl ethers by the use of MeOTf + 2,6-di-t-butylpyridine or 2,6-di-t-butyl-4-methylpyridine. This procedure was initially developed in the carbohydrate field.52 Me3PO4 provides a good polar solvent for this process.53 A recent application, in the synthesis directed at lonomycin, was to methylation of the complex alcohol (1) without causing retro-aldol cleaveage.54

MeOTf has been reported to effect complete methylation of inositol polyphosphates, P-OMe groups being formed as well.55 MeOTf will effect O-alkylation at the anomeric center, but the stereochemistry is affected by the presence of a crown ether.56 Reaction of Meisenheimer complexes with MeOSO2F can lead to capture of the anion as a nitronate ester.57

Alkylation at Sulfur and Selenium.

Dialkyl and most arylalkyl sulfides are readily converted into sulfonium salts.1 Cyclic sulfides, especially dithiolanes, react somewhat faster.58 Reaction of disulfides with MeOTf gives Me2SSMe+ OTf-; this salt, with Triphenylphosphine, reacts with alkenes in a stereo- and regioselective fashion and the products can be converted into vinylphosphonium salts.59 Thione groups are also alkylated even when electronegative groups are present. Thus 4,5-bis(trifluoromethyl)-1,3-dithiolane-2-thione was converted into a methylated salt.60 Sulfoxides are O-alkylated,1 and formation of various oxa- and azasulfonium ions has been reported, up to and including triazasulfonium salts.61 Alkylation of R2SO with MeOSO2F, followed by reduction with Sodium Cyanoborohydride, leads to sulfides.62

Reaction of MeOTf with the product from P2S5/Na2CO3 (Na2P4S10O) gave a useful electrophilic thionation reagent.63 MeOSO2F has been used in the conversion of thiols to reactive sulfenating agents (eq 3).64

Methylation of dithioacetals by MeOSO2F, followed by reaction with various nucleophiles, has been used for the removal of this protecting group or its conversion into other protecting groups, e.g. acetals (eq 4).65-68

The reaction of the sulfonium intermediate with alcohols leads to their protection as hemithioacetals.69 Treatment of thioglycosides with MeOTf gives an efficient glycosylating agent,70 and pyruvic acetal formation from a pyruvyl thioacetal has been achieved in a reaction catalyzed by MeOTf (amongst other electrophiles).71

Alkenes can be prepared by methylation of selenides by MeOSO2F and treatment of the selenonium ions formed with Potassium t-Butoxide.72

Alkylation at Phosphorus.

Phosphines and phosphites undergo easy quaternization. Thus methylation of tris(2,6-dimethylphenoxy)phosphine with MeOTf, followed by treatment of the product with sodium 2,6-dimethylphenoxide, gave methyltetrakis(2,6-dimethylphenoxy)phosphane.73 Methoxyphosphonium triflates are relatively stable intermediates in Arbuzov reactions.74 Phosphine oxides and sulfides are alkylated. S-Methylation of chiral phosphine sulfides, followed by treatment with Hexamethylphosphorous Triamide, has been advocated as a general synthesis of optically active phosphines.75

Ambident Nucleophiles.

Amides and related functional groups can be alkylated on oxygen or nitrogen and, as has been noted already, alkylation on carbonyl oxygen normally predominates. In the case of carbamates, O-alkylation by MeOSO2F can be faster, but N-alkylation predominates at equilibrium.76 It has been noted that methylation of secondary amides and thioamides occurs at the protonless heteroatom in the major tautomer.77 The ionic products of these reactions can be deprotonated to give synthetically useful products, e.g. imidates,78 but excess MeOSO2F should be removed before treatment with base.77

Reaction of most enolates with MeOTf or MeOSO2F is always likely to be kinetically controlled. There does not appear to have been a definitive study, but O-alkylation is the normal outcome. O-Alkylation of a bicyclodecatrienone by MeOSO2F is enhanced by the use of polar solvents like HMPA.79 O-Alkylation of enolates of appropriate cyclohexadienones by MeOTf has been used to generate various 3aH-indenes.80 A ketene acetal is formed by exclusive O-alkylation of the sodium enolate of isopropyl bis(pentachlorophenyl)acetate by MeOTf.81

Alkylations at Carbon.

In an important recent development, primary a-alkylation of carbonyl compounds under nonbasic conditions has been achieved (eq 5) by alkylation of silyl enol ethers with MeOTf and other primary alkyl triflates, catalyzed by Methylaluminum Bis(4-bromo-2,6-di-t-butylphenoxide) (MABR).82

Related Reagents.

Dimethoxycarbenium Tetrafluoroborate; Dimethyliodonium Hexafluoroantimonate; O-Methyldibenzofuranium Tetrafluoroborate; Triethyloxonium Tetrafluoroborate.

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Roger W. Alder & Justin G. E. Phillips

University of Bristol, UK

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.