Trimethylsilyl Trifluoromethanesulfonate1

[88248-68-4; 27607-77-8]  · C4H9F3O3SSi  · Trimethylsilyl Trifluoromethanesulfonate  · (MW 222.29)

Alternate Name: TMSOTf.

Physical Data: bp 45-47 °C/17 mmHg, 39-40 °C/12mmHg; d 1.225 g cm-3.

Solubility: sol aliphatic and aromatic hydrocarbons, haloalkanes, ethers.

Form Supplied in: colorless liquid; commercially available.

Preparative Methods: may be prepared by a variety of methods.2

Handling, Storage, and Precautions: flammable; corrosive; very hygroscopic.

Silylation.

TMSOTf is widely used in the conversion of carbonyl compounds to their enol ethers. The conversion is some 109 faster with TMSOTf/Triethylamine than with Chlorotrimethylsilane (eqs 1-3).3-5

Dicarbonyl compounds are converted to the corresponding bis-enol ethers; this method is an improvement over the previous two-step method (eq 4).6

In general, TMSOTf has a tendency to C-silylation which is seen most clearly in the reaction of esters, where C-silylation dominates over O-silylation. The exact ratio of products obtained depends on the ester structure7 (eq 5).8 Nitriles undergo C-silylation; primary nitriles may undergo C,C-disilylation.9

TMS enol ethers may be prepared by rearrangement of a-ketosilanes in the presence of catalytic TMSOTf (eq 6).10,11

Enhanced regioselectivity is obtained when trimethylsilyl enol ethers are prepared by treatment of a-trimethylsilyl ketones with catalytic TMSOTf (eq 7).12

The reaction of imines with TMSOTf in the presence of Et3N gives N-silylenamines.13

Ethers do not react, but epoxides are cleaved to give silyl ethers of allylic alcohols in the presence of TMSOTf and 1,8-Diazabicyclo[5.4.0]undec-7-ene; The regiochemistry of the reaction is dependent on the structure of the epoxide (eq 8).14

Indoles and pyrroles undergo efficient C-silylation with TMSOTf (eq 9).15

t-Butyl esters are dealkylatively silylated to give TMS esters by TMSOTf; benzyl esters are inert under the same conditions.16

Imines formed from unsaturated amines and a-carbonyl esters undergo ene reactions in the presence of TMSOTf to form cyclic amino acids.17

Carbonyl Activation.

1,3-Dioxolanation of conjugated enals is facilitated by TMSOTf in the presence of 1,2-bis(trimethylsilyloxy)ethane. In particular, highly selective protection of sterically differentiated ketones is possible (eq 10).18 Selective protection of ketones in the presence of enals is also facilitated (eq 11).19

The similar reaction of 2-alkyl-1,3-disilyloxypropanes with chiral ketones is highly selective and has been used to prepare spiroacetal starting materials for an asymmetric synthesis of a-tocopherol subunits (eq 12).20

The preparation of spiro-fused dioxolanes (useful as chiral glycolic enolate equivalents) also employs TMSOTf (eq 13).21

TMSOTf mediates a stereoselective aldol-type condensation of silyl enol ethers and acetals (or orthoesters). The nonbasic reaction conditions are extremely mild. TMSOTf catalyzes many aldol-type reactions; in particular, the reaction of relatively nonnucleophilic enol derivatives with carbonyl compounds is facile in the presence of the silyl triflate. The activation of acetals was first reported by Noyori and has since been widely employed (eq 14).22,23

In an extension to this work, TMSOTf catalyzes the first step of a [3 + 2] annulation sequence which allows facile synthesis of fused cyclopentanes possessing bridgehead hydroxy groups (eq 15).24

The use of TMSOTf in aldol reactions of silyl enol ethers and ketene acetals with aldehydes is ubiquitous. Many refinements of the basic reaction have appeared. An example is shown in eq 16.25

The use of TMSOTf in the reaction of silyl ketene acetals with imines offers an improvement over other methods (such as TiIV- or ZnII-mediated processes) in that truly catalytic amounts of activator may be used (eq 17);26 this reaction may be used as the crucial step in a general synthesis of 3-(1-hydroxyethyl)-2-azetidinones (eq 18).27

Stereoselective cyclization of a,b-unsaturated enamide esters is induced by TMSOTf and has been used as a route to quinolizidines and indolizidines (eq 19).28

The formation of nitrones by reaction of aldehydes and ketones with N-Methyl-N,O-bis(trimethylsilyl)hydroxylamine is accelerated when TMSOTf is used as a catalyst; the acceleration is particularly pronounced when the carbonyl group is under a strong electronic influence (eq 20).29

b-Stannylcyclohexanones undergo a stereoselective ring contraction when treated with TMSOTf at low temperature. When other Lewis acids were employed, a mixture of ring-contracted and protiodestannylated products was obtained (eq 21).30

The often difficult conjugate addition of alkynyl organometallic reagents to enones is greatly facilitated by TMSOTf. In particular, alkynyl zinc reagents (normally unreactive with a,b-unsaturated carbonyl compounds) add in good yield (eq 22).31 The proportion of 1,4-addition depends on the substitution pattern of the substrate.

The 1,4-addition of phosphines to enones in the presence of TMSOTf gives b-phosphonium silyl enol ethers, which may be deprotonated and alkylated in situ (eq 23).32

Miscellaneous.

Methyl glucopyranosides and glycopyranosyl chlorides undergo allylation with allylsilanes under TMSOTf catalysis to give predominantly a-allylated carbohydrate analogs (eq 24).33

Glycosidation is a reaction of massive importance and widespread employment. TMSOTf activates many selective glycosidation reactions (eq 25).34

TMSOTf activation for coupling of 1-O-acylated glycosyl donors has been employed in a synthesis of avermectin disaccharides (eq 26).35

Similar activation is efficient in couplings with trichloroimidates36 and O-silylated sugars.37,38

2-Substituted D3-piperidines may be prepared by the reaction of 4-hydroxy-1,2,3,4-tetrahydropyridines with a variety of carbon and heteronucleophiles in the presence of TMSOTf (eqs 27 and 28).39

Iodolactamization is facilitated by the sequential reaction of unsaturated amides with TMSOTf and Iodine (eq 29).40

By use of a silicon-directed Beckmann fragmentation, cyclic (E)-b-trimethylsilylketoxime acetates are cleaved in high yield in the presence of catalytic TMSOTf to give the corresponding unsaturated nitriles. Regio- and stereocontrol are complete (eq 30).41

A general route to enol ethers is provided by the reaction of acetals with TMSOTf in the presence of a hindered base (eq 31).42 The method is efficient for dioxolanes and noncyclic acetals.

a-Halo sulfoxides are converted to a-halovinyl sulfides by reaction with excess TMSOTf (eq 32),43 while a-cyano- and a-alkoxycarbonyl sulfoxides undergo a similar reaction (eq 33).44 TMSOTf is reported as much superior to Iodotrimethylsilane in these reactions.


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Joseph Sweeney & Gemma Perkins

University of Bristol, UK



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