TMS enol ether

This valuable method utilizes the O-TMS enol ethers derived from either pentane-2,4-dione or methyl acetoacetate, the former being the more reactive. Even t-alcohols are rapidly and quantitatively silylated in DMF at room temperature. A similar technique can be used to introduce the TBDMS group, although here ptsa catalysis is required (4). 

Acetophenone TMS enol ether + acetone, using TiCl4,70-74%. 

Notes. TMS enol ethers with aldehydes, ketones, using TiCl4 acetals using TMSOTf. /3-Ketosilanes with aldehydes. 

Scheme 10.33. Domino Knoevenagel/hetero-Diels-Alder hydrogenation sequence using TMS enol ethers as dienophiles.

The method can be further improved using trimethylsilyl (TMS) enol ethers, which can be prepared in situ from aldehydes and ketones [49]. TMS enol ethers of cyclic ketones are also suitable, and diversity can be enhanced by making either the kinetic or thermodynamic enol ether, as shown for benzyl methyl ketone. Thus, reaction of the kinetic TMS enol ether 10-133 with the amino aldehyde 10-134 and dimethylbarbituric acid 10-135 yielded 10-136, whereas the thermodynamic TMS enol ether 10-137 led to 10-138, again in excellent purity, simply by adding diethyl ether to the reaction mixture (Scheme 10.33). 

Next is the construction of the D ring. The TMS enol ether of compound 111 undergoes oxidation with m-CPBA, providing the C-5a trimethylsilyloxy ketone 112. Addition of methyl Grignard reagent to the ketone group and subsequent dehydration provides compound 113. Osmylation of the C=C double... 

Next, the TMS enol ether of 53c underwent oxidation with MCPBA to trimethylsilyloxy ketone 57. in 86% yield (86% conversion). Addition of methylmagnesium bromide in methylene chloride proceeded in almost quantitative yield (95%) to give tertiary alcohol 58. Dehydration with Burgess reagent [19] and acidic workup provided the allylic alcohol 59a in 63% yield, which was converted... 

While the ambiguity of the catalysis of the Diels-Alder reaction needs to be carefully elucidated, the application of the ferrocenyl carbocations in the Mukaiyama aldolization turned out evidently to be unrealisable due to their interaction with the TMS enol ether that produces TMSOTf, which proved readily to catalyze the aldolization [154]. 

Notes A very efficient Lewis acid. Useful for the conversion of ketones to their corresponding TMS enol ethers ... 

An RCu(LiI)/TMSI combination13 promotes conjugate addition to a,/)-unsaturated ketones, leading directly to TMS enol ethers from a presumed organocopper-enone jr-complex, thus ruling out significant amounts of enolate as an intermediate on the reaction pathway (equation 2). However, these results do not allow discrimination between an a-cuprio ketone or a /i-silyl copper species. 

Aminocarbonyl compounds have been prepared via Lewis base-catalysed Man-nich reaction of TMS enol ethers and iV-tosylaldimines, ArCH=N-Ts, with excellent anti selectivity in some cases.30... 

TMS enol ether has been shown to rearrange with good enantioselectivity, presumably because the boat-shaped transition state is sterically disfavoured. Rearrangement of the enantiomeric starting material has been used as a key step in a total synthesis of (+)-alline.13... 

Therefore the value of the procedure is greatly improved by using trimethylsilyl (TMS) enol ethers 200, which are easily accessible in situ from aldehydes and ketones in an ( )- or (Z)-selective way [56], Here the liberation of the aldehyde moiety from the initially formed dihydropyran takes place under the reaction conditions after the cycloaddition. TBDMS ethers 197 are too stable and can not be used in the domino process (Scheme 5.39). 

The reaction of TMS enol ether 200 with N,N-dimethylbarbituric acid 2 and the protected amino aldehyde 199 in the presence of TMOF and catalytic amounts of EDDA in an ultrasonic bath at 50-60 °C for 15 h followed by hydrogenation using... 

One practical limitation is the availability, storage, and handling of reactive tri-chlorosilyl enolates. Addressing this issue, Denmark et al. developed an interesting, more practical procedure entailing in situ preparation of those reactive species. Starting from a TMS enol ether 29, in situ preparation of the trichlorosilyl enolate with tetrachlorosilane and mercury acetate, followed by subsequent asymmetric al-dol reaction, gave the aldol product (S)-25 in 89% yield and with 92% ee (Scheme 6.14). 

To achieve good yields excess of TMS enol ether 29 must be used. Although replacement of the required mercury salt would be desirable, this in situ preparation of the enolate and subsequent asymmetric aldol reaction is a practical method on a laboratory scale. 

In the second step the TMS enol ether collapses in a 3 1 1 mixture of acetic acid,water and THF to the corresponding ketone. Also the TBS protecting group is removed leading in 72 % yield (from 11) to the primary alcohol.15... 

Dihydro-3-methylenethiopyran-4-one is available from the TMS enol ether of 2//-thiopyran4-one by conversion to the 2,3-dihydro-3-methoxymethylthiopyran4-one and successive treatment with trifluoroacetic acid and triethyl-amine (Scheme 219) <1996SL261>. 

If silylation alone (0.2 ml of BSTFA + 0.05 ml of TMCS) without the preceding methoximation is carried out, TMS enol ether—TMS esters are produced from keto acids. Using the procedure described, methoxime-TMS esters of keto acids and TMS ether—TMS esters of hydroxy acids are produced. Unsubstituted acids give TMS esters. The procedure eliminates possible losses of the derivatives, which can be caused by, e.g., evaporation of the solvent between the esterification and the silylation steps, and is quantitative. SE-30, OV-17 and OV-22 can be used and retention data on these stationary phases have been reported for 15 acids [159]. An example of the separation of the derivatives of some acids prepared by this procedure is illustrated in Fig. 5.12. 

An alternative to the direct a-deprotonation of a ketone is the conversion of its enol ether (in particular, TMS enol ethers) or ester (in particular, acetates) into the corresponding lithium enolate. The advantage of this detour is that the enol ethers and esters can either be prepared as a single isomer or the mixture of isomers can be separated by distillation or chromatography108, while their conversion into enolates takes place in a regio-and stereospecific manner. 

The synthetic utility of this method was further developed through investigation of substrates in which the arylation took place intramolecularly. Treatment of the TMS enol ether 70 with 2.5 mol% of Pd2(dba)3 and 6 mol% of f-BusP in the presence of 1 eq. BusSnF afforded the bicyclic arylation product 71 in 84% yield (equation 21) . 

Table 6 Addition of TMS enol ether 17 to aldehydes catalyzed by la...

In the first step of the reaction silyl enol ether 23 is formed. The use of bulky bases like NaHMDS at -78 °C ensures the formation of the so-called kinetic enolate 22, which is obtained by deprotonation of the ketone at the less-hindered a-position. Afterwards, 22 is protected by trimethylsilyl chloride (TMSCl), yielding TMS-enol ether 23. TMS ethers are often unstable under acidic and basic conditions and barely survive the simplest chemical transformation. TMS-enol ethers of this type are often used in Mukaiyama aldol reactions with catalytic amounts of Lewis acids. 

---