Desilylation, electrophilic

Desilylation-electrophilic substitution of trimethylsilylbenzenes provides a route to a number of mefa-substituted fluorobenzene derivatives such as 3-fluoro-acetophenone, which is unobtainable under normal Friedel-Crafts conditions [36] (equation 25). 

Synthetic Applications. In recent years, 2-trimethylsilyloxy-furan has emerged as a keystone for the rapid assembly of a wide variety of 5-substimted 2(5//)-furanones. This is readily achieved by reaction with an electrophile and desilylation. Electrophilic attack usually occurs exclusively at C-5 products arising by C-3 attack are observed only rarely. Consequently, this electron-rich furan is viewed as a stable, readily accessible syn-thon for the y-anion of 2(5/f)-furanone (1). 

The silyl group directs electrophiles to the substituted position. That is, it is an ipso-directing group. Because of the polarity of the carbon-silicon bond, the substituted position is relatively electron-rich. The ability of silicon substituents to stabilize carboca-tion character at )9-carbon atoms (see Section 6.10, p. 393) also promotes ipso substitution. The silicon substituent is easily removed from the c-complex by reaction with a nucleophile. The desilylation step probably occurs through a pentavalent silicon species ... 

Certain representative examples of electrophile-induced desilylation of lallylsilanes are given below. 

However, such exceptions are relatively rare. Some typical examples of electrophile-induced desilylation are given on p. 16. 

Replacement of an aromatic/heteroaromatic proton with a trialkylsilyl group can confer a variety of synthetic advantages. The silyl moiety can mask a potentially acidic proton, and it can be readily removed by electrophiles, normally resulting in a process of ipso desilylation ... 

Alkylsilanes are not very nucleophilic because there are no high-energy electrons in the sp3-sp3 carbon-silicon bond. Most of the valuable synthetic procedures based on organosilanes involve either alkenyl or allylic silicon substituents. The dominant reactivity pattern involves attack by an electrophilic carbon intermediate at the double bond that is followed by desilylation. Attack on alkenylsilanes takes place at the a-carbon and results in overall replacement of the silicon substituent by the electrophile. Attack on allylic groups is at the y-carbon and results in loss of the silicon substituent and an allylic shift of the double bond. 

Silyl enol ethers and silyl ketene acetals also offer both enhanced reactivity and a favorable termination step. Electrophilic attack is followed by desilylation to give an a-substituted carbonyl compound. The carbocations can be generated from tertiary chlorides and a Lewis acid, such as TiCl4. This reaction provides a method for introducing tertiary alkyl groups a to a carbonyl, a transformation that cannot be achieved by base-catalyzed alkylation because of the strong tendency for tertiary halides to undergo elimination. 

In 1998, Harmata and co-workers <98T9995> published a new synthesis of 2-alkenyl anilines. The silylated 2,1-benzothiazines 187 could be deprotonated by n-BuLi and alkylated by different electrophiles. The corresponding products could be desilylated by fluoride with concomitant cleavage of the carbon-sulfur bond to give 2-alkenylsulfinanilides that can then be hydrolyzed by base to the anilines 195 in good yields (Scheme 55). 

The synthetic usefulness of reactions of lithiated methoxyallene 42 with suitable electrophiles was demonstrated by several syntheses of bioactive natural products or substructures thereof [52-58]. An interesting application was described by Fall et al. [52] after addition of alkyl iodide 55 to lithiated methoxyallene 42, deprotonation by tert-butyllithium and addition of carbon dioxide occurred at the terminal y-carbon and thus provided butenolide 57 after acidic workup. Desilylation of this intermediate with TBAF finally gave bicyclic oxepane derivative 58 in good overall yield (Scheme 8.14). 

Although the preparation of the substituted allene ether substrates for the Nazarov reaction is not the topic of this chapter, it is necessary to mention a few aspects of their synthesis. Lithioallene 1 (Eq. 13.13) can be trapped with chlorotri-methylsilane to give 35 [6]. Exposure of 35 to sec- or tert-butyllithium leads to allenyl-lithium 36, which can be trapped with alkyl halides or other electrophiles to give 37. Desilylation of 37 leads to 38. This is somewhat laborious, but it leads to allene 38 uncontaminated by propargyl ether 39. Exposure of 39 to n-butyllithium, followed by quenching with acid, typically produces mixtures of 38 and 39 that are difficult to separate. Fortunately, one need not prepare allenes 38 in order to access the C6-sub-... 

The first step is addition of Cl 1 to C4. We still need to form C10-C1 and break C4-C3. Since we have a 1,5-diene (Cl 1=C10-C4-C3-C2=C1), we can do an oxy-Cope rearrangement. This gives a 5-8 system in which we only have to form the C4-C2 bond. C4 is neither nucleophilic nor electrophilic, while Cl 1 is nucleophilic (conjugation from OSiMe3). Upon quenching with water, however, C4 becomes an electrophilic carbonyl C, whereupon Cl 1 attacks with concomitant desilylation of O to give the product. 

Marino and his coworkers [20a], on the other hand, studied the fluoride ion-induced desilylation of ethyl 2-silyloxycyclopanecarboxylates 24 and the resulting "homoenolate" anion 25 was allowed to react with different electrophiles, such as Michael acceptors, to give dissonant cyclopentene rings (26) via a [3 -i- 2] annulation strategy (Scheme 5.16). 

Ring nitrogens in pyrazines and the benzo derivatives react with electrophiles to form quaternary ammonium species such as iV-alkylpyrazinium salts and pyrazine iV-oxides. N-Alkylation has generally been performed by treatment with a reactive alkyl iodide. The N-1 nitrogen in 2(l//)-pyrazinone 5 is methylated using chloro(chloromethyl)dimethyl-silane followed by desilylation with cesium fluoride to yield l-methyl-2(l//)-pyrazinone <2000TL4933>. 

The enolates derived from racemic 2-(trimethylsiIyI)- or 2-benzyl-3-ethoxy-2,3,3a<4,7,7a-hexa-hydro-1 //-isoindol-l-one (13) react with some haloalkynes. Attack by the electrophile occurs at the bridgehead carbon (7a) from the least hindered side, to afford only one diastereomer of the alkylation product 14, as judged by spectroscopic properties14,15. In some experiments 2-desilylation is effected before product isolation15. 

TMS derivative 314 and electrophile quench afford compounds 316, which can be selectively C-4 desilylated to give product 315 (Scheme 95). 

Substitution of R in R3 S i by more electronegative groups both decreases the extent of desilylation and increases the proportion of meta substitution. The overall rate of electrophilic substitution is also decreased as the R3Si group becomes more electron-withdrawing. 

As described in Section II, Lewis acid catalyzed desilylative carbon-carbon bond formation with an electrophile has been shown to be very versatile in organic synthesis. Occasionally, depending on the nature of the substrates (e.g. the presence of appropriate functional groups), the carbon-silicon bond may remain intact. For example, treatment of 132 with a Lewis acid affords a mixture of cyclization products 133-135 (equation 113). The isolation of 133 indicates that the carbocation intermediate thus formed is trapped by the oxygen nucleophile before elimination of the silyl moiety occurs204. 

SnCLt-mediated intramolecular cyclization of vinylsilane 136 with the acetal moiety leads to the corresponding cyclization product 137 (equation 114). The electrophile apparently attacks at the /1-carbon to the silyl substituent205. It is noteworthy that desilylation has been observed in the similar case of 138 when BCI3 is employed as the Lewis acid catalyst (equation 115)206. 

As observed previously, the values for CT+Ph vary by as much as a factor of two and appear to depend on the value of the reaction constant. The parameters ascertained for electrophilic substitution in the 2-position of fluorene are far less variable. No systematic dependence on p is detectable. The results for desilylation deviate seriously from the general pattern but this observation appears exceptional. Although the limited information does not permit a final conclusion, we believe that the data support the idea that the response of the 2-fluorenyl group to changes in electron demand is negligibly small. 

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