Silylation Chapter

Unfortunately, space does not permit a full review, so that many examples and important applications of derivatives in GC—MS have been omitted. However, some mass spectrometric properties and applications as well as detailed derivative preparation instructions are given in the specialist chapters on Esterification (Chapter 2), Acylation (Chapter 3), Silylation (Chapter 4), Formation of cydic derivatives (Chapter 7), and also in the respective chapters of the first edition of the handbook [12]. 

The combination of silyl enol ethers and fluoride ion provides more reactive anions to give alkylated nitre compounds in good yields after oxidation v/ith DDQ, as shovm in Eq. 9.22. This process provides a new method for synthesis of indoles and oxyindoles fsee Chapter 10, Symhesis of Hatarocydic Compoioids). 

There are, however, two disadvantages associated with use of the phenyldimethylsilyl group. Based on the reaction stoichiometry, for each equivalent of substrate, one silyl group is unused, and after work-up this appears as a relatively involatile by-product. Secondly, after synthetic use of such vinylsilanes involving desilylation, a similar problem of by-product formation arises. One solution to these problems lies in the use of the tri-methylsilyl group (Chapter 8), since the by-product, hexamethyldisiloxane, is volatile and normally disappears on work-up. 

Kuwajima (75) has provided full details of the regiospecific monoalkylation of carbonyl compounds via their silyl enol ethers, using stoichiometric amounts of fluoride ion. Noyori (76) has given more information on the use of the complex fluoride source (2) (Chapter 18)... 

The most frequently encountered, and most useful, cycloaddition reactions of silyl enol ethers are Diels-Alder reactions involving silyloxybutadicncs (Chapter 18). Danishefsky (30) has reviewed his pioneering work in this area, and has extended his studies to include heterodienophiles, particularly aldehydes. Lewis acid catalysis is required in such cases, and substantial asymmetric induction can be achieved using either a chiral lanthanide catalyst or an a-chiral aldehyde. 

Fleming has shown (2) that the cuprate reagent (Chapter 8) derived from dimethylphenylsilyl lithium and copper(t) cyanide (molar ratio 2 1) adds regioselectively in an overall syn manner to terminal alkynes, the silyl moiety becoming attached to the terminal carbon atom (variation in reagent... 

Geometrically defined a/ -epoxysilanes have been shown (6) to undergo a highly stereoselective rearrangement to silyl enol ethers (see also Chapter 15). This rearrangement is catalysed by boron trifluoride etherate, and seems to involved-opening of the epoxysilane, as shown ... 

A variety of routes are available for the preparation of allylsilanes (/) with the simplest and most direct being the silylation of allyl-metal species. Other routes exemplified in this chapter include Wittig methodology, the use of silyl anions/anionoids in allylic substitution, and hydrometallation of... 

Rhodium-catalysed addition (10) of hydridosilanes (Chapter 17) to a/3-unsaturated carbonyl compounds can be performed regioselectively, to afford either the product of 1,2-addition, or, perhaps more usefully, that of 1,4-addition, i.e. the corresponding silyl enol ether this latter process is an excellent method for the regiospecific generation of silyl enol ethers. Of all catalyst systems investigated, tris(triphenylphosphine)rhodium(l) chloride proved to be the best. 

The transition metal catalysed addition of a hydridosilane to a multiply-bonded system is known as hydrosilylation (1). Under such conditions, alkynes undergo clear cis-addition, so providing one of the most direct routes to vinylsilanes (Chapter 3). Hydridosilanes also add to the carbonyl group of saturated aldehydes and ketones, to produce alkyl silyl ethers. Fot example, under suitable conditions, 4-t-butylcyclohexanone (2) can be reduced with a high degree of stereoselectivity. 

This chapter will not cover compounds containing heteroatoms hnked to the P and/or N atom of the P-N unit, with the notorious exception of those with N-Si bonds (A/-silyl phosphinous amides) due to its particular relevance in terms of chemical reactivity. 

For further related silylation-amination-cyclizations, see also Chapter 10. 

Acetalization or ketalization with silylated glycols or 1,3-propanediols and the formation of thioketals by use of silylated 1,2-ethylenedithiols and silylated 2-mer-captoethylamines have already been discussed in Sections 5.1.1 and 5.1.5. For cyclizations of ketones such as cyclohexanone or of benzaldehyde dimethyl acetal 121 with co-silyl oxyallyltrimethylsilanes 640 to form unsaturated spiro ethers 642 and substituted tetrahydrofurans such as 647, see also Section 5.1.4. (cf. also the reaction of 654 to give 655 in Section 5.2) Likewise, Sila-Pummerer cyclizations have been discussed in Chapter 8 (Schemes 8.17-8.20). 

Silylated acetylenic alcohols such as 1500 cyclize on treatment with HMDS-Li to give, via 1501 and 1502, 2-phenylpyrrole 1503 [46] (Scheme 9.27 compare also the formation of 2-pyridyl-2-pyrrole 543 in Chapter 5). 

There are, however, serious problems that must be overcome in the application of this reaction to synthesis. The product is a new carbocation that can react further. Repetitive addition to alkene molecules leads to polymerization. Indeed, this is the mechanism of acid-catalyzed polymerization of alkenes. There is also the possibility of rearrangement. A key requirement for adapting the reaction of carbocations with alkenes to the synthesis of small molecules is control of the reactivity of the newly formed carbocation intermediate. Synthetically useful carbocation-alkene reactions require a suitable termination step. We have already encountered one successful strategy in the reaction of alkenyl and allylic silanes and stannanes with electrophilic carbon (see Chapter 9). In those reactions, the silyl or stannyl substituent is eliminated and a stable alkene is formed. The increased reactivity of the silyl- and stannyl-substituted alkenes is also favorable to the synthetic utility of carbocation-alkene reactions because the reactants are more nucleophilic than the product alkenes. 

The focus of Chapters 1 and 2 is enolates and related carbon nucleophiles such as silyl enol ethers, enamines, and imine anions, which can be referred to as enolate equivalents. 

A series of 3-substituted-2-isoxazoles are prepared by the following simple procedure in situ conversion of nitroalkane to the silyl nitronate is followed by 1,3-dipolar cycloaddition to produce the adduct, which undergoes thermal elimination during distillation to furnish the isoxazole (Eq. 8.74). 5 Isoxazoles are useful synthetic intermediates (discussed in the chapter on nitrile oxides Section 8.2.2). Furthermore, the nucleophilic addition to the C=N bond leads to new heterocyclic systems. For example, the addition of diallyl zinc to 5-aryl-4,5-dihydroi-soxazole occurs with high diastereoselectivity (Eq. 8.75).126 Numerous synthetic applications of 1,3-dipolar cycloaddition of nitronates are summarized in work by Torssell and coworker.63a... 

As discussed in Chapter 9, various nucleophiles can be introduced at the ortho position of nitroarenes via the VNS process. This provides a useful strategy for the synthesis of indoles. One of the most attractive and general methods of indoles and indolinones would be the reductive cyclization of a-nitroaryl carbonyl compounds (Eq. 10.54). The VNS and related reactions afford a-nitroaryl carbonyl compounds by a simple procedure. For example, alkylation of 4-fluoronitrobenzene with a lactone silyl enol ether followed by reductive cyclization leads to tryptophols (Eq. 10.55).73... 

Instead of the wet chemical hydrolysis and derivatization before GC/MS analysis, methods based on pyrolysis-GC/MS with in situ thermally assisted hydrolysis and methylation or silylation can be used, as described in detail in Chapters 11 and 12. 

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