Silyl ethers basicity

Silyl ethers are among the most frequently used protective groups for the alcohol function. This stems largely from the fact that their reactivity (both formation and cleavage) can be modulated by a suitable choice of substituents on the silicon atom. Both steric and electronic effects are the basic controlling elements that regulate the ease of cleavage in multiply functionalized substrates. In plan-... 

The synthesis of this derivative of KDG was accomplished following the sequence depicted in figure 6. Methylation of the intermediate 8 with methyl Inflate afforded compotmd 21. Subsequent removal of the enol benzoate group at C-2 and of the silyl ether at C-6 provided the target compound 23 in 11% overall yield based on 8. This low yield could be due to the unstability of compotmds 8, 21 and 22 in a basic medium. However 24 was obtained in quantity sufficient for testing. 

It has been known for some time that the basicities of a heteroatom decrease upon a-silyl substitution [12], For example, alkyl silyl ethers (R3Si-0-R ) are less basic than dialkly ethers. Silylamines are weak bases compared to alkylam-ines. This electron-withdrawing effect of silyl groups has been explained in terms of the interaction between low lying vacant orbitals such as 3d orbitals of silicon or a orbitals with the nonbonding p orbitals (lone pairs) of the heteroatom (Fig. 4). This interaction decreases the HOMO level which in turn lowers the basicity of the heteroatom. Such effect may also cause the increase of the oxidation potentials, but little study has been reported on the electrochemical properties of this type of compounds. 

Silyl ethers of aliphatic alcohols are inert towards strong bases, oxidants (ozone [81], Dess-Martin periodinane [605], iodonium salts [610,611], sulfur trioxide-pyridine complex [398]), and weak acids (e.g., 1 mol/L HC02H in DCM [605]), but can be selectively cleaved by treatment with HF in pyridine or with TBAF (Table 3.32). Phenols can also be linked to insoluble supports as silyl ethers, but these are less stable than alkyl silyl ethers and can even be cleaved by treatment with acyl halides under basic reaction conditions [595], Silyl ether attachment has been successfully used for the solid-phase synthesis of oligosaccharides [600,601,612,613] and peptides [614]. 

Methyl ethers are stable to acidic and basic conditions, and oxidising or reducing reagents. Deprotection to regenerate the alcohol is difficult (see Section 9.6.10, p. 1254) a convenient mild procedure uses iodotrimethylsilane in chloroform solution at room temperature.768 The alkyl methyl ether under these conditions gives the alkyl silyl ether and methyl iodide the former on treatment with methanol gives the deprotected alcohol. 

The solution12 is to carry out the reaction in the presence of M SiCl. This does two things. The more obvious is that the enediol dianion 51 is trapped as the silyl enol ether 56, a useful intermediate, but the more important thing is the removal of the basic ethoxide ions as the neutral silyl ether EtOSiMe3. 

Silylation reactions on polysaccharides with chlorosilanes and silazanes were attempted more than 50 years ago resulting in hydrophobic silyl ethers with both increased thermal stability and solubility in organic solvents [376]. The silylation reaction for the protection of hydroxyl groups in mono- and polysaccharides exhibits many advantages, e.g. fast silylation, solubility of silylether in organic solvents suitable for subsequent derivatisation, stability of the resulting silylether under basic conditions but easy deprotection of the silyl moieties by acid hydrolysis or nucleophilic agents like fluoride and cyanide ions [377]. The partial and complete silylation of dextran was studied in detail by Ydens and Nouvel [215-217]. 

Trimethylsilyl ethers are sensitive to certain reagents used in organic synthesis. For example, they are attacked by nucleophiles, readily cleaved under acidic or basic conditions, and they do not survive hydrogenolysis. To overcome these problems a number of reagents which form more bulky silyl ethers have been developed some of these are shown in Figure Si2.2. 

Silyl ethers are cleaved to their parent alcohols by nucleophiles (often alcohols) under a range of acidic or basic conditions (Equation Si2.4). 

Silyl ethers are cleaved under basic and acidic conditions as well as by nucleophilic attack by fluoride ions. The driving force of the latter... 

The mechanism of silane alcoholysis has been the focus of discussions over many years.10a 14 15 17 25 30 A general mechanism is outlined below. This mechanism begins with oxidative addition of the metal into the Si-H bond to form either a r 2 complex (la) or a silyl hydride (lb) (Figure 5). The alcohol then coordinates to the silicon forming a new complex (II) which can lose silyl ether to form a metal dihydrogen complex (HI). The catalyst is regenerated when another silane displace molecular hydrogen from the catalyst. There are several minor variations of this mechanism however this basic mechanism is believed to hold for many catalytic systems. 

In the case where the silyl ketal is made up of the 2-phenylethanol and (+)-ethyl lactate (3a), the more basic oxygen would be the one on the 2-phenylethanol moiety. However protonation and eventually dissociation of this alcohol leads back to the starting silyl ether. Protonation could also occur on the oxygen of the (+)-ethyl lactate moiety. Once the (+)-ethyl lactate is protonated it could dissociate resulting in newly formed silyl ether. This newly formed silyl ether can react with the dissociated (+)-ethyl lactate, or it can go on to react with another 2-phenethyl ethanol which is present in a higher concentration than the dissociated (+)-ethyl... 

Just as there is no single measure of acidity and basicity, there is no single measure of nucleophilicity and electrophilicity—the rank order of nucleophiles changes when the reference electrophile changes. A hard nucleophile like a fluoride ion reacts fast with a silyl ether in an SN2 reaction at the silicon atom, which is relatively hard, but a soft nucleophile like triethylamine does not. In contrast, triethylamine reacts with methyl iodide in an SN2 reaction at a carbon atom, but fluoride ion does not. These examples, which are all equilibria, are governed by... 

During a synthesis of Hennoxazole, Wipf and Lim97 found that Lithium hydroxide at 90 3 C offered a convenient method for removing a TBS ether in the presence of a TIPS ether [Scheme 4.59], This is a rare example of the use of basic hydrolysis in selective alkyl silyl ether deprotection. 

In a short known reaction sequence, enal 250 was obtained from commercially available material 184). With methylamine and magnesium sulfate imine 251 was formed and combined with acyl chloride 252 185) (>4 steps). The use of low temperatures for this acylation led exclusively to the less substituted dienamide 253. The desired basic skeleton of dendrobine 254 was obtained by cyclizing 253 at 180°C in an acceptable 50% yield, Adduct 254 was accompanied by small amounts of the exo-adduct. Epoxidation led exclusively to exo-epoxide 255, which by means of trimethylsilyltriflate was converted into the allylic silyl ether. Acid treatment liberated the hydroxy group and subsequent oxidation of alcohol 256 led to enone 163, an intermediate of Inubushi s dendrobine synthesis and thus concluded this formal synthesis. The intermediate 163 was obtained from commercially not available materials in seven steps in 22.5% overall yield. To reach ( )-dendrobine according to Inubushi et al. would afford six additional steps, reducing the overall yield to 0.4% without including the preparation of the starting materials from commercially available compounds. 

---