Silyl enol ethers as nucleophiles

Ketone Enolates Derived from Silyl Enol Ethers as Nucleophiles... 

Scheme 9.15 Alkylations with ketone enolates derived from silyl enol ethers as nucleophiles.

Even if silicon chemistry is new to you, you should by now have a picture of stable compounds with C-Si bonds and selective reaction with fluoride. You are already familiar with silyl enol ethers as nucleophilic enolate equivalents and allyl silanes resemble these in many ways. The missing link is the i-silyl effect. A Si atom stabilises a cation in the p-posit ion by overlap of the populated and relatively high energy C-Si c-orbital with the empty p orbital of the cation. This overlap is already present in the preferred conformation 95a of the allyl silane 95 as an anti-bonding interaction 95b between the C-Si c-orbital and the n orbital of the double bond. The resultant molecular orbital (the new HOMO) 95c increases the nucleophilic reactivity of the carbon atom in the y-position. 

Alternatively, the iminium-activation strategy has also been apphed to the Mukaiyama-Michael reaction, which involves the use of silyl enol ethers as nucleophiles. In this context, imidazolidinone 50a was identified as an excellent chiral catalyst for the enantioselective conjugate addition of silyloxyfuran to a,p-unsaturated aldehydes, providing a direct and efficient route to the y-butenolide architecture (Scheme 3.15). This is a clear example of the chemical complementarity between organocatalysis and transition-metal catalysis, with the latter usually furnishing the 1,2-addition product (Mukaiyama aldol) while the former proceeds via 1,4-addition when ambident electrophiles such as a,p-unsaturated aldehydes are employed. This reaction needed the incorporation of 2,4-dinitrobenzoic acid (DNBA) as a Bronsted acid co-catalyst assisting the formation of the intermediate iminium ion, and also two equivalents of water had to be included as additive for the reaction to proceed to completion, which... 

The Mukaiyama aldol reaction is a highly selective cross aldol condensation using a silyl enol ether as nucleophile and a Lewis acid-coordinated carbonyl compound as electrophile. 

Scheme 2.2 illustrates several examples of the Mukaiyama aldol reaction. Entries 1 to 3 are cases of addition reactions with silyl enol ethers as the nucleophile and TiCl4 as the Lewis acid. Entry 2 demonstrates steric approach control with respect to the silyl enol ether, but in this case the relative configuration of the hydroxyl group was not assigned. Entry 4 shows a fully substituted silyl enol ether. The favored product places the larger C(2) substituent syn to the hydroxy group. Entry 5 uses a silyl ketene thioacetal. This reaction proceeds through an open TS and favors the anti product. 

Various nucleophiles, such as alcohols, fluoride ion, amides, allylsilane, and electron-rich aromatic rings, have been successfully used in this reaction in either an inter- or intra-molecular mode. A recent example of a new C-C bond formation in this reaction in the inter-molecular mode includes the preparation of derivatives 17 by the oxidation of 2-alkoxynaphthols 16 in the presence of an allylsilane or a silyl enol ether as a carbon-based nucleophile (Scheme 7) [22]. 

In modern organic chemistry, silyl enol ethers, as well as the corresponding titanium, tin, boron, or zirconium derivatives, are widely employed as nucleophilic components in enolate alkylation reactions. Their usefulness prompted the elaboration of numerous methods for the selective production of isomeri-cally pure enol ethers from almost any type of carbonyl compounds. 

Compounds with an additional 2-vinyl group, easily available in two steps from a,J -unsaturated ketones, are of special interest. If the reactive vinyl ketone moiety is liberated, it can be trapped in situ by suitable nucleophiles, e.g. CH-acids, generating polyfunctional compounds or by a diene unit which undergoes an intramolecular Diels-Alder reaction (equation 93). Besides, radical additions to the vinylcyclopropane are also possible giving silyl enol ethers as ring-opened products . Future synthetic applications of theses processes are obvious. 

A review of the Pummerer reaction describes much of the breadth of this work [18], but a more recent paper expanded this chemistry to form spirocycles which contain adjacent quaternary carbons [20]. While the test cases (22 to form the spirocycle 23) proceeded smoothly, the application to a more complicated structure (24), which would be closer to the ring system seen in the natural product, crassanine, demonstrated that a nearby amine would interfere with the addition of the silyl enol ether as a nucleophile. While this precludes the utility of this reaction for the crassanine alkaloids, the unusual ring formed in 25, a C-3-azetidine spirocyclic indolenine, is found in the chartelline alkaoids. 

The ketone is added to a large excess of a strong base at low temperature, usually LDA in THF at -78 °C. The more acidic and less sterically hindered proton is removed in a kineti-cally controlled reaction. The equilibrium with a thermodynamically more stable enolate (generally the one which is more stabilized by substituents) is only reached very slowly (H.O. House, 1977), and the kinetic enolates may be trapped and isolated as silyl enol ethers (J.K. Rasmussen, 1977 H.O. House, 1969). If, on the other hand, a weak acid is added to the solution, e.g. an excess of the non-ionized ketone or a non-nucleophilic alcohol such as cert-butanol, then the tautomeric enolate is preferentially formed (stabilized mostly by hyperconjugation effects). The rate of approach to equilibrium is particularly slow with lithium as the counterion and much faster with potassium or sodium. 

This area of reactivity has been the subject of excellent reviews (J5). Silyl enol ethers are not sufficiently nucleophilic to react spontaneously with carbonyl compounds they do so under the influence of either Lewis acids or fluoride ion, as detailed above. Few clear trends have emerged from the somewhat limited number of definitive studies reported so far, with ambiguities in diastereoisomeric assignments occasionally complicating the issue even further. 

Reaction conditions that involve other enolate derivatives as nucleophiles have been developed, including boron enolates and enolates with titanium, tin, or zirconium as the metal. These systems are discussed in detail in the sections that follow, and in Section 2.1.2.5, we discuss reactions that involve covalent enolate equivalents, particularly silyl enol ethers. Scheme 2.1 illustrates some of the procedures that have been developed. A variety of carbon nucleophiles are represented in Scheme 2.1, including lithium and boron enolates, as well as titanium and tin derivatives, but in... 

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. 

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... 

When furans were tethered to silyl enol ethers at the 2-position, spiroannulation also occurred at the 2-position under electrochemical conditions <06CC194>, as exemplified below. The formation of the kinetic products is the result of the higher nucleophilicity of the furan C2-position. 

Reaction of 4a with TiCl4 was carried out in the presence of siloxyalkene 3 as nucleophile and the results are summarized in Table III. In the reaction with ketene silyl acetals 3a and 3e at -78 °C, y-ketoesters 15a and 15e were obtained instead of chloride product 8 which is a major product in the absence of 3. Formation of product 15 is likely to result from trapping of alkylideneallyl cation 5 with 3 at the sp2 carbon. In contrast, the reactions with silyl enol ethers 3f and 3g gave no acyclic product 15, but gave cyclopentanone derivatives 16-18. The product distribution depends on the mode of addition of TiCl4 (entries 4-7). 

Various carbon nucleophiles, such as allylsilanes, allylstannanes, silyl enol ethers, ketene silyl acetals, organoaluminum compounds, and Grignard reagents were effective as carbon nucleophiles. 

Different nucleophiles such as methanol, allylsilanes, silyl enol ethers, trimethylsilyl-cyanide, and arenes can be used in this process [62]. When the sulfide itself contains an unsaturated or aromatic fragment and the process is carried out in the absence of a nucleophile, an intramolecular anodic sub-stitution/cyclization might occur [61-63]. Methyl esters of 2-benzothiazolyl-2-alkyl or aryl-acetic acid, oxidized in MeOH/Et4 NCIO4 or H2SO4 in the presence of CUCI2, form 2,2-dimethoxy products (Eq. 7) [64]. 

Whilst the method described above appears very elegant, Weix and Hartwig expressed their discontent about the allylations of aliphatic silyl enol ethers and developed an alternative system using enamines as nucleophiles. Once the considerable initial difficulties had been overcome, these authors were able to present a procedure that gave excellent results (Scheme 9.16) [50]. 

Mattay et al. examined the regioselective and stereoselective cyclization of unsaturated silyl enol ethers by photoinduced electron transfer using DCA and DCN as sensitizers. Thereby the regiochemistry (6-endo versus 5-exo) of the cyclization could be controlled because in the absence of a nucleophile, like an alcohol, the cyclization of the siloxy radical cation is dominant, whereas the presence of a nucleophile favors the reaction pathway via the corresponding a-keto radical. The resulting stereoselective cis ring juncture is due to a favored reactive chair like conformer with the substituents pseudoaxial arranged (Scheme 27) [36,37]. 

Similarly, C-glycosylation reaction of I-0-acylsugars with silylated carbon nucleophiles, such as silyl enol ethers, proceeded to give the corresponding C-glycosides in good yields in the presence of a catalytic amount of trityl perchlorate ( ). This reaction was also catalyzed by ploymer-bound trityl perchlorate (Mukaiyama, T. Kobayashi, S. Carbohydrate Research, in press.)... 

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