Methods of Ketene Acetal Formation

The most frequently employed method of formation of silyl ketene acetals is deprotonation of an allyUc ester by a strong base, most commonly LDA, LHMDS or KHMDS. A variety of other strategies have been developed for generation of the silyl ketene acetal intermediate. 

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After some preliminary discussion of history and nomenclature, the review will briefly cover issues of rearrangement temperature, substituent effects and catalysis. Transition state stracture as determined by isotope effects combined with theoretical studies will then be described. Stereochemical aspects of the reaction will be examined in detail with accompanying examples. The remainder of the chapter will describe the various methods of ketene acetal formation, structural variety in the allyUc ester substrates and apphcations to natural product synthesis. The presentation of the material is somewhat arbitrary, and indeed most examples could well have been placed under more than one sub-heading. 

The addition of alcohols to ketene acetals allows the synthesis of mixed ortho esters [96, 120a-c, 121a, b, 124, 125a, b]. a-Haloaldehydes may be converted to ortho esters by the following process (a) acetal formation, (b) de-hydrohalogenation, and (c) reaction with alcohols via addition reaction (33). In general, the method above, using ketene acetals, is not practical since ketene acetals are not readily available and are difficult to prepare. However, the method is useful because it allows the synthesis of mixed ortho esters and other ortho esters more difficult to synthesize [122-127]. Recently a simple one-step synthesis of ketene acetals and ortho esters has been reported (see p. 56). 

The enolates of other carbonyl compounds can be used in mixed aldol reactions. Extensive use has been made of the enolates of esters, thiol esters, amides, and imides, including several that serve as chiral auxiliaries. The methods for formation of these enolates are similar to those for ketones. Lithium, boron, titanium, and tin derivatives have all been widely used. The silyl ethers of ester enolates, which are called silyl ketene acetals, show reactivity that is analogous to silyl enol ethers and are covalent equivalents of ester enolates. The silyl thioketene acetal derivatives of thiol esters are also useful. The reactions of these enolate equivalents are discussed in Section 2.1.4. 

The reaction of alkynes with nitric acid or mixed acid is generally not synthetically useful. An exception is the reaction of acetylene with mixed acid or fuming nitric acid which leads to the formation of tetranitromethane. A modification to this reaction uses a mixture of anhydrous nitric acid and mercuric nitrate to form trinitromethane (nitroform) from acetylene. Nitroform is produced industrially via this method in a continuous process in 74 % yield. " The reaction of ethylene with 95-100 % nitric acid is also reported to yield nitroform (and 2-nitroethanol). The nitration of ketene with fuming nitric acid is reported to yield tetranitromethane. Tetranitromethane is conveniently synthesized in the laboratory by leaving a mixture of fuming nitric acid and acetic anhydride to stand at room temperature for several days. ... 

To avoid the formation of ketenes by alkoxide elimination, ester enolates are often prepared at low temperatures. If unreactive alkyl halides are used, the addition of BU4NI to the reaction mixture can be beneficial [134]. Examples of the radical-mediated a-alkylation of support-bound a-haloesters are given in Table 5.4. Further methods for C-alkylating esters on insoluble supports include the Ireland-Claisen rearrangement of O-allyl ketene acetals (Entry 6, Table 13.16). Malonic esters and similar strongly C,H-acidic compounds have been C-alkylated with Merrifield resin [237,238]. 

Schollkopf and co-workers have synthesized a number of cyclopropanone acetals by the addition of various sulfur- and oxygen-containing carbenes to ketene diethylacetals (Table 3).26>27> Similarly, cyclopropanone dithioacetals may be prepared by the addition of the Ws-thiomethyl and Ws-thiobenzylcarbenes 12a, b to olefins.29) However, cyclopropanone acetal formation by this method requires double bonds with considerable electron enrichment and the yields are generally low. With unsubstituted olefins such as cyclohexene, the carbenes 12 a, b tend to form dimeric and trimeric products such as 13 and 14, instead of the double bond addition products. 

Fu has demonstrated that acetate anion attack on the silicon center of the silyl ketene acetal, as well as formation of an acyl pyridinium salt, contribute towards the promotion of these reactions [62]. Additionally, silyl ketene imines have also been shown to participate in analogous asymmetric C-acylation reactions to yield chiral quaternary nitriles, and this method was employed as a key step in the synthesis of verapamil [65]. 

This method was further improved when it was found that readily available allyl esters of the general formula 493 could also be involved in Claisen rearrangements via intermediate formation of ketene derivatives such as lithium enolates 494 or trimethylsilyl ketene acetals 495 (the Ireland-Claisen variant" ). Moreover, rearrangement of these substrates into unsaturated acids 496 occurred easily at room temperature or below. This was in striking contrast to all previous versions of the Claisen rearrangement, which required heating at elevated temperatures (140-160 °C). The Ireland (silyl ketene acetal) variant of... 

The transition metal-catalyzed allylation of carbon nucleophiles was a widely used method until Grieco and Pearson discovered LPDE-mediated allylic substitutions in 1992. Grieco investigated substitution reactions of cyclic allyl alcohols with silyl ketene acetals such as Si-1 by use of LPDE solution [95]. The concentration of LPDE seems to be important. For example, the use of 2.0 M LPDE resulted in formation of silyl ether 88 with 86 and 87 in the ratio 2 6.4 1. In contrast, 3.0 m LPDE afforded an excellent yield (90 %) of 86 and 87 (5.8 1), and the less hindered side of the allylic unit is alkylated regioselectively. It is of interest to note that this chemistry is also applicable to cyclopropyl carbinol 89 (Sch. 44). 

The pioneering discovery by Mukaiyama in 1974 of the Lewis acid mediated aldol addition reaction of enol silanes and aldehydes paved the way for subsequent explosive development of this innovative method for C-C bond formation. One of the central features of the Mukaiyama aldol process is that the typical enol silane is un-reactive at ambient temperatures with typical aldehydes. This reactivity profile allows exquisite control of the reaction stereoselectivity by various Lewis acids additionally, it has led to the advances in catalytic, enantioselective aldol methodology. Recent observations involving novel enol silanes, such as enoxy silacyclobutanes and O-si-lyl M(9-ketene acetals have expanded the scope of this process and provided additional insight into the mechanistic manifolds available to this versatile reaction. 

Acetic anhydride (rf ° = l.082u bp1013 = 138.6 0 is used chiefly to manufacture cellulose acetate. Since the turn of the century, several methods have been developed to produce it. Three leading methods exist today in the industrial stage, differing mainly in the type of raw material employed, acetic arid, acetone or acetaldehyde, and the first two are based on the intermediate formation of ketene. 

The convenient synthesis of a-hydroxyl-co-methoxycarbonyl asymmetric telechelic PIBs has been achieved by the combination of two recently discovered techniques, haloboration-initiation and end capping with 1,1-diphenylethylene followed by end quenching with silyl ketene acetals, 1 -methoxy-1 -trimethylsiloxy-2-methyl-propene (MTSMP), 1-methoxy-1-trimethylsiloxy-propene (MTSP), and 1-methoxy-l-trimethylsiloxy-ethene (MTSE). Nearly quantitative chain end functionalization has been proved by NMR, quantitative NMR, and FT-IR spectroscopy. The methoxycarhonyl end arising by quenching with MTSMP could not be hydrolyzed under either basic or acidic conditions. These methods also failed to yield the acid when the corresponding diisobutylene derivative was used. The sterically less hindered esters, however, readily underwent hydrolysis resulting in the formation of a-hydroxyl-co-carboxyl asymmetric telechelic PIBs. 

The treatment of an ester (or lactone) with a base and a silyl halide or trillate gives rise to a particular type of sUyl enol ether normally referred to as a silyl ketene acetal. The extent of O- versus C-silylation depends on the structure of the ester and the reaction conditions. The less-bulky methyl or ethyl (or 5-tert-butyl) esters are normally good substrates for O-silylation using LDA as the base. Acyclic esters can give rise to two geometrical isomers of the silyl ketene acetal. Good control of the ratio of these isomers is often possible by careful choice of the conditions. The f-isomer is favoured with LDA in THF, whereas the Z-isomer is formed exclusively by using THF/HMPA (1.24). Methods to effect stereoselective silyl enol ether formation from acyclic ketones are less well documented. ... 

It was found that the vinylogons Mukaiyama aldol reaction proceeds smoothly with dioxinone-derived silyl ketene acetal and a catalytic amount of Bi(0Tf)3 4H20. This method offers several advantages including mild reaction conditions, highly catalytic (1%) process, and no formation of by-products (Equation 11) [32g]. 

Alternate Name ethyl 2-(methyldiphenylsilyl)propionate. Physical Data clear to pale yellow liquid 1.5407. Preparative Method whereas the direct silylation of the lithium enolate of an ester normally results in the formation of a mixture of the a-silyl ester and the corresponding silyl ketene acetal, the reaction of lithium ester enolates with methyldiphenylchlorosi-lane gives exclusively the a-methyldiphenylsilyl ester. This direct C-sUylation is the best general route to a-sUyl esters. Purification can be purified by silica gel chromatography, eluting with ethyl acetate/hexane (2 98 v/v), or by short path distUlation. 

Next, the application of ketene silyl acetals was tried in the above aqueous reactions of silyl enolates with aldehydes. Ketene silyl acetals are useful ester enolate equivalents that can be isolated [27, 28], and the aldol-type reaction of ketene silyl acetals with aldehydes is among the most important and mildest methods of carbon-carbon bond formation [29]. Disappointingly, no aldol adduct was obtained when the ketene silyl acetal derived from methyl 2-methylpropionate (3) was employed as a representative ketene silyl acetal (structure 3 is shown later in Table 8.10). In aqueous media, hydrolysis of the ketene silyl acetal preceded the desired aldol reaction. 

One method for the synthesis of hydroxyalkyl-substituted P-lactams is by the Staudinger reaction, the most frequently used method for the synthesis of P-lactams.86 This method for the preparation of 4-acetoxy- and 4-formyl-substituted P-lactams involves the use of diazoketones prepared from amino acids. These diazoketones are precursors for ketenes, in a diastereoselective, photochemically induced reaction to produce exclusively tram-substituted P-lactams. The use of cinnamaldimines 96, considered as vinylogous benzaldimines, resulted in the formation of styryl-substituted P-lactams. Ozonolysis, followed by reductive workup with dimethyl sulfide, led to the formation of the aldehyde 97, whereas addition of trimethyl orthoformate permitted the production of the dimethyl acetal 98 (Scheme 11.26). 

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