Orthoesters, ketals

Ethylene ketals. The exchange reaction between dialkyl acetals or dialkyl ketals and 1,2-glycols as a route to cyclic acetals and ketals was first described by Delepine. This method in combination with Claisen s orthoester ketalization procedure (1, 1206) constitutes a convenient route to ethylene ketals (1, 376). The mixed orthoester 1 is probably the actual reagent involved in the Delepine method. It is convenient to prepare and use for ketalization of carbonyl compounds under mild conditions. A striking example is the ready conversion of the acid-sensitive 2 into 3, a reaction that proceeds by other known methods in yields of only 30%. 

Polyketals are a new class of degradable polymers that have ketal linkages in their backbone, which consists of a carbon bonded to two alkoxy groups. While chemically similar to orthoesters, ketals have the unique property of degrading into neutral degradation products. This eliminates the issues of acidic degradation products and has been shown to be beneficial in treating a variety of inflammatory diseases. 

The most commonly used protected derivatives of aldehydes and ketones are 1,3-dioxolanes and 1,3-oxathiolanes. They are obtained from the carbonyl compounds and 1,2-ethanediol or 2-mercaptoethanol, respectively, in aprotic solvents and in the presence of catalysts, e.g. BF, (L.F. Fieser, 1954 G.E. Wilson, Jr., 1968), and water scavengers, e.g. orthoesters (P. Doyle. 1965). Acid-catalyzed exchange dioxolanation with dioxolanes of low boiling ketones, e.g. acetone, which are distilled during the reaction, can also be applied (H. J. Dauben, Jr., 1954). Selective monoketalization of diketones is often used with good success (C. Mercier, 1973). Even from diketones with two keto groups of very similar reactivity monoketals may be obtained by repeated acid-catalyzed equilibration (W.S. Johnson, 1962 A.G. Hortmann, 1969). Most aldehydes are easily converted into acetals. The ketalization of ketones is more difficult for sterical reasons and often requires long reaction times at elevated temperatures. a, -Unsaturated ketones react more slowly than saturated ketones. 2-Mercaptoethanol is more reactive than 1,2-ethanediol (J. Romo, 1951 C. Djerassi, 1952 G.E. Wilson, Jr., 1968). 

Deep fluorinalion of alkanes, ethers, acid fmlides, esters, alkyl chlorides, most ketones, ketals, orthoesters, and combinations of these functional groups produces principally the perfluonnated analogues (Table 2) Chlorine substituents (or chloro groups) usually survive fluorination... 

Reduction of Acetals, Ketals, Hemiacetals, Hemiketals, and Orthoesters... 

Stereoselective aldol-type condensation.1 Enol silyl ethers do not undergo aldol condensation with aldehydes or ketones in the presence of this triflate,. but the reaction occurs at —78° (4-12 hours) with the corresponding acetals or ketals (and certain orthoesters). Moreover the erythro-aldol is formed with high stereoselectivity. 

S. S. Bhattacharjee and P. A. J. Gorin, Hydrogenolysis of carbohydrate acetals, ketals and cyclic orthoesters with lithium aluminium hydride-aluminium trichloride, Con. J. Chem 47 1195 (1969). 

The reaction of orthoesters with Grignard reagents provides a well known route to acetals and ketals U->-2). Eliel and Nader (1) have investigated the stereochemistry of this reaction and have concluded that it is governed by powerful stereoelectronic effects. 

Alkoxy or 2,2-dialkoxy nitriles.10 Ketals or orthoesters are converted into 2-alkoxy or 2,2-dialkoxy nitriles, respectively, by reaction with cyanotrimethylsilane in the presence of SnCl2 or BF3-0(C2H5)2 as catalyst. A typical reaction is the preparation of dimethoxyacetonitrile (1), which is a useful reagent for conversion of alkyl halides to the homologous methyl carboxylate (equation I). 

In order to circumvent such a drawback, there has been a recent focus on the design of cleavable lipids whose hydrolysis is catalyzed by the drop in pH.10 This approach exploits acid-labile chemical groups such as acetals, ketals, orthoesters, and vinyl ethers. Such functional groups... 

General Acid Catalysis of Acetal, Ketal. and Orthoester Hydrolysis. Fife, T. H. Acc. Chem. Res. 1972, 5, 264. 

Acid catalyzed hydrolyses of acetals, ketals, and orthoesters... 

The hydrolysis reactions of acetals, ketals, and orthoesters are catalyzed by acids but not by bases. It has been found that these three groups of substrates are hydrolyzed via a common general mechanism — involving similar types of intermediates — though the rate-determining step may vary from case to case. In the hydrolyses of ethyl orthoacetate, orthopropionate, and orthocarbonate, general acid catalysis was unambiguously established for the first time by Bronsted and Wynne-Jones [158]. 

Rate coefficients and Arrhenius parameters of the acid catalyzed hydrolyses of acetals, ketals, and orthoesters in water at 20 °C... 

Second-order rate coefficients, kH (= rate/[S] [H30+]), for the hydrolyses of some typical acetals, ketals, and orthoesters in purely aqueous solutions are collected in Table 12. In a compilation of data from one single source [162], ftH values can be found for the reactions of a large number of diethyl acetals and ketals in 50 % dioxane—water at 25 °C. In more recent studies, kH values have been determined for the hydrolyses of substituted benzaldehyde diethylacetals [163] and benzophenone diethyl-ketal [164] in the same solvent (Table 13). The hydrolyses of para-substituted methyl orthobenzoates have been studied in 70 % methanol-water [169]. A large amount of other work is concerned with various special examples. 

First-order rate coefficients of hydrolysis of ketals and orthoesters in equimolar mixtures of CD3OD and DjO with 0.006 M acetate buffer, half-neutralized, at 25 °C [187]... 

Estimated pK values for some acetals, ketals and orthoesters and single-step rate coefficients for hydrolysis in water at 25 °C... 

Acetals, ketals, and orthoesters are polyethers, represented by the following structural formulas ... 

Scheme 39) The 2-phenylsulfonyl cyclopropanone ketals could be converted to orthoesters (101) on prolonged treatment with alkoxides. 

In addition to toe ketals and the acetals, cyclic orthoesters are sometimes used for the protection of 1,2-diols. They are more readily cleaved by acids than the acetonides. In nucleoside chemistry formic acid, acetic acid and benzoic acid orthoesters were applied to temporarily mask the carbohydrate part. ° Also the metooxyacetic acid orthoester (55) was useful because it allowed the selective liberation of toe 3 -... 

Hollis, T. K., Robinson, N. p., Whelan, J., Bosnich, B. Homogeneous catalysis. Use of the TiCp2(CF3S03)2] catalyst for the Sakurai reaction of allylic silanes with orthoesters, acetals, ketals and carbonyl compounds. Tetrahedron Lett. 1993, 34,4309-4312. 

The complex [Cp 2Ti(F[20)2](CF3S03)2 is an efficient catalyst for the Diels-Alder reaction even when water is present, while Cp2Ti(CF3S03)2 is an efficient catalyst for the Diels-Alder and Mukaiyama reactions1560 as well as for a variety of reactions between allylic silanes and orthoesters, acetals, ketals, aldehydes, and ketones for the Sakurai reaction.1561... 

Another very useful method for the preparation of acetals or ketals is based upon the use of orthoesters.10 The reaction is usually carried out by heating the carbonyl compound with ethyl orthoformate in ethanol solution containing a small amount of ammonium chloride or dry hy-... 

Compounds with more than one leaving group are just a subset of this class. Ketals, R2C(0R)2, and orthoesters, RC(OR)3, are common examples. 

Melamine (2,4,6-triamino-l,3,5-triazine) is used with formaldehyde to produce resins for use in counter tops, dishes, and such. A third route reacts carbon dioxide with orthoesters or ketals using an iodide catalyst.35 The byproduct ketone can be reconverted to the ketal (2.11) and used in the next run, so that there is no waste. The selectivity was 86% at 94% conversion using a cesium iodide catalyst. 

Systems involving ketal and orthoester cleavages may be too expensive for anything other than specialized applications. 

In addition to aldehydes and ketones, acetals, ketals, orthoesters," a-halo ethers, a-halo sulfides, amino acetals and their equivalents also react with enol silyl ethers in the presence of Lewis acid to af-... 

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