Mixed orthoester

Scheme 5.19 Regioselectivity issue in the rearrangement of mixed orthoesters.

Heating of an allylic alcohol with an excess of trialkyl orthoacetate in the presence of trace amounts of a weak acid to give a mixed orthoester. The orthoester loses ethanol to generate the ketene acetal, which undergoes [3,3]-sigmatropic rearrangement to give a Y,5-unsaturated ester. 

The first step in the Johnson orthocster methyl is a transacetali-zation of the orthoacetate leading to mixed orthoester 26. The ke-tene acetal 27 required for rearrangement arises upon acid-catalyzed 28 elimination of methanol. The necessarily six-membered transition... 

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%. 

This reaction was first reported by Johnson et al. in 1970. It is a highly stereoselective synthesis of y,5-unsaturated esters from the reaction between allylic alcohols and an orthoester in the presence of a trace amount of weak acid, such as propionic acid. Because this reaction is the modification or variant of the Claisen Rearrangement, it is often referred to as the Johnson orthoester Claisen rearrangement. Occasionally, this reaction is also known as the Claisen-Johnson orthoester rearrangement, " or Johnson orthoester protocol. This reaction involves the formation of mixed orthoester from allyl alcohol and the added orthoester, which loses an alcoholic component to form a ketene acetal then migrates to unsaturated carbonyl compounds via the Claisen Rearmagement with high syn selectivity. Posner further extended this reaction to use sulfonyl orthoester. Overall, this reaction has been applied to the synthesis of a variety of complicated natural products, such as squalenes. ... 

The Claisen-Johnson rearrangement [7] is closely related to both Saucy vinyl allyl ether rearrangement and Eschenmoser rearrangement. The reaction proceeds via a ketene acetal, which results from the condensation between an ortho-ester and an aUylic alcohol giving rise to a mixed orthoester followed by the elimination of the low-boihng-point alcohol. This ketene intermediate forms after rearrangement of a y,d-unsaturated ester (Scheme 6.1). 

There are several variants of the Claisen rearrangement that increase its versatility and have made it a powerful synthetic tool. The orthoester modification of the Claisen rearrangement allows carboalkoxymethyl groups to be introduced at the y position of allylic alcohols. A mixed orthoester is formed as an intermediate and undergoes sequential elimination and rearrangement. 

This stereoselective version of the Claisen rearrangement leading to tro/is-trisubstituted olefinic bonds has been developed by W. S. Johnson, L. Werthmann, W. R. Bartlett, T. j. Brocksom, T.-t. Li, D. j. Faulkner and M. R. Petersen, J. Amer. Chem. Soc., 92, 741 (1970). The reaction evidently involves formation of a mixed orthoester (i), and loss of ethanol to form the ketene acetal (ii) which rearranges to the olefinic ester (iii). 

The phosphazinium bromides (25), conveniently prepared from hydrazinotri-phenylphosphonium bromide and orthoesters, when treated with base (Scheme 6) give the thermally stable ylides as a mixture of syn- and a/ift-forms.28 These ylides are converted efficiently by various aromatic aldehydes into mixed azines. 

Preparation of mixed acetals, 416 Preparation of nitrates, 415 Preparation of orthoesters, 414 Preparation of pregna-5,6-diene-3,20-dione, 316... 

A mixture of 2-aminoaromatic 1 (10 mmol), orthoester 2a or 2b (10 mmol) and KSF clay (2 g) in a Pyrex tube under nitrogen was mixed and then irradiated in a focused microwave cavity (cavity E013 of MES) for 5 min with a power of 60 W. The mixture was extracted with CH2CI2 (3x20 mL) and the solvent was evaporated in vacuum. The residue was distilled or recrystallized. 

The permanganate oxidation of axial and equatorial vinyl orthoesters 140 and 141 was carried out in a buffered solution (pH =10) mixed with acetonitrile. The reaction mixture was then esterified with acetic anhydride and pyridine. Both vinyl orthoesters gave an identical result >95% of acetoxy ester J46 and <5% of bicyclic lactone 147. 

Cyclic orthoesters derived from gem-diols offer a further route to alkenes. As part of a three-step conversion, they may be ring opened with hydrobromic acid to give O-acyl bromodeoxy compounds that undergo reductive elimination with copper-zinc. In this way, unsaturated nucleosides have been made by way of mixed 2y3,-bromo-2y3,-deoxy-3,/2, carboxyl-ates.174 A more direct route to alkenes from cyclic orthoesters involves heating in acetic anhydride together with zirconium oxide.175... 

The tendency to hydrolyze by a relatively slow and controllable stepwise reaction is characteristic of all the silicon orthoesters. When ethyl silicate, for example, is poured into water it remains immiscible and hydrolyzes at the interface over a period of many days or even months. If both the ester and the water are dissolved in alcohol, however, a much faster reaction in the homogeneous medium becomes possible. If a drop of strong acid then is added to the solution, the hydrolysis is further accelerated to such an extent that the solution becomes warm and silica is precipitated as solid or gel. If less than the equivalent amount of water is used, there is formed a viscous nonvolatile liquid which may be stored for long periods. The addition of further water (as in mixing an ethyl silicate paint) then... 

Mixed substituted orthoesters, e.g. (383 equation 180), can be obtained by addition of alcohols to ketene 0,0-acetals. With the aid of phosphoranes containing a ketene O,(7-acetal structure, various orthoesters, e.g. (384) and (385) (Scheme 70) were prepared. " Cyclic orthoesters (386)-(390) (Scheme 71) are formed in cycloaddition reactions of ketene 0,0-acetals with aldehydes, ketones, 7.848 gj.yj cyanides, oxiranes, a-keto esters, o-diketones or ketones (with irradiation), a,3-unsaturated aldehydes and ketones (under pressure or catalyzed by ZnCh), diazoaceto-phenone, 7 diazoacetone and azodicarboxylate. ... 

Ethoxyacetylene adds, catalyzed by mercury acetate and ZnCh, alii atic or aromatic alcohols to produce mixed substituted orthoesters, e.g. (391)-(393) (Scheme 72). ° Acyl ketenes are formed on thermolysis of l,3-dioxin-4-ones, which can be trapped with ketene acetals to give orthoesters (394 equation 181) 861-863 2,2-Dialkoxydihydrofurans (395 equation 182) are accessible by addition of ketones to cy-clopropenone acetals. Treatment of 2-chloro-2,3-dimethoxy-l,4-dioxane with sodium methoxide affords the 2,2,3-trimethoxy-l,4-dioxane (396 equation 183). ... 

In their short synthesis of ( - )-162, Pearson and Hembre also began with the protected D-erythronolactone derivative 197, which was converted in three steps into a mixture (97 3) of diastereomeric allylic alcohols 203 (Scheme 29) 127). Separation of the epimers, although possible, was not necessary as both alcohols yielded the same product 204 after Johnson orthoester Claisen rearrangement. Subsequent Sharpless asymmetric dihydroxylation with AD-Mix-p gave as major... 

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