Acetals and Orthoesters

It is for this reason that orthoesters and acetals are (comparatively) stable in the absence of an acid. Alternatively, one can have an uncatalyzed mechanism involving preliminary tautomerization to a zwitterion, but the thermodynamic cost of this imposes a considerable barrier to reaction. 

This variation in the relative rates of C— bond cleavage of analogous orthoesters and hemiorthoesters (and of acetals and hemiacetals) is of course a reflection of the different effect of substituents on the rates of these two classes of reaction. As discussed above, substituents capable of stabilizing carbocations have a greater effect on the rates of C— bond cleavage of orthoesters (and acetals) than of hemiorthoesters (and hemiacetals). 

The available data on the effects of micellar systems on orthoester and acetal hydrolyses are summarized in Table 6. 

Substitution reactions of orthoesters and acetals,including anomeric bond formation in carbohydrates (eq 13), have been catalyzed by Znl2. 

Alkyl and aryl thiohydrazide derivatives react with orthoesters and trihalomethyls to afford 1,3,4-thiadiazoles. The reactions proceed via a thiosemicarbazone intermediate which cyclizes to eliminate either alcohol or hydrogen chloride. Treatment of the iV-thiohydrazide pyrazole 143 with triethyl orthoformate in acetic acid at reflux gave the 5-acetamido-l,3,4-thiadiazol-2-ylpyrazole 144 (Equation 51), and in the absence of acetic acid the 5-amino-l,3,4-thiadiazol-2-ylpyrazole 145 in 76% yield <2000JCM544>. 

The reactivity of the methoxyethy1idene derivatives with nucleophiles other than water has been examined. It has been already found (13) that they may be readily opened by halogenating reagents ( N -b romo succ i n i-mide for instance) to give a or 3-ha 1 oacetates (respectively from five- or six-membered-ring orthoesters), and this reaction may be compare with the familiar Hanessian procedure for conversion of henzylidene acetals iiito bro-mo-deoXybenzoates (68). ... 

Orthoesters and related species as precursors 49 Amide acetals as precursors 55 Ketene acetals as precursors 57 Oxocarbocations as precursors 59... 

Summarizing, it may be concluded that the ease of hydrogenolysis is (1) cyclic orthoester > isopropylidene acetal, cyclohexylidene acetal > benzylidene acetal > ethylidene acetal > methylene acetal, and (2) 5,6-O-linked and 3,5-O-linked > 1,2-0-linked acetals. 

The reactivity of functional groups presenting some similarities to cyclic acetals, such as cyclic orthoesters, and stannylidene and amide acetals, falls outside the scope of the present article, but attention has to be drawn to the fact that they may be considered to be special types of acetals having distinct properties, and a growing interest is focused... 

Ozone oxidation of the trans-decal in di of benzylidene 133 has been carried out (71). Under kinetically controlled conditions, it produces the axial benzoate 134 in preference to the more stable equatorial benzoate 135. Similar results were obtained with an analogous case derived from cholestane-2e,3e-diol. These results are essentially identical to those obtained by King and Allbutt (60, 62) in their study on the hydrolysis of dioxolane orthoesters and dioxolenium salts (cf. p. 82), and can therefore be explained in the same manner. These results further confirm that the oxidation of acetals by ozone produces an intermediate which behaves like the hemiorthoester tetrahedral intermediate which is formed in the hydrolysis of orthoesters. 

In previous studies, i,e. concurrent carbonyl-oxygen exchange in the hydrolysis of esters, acid hydrolysis of orthoesters and oxidation of acetals by ozone, the configuration of the tetrahedral intermediate was determined by the application of the principle of stereoelectronic control. There could be some ambiguity in these experiments as the theory of stereoelectronic control is used to predict both the stereochemistry of the tetrahedral intermediate as well as its breakdown. The oxidation cleavage of vinyl orthoesters can therefore be considered a more powerful experimental technique in that respect because the configuration of the hemi-orthoester... 

Mannosides of phosphatidylinositol are important serologically active components of Mycobacterium tuberculosis. For the synthesis of the 2-O-mannosyl derivative (421), Stepanov et al. [291] treated the chiral prop-l-enyl ether (414) [and the corresponding racemic prop-l-enyl ether and racemic benzoate (415)] with the orthoesters (416) or (417) to give the disaccharide (418) [from chiral (414) and acetate (416)] in moderate yield. The disaccharide obtained from racemic (414) contained a high proportion of (418) as a result of asymmetric synthesis. Acidic hydrolysis of (418) gave in low yield (30%) the alcohol (419). 

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... 

This feature of PLNM immediately explains why least motion effects are not observed in cleavage of acetals, but are observed in cleavage of orthoesters and other substrates at the acyl level of oxidation the transition state for acetal cleavage is late, whereas that for orthoester hydrolysis is more central (Sinnott, 1984 Cordes and Bull, 1974). 

The difference between the hydrolysis of an orthoester and the hydrolysis of an acetal is that profanation and C-O bond cleavage occur together in the former. In the hydrolysis of an acetal, the protonated form of the acetal is produced as an intermediate in the reaction. While we will not go into details here, the hydrolysis of the orthoester constitutes a case of what is known as general acid catalysis, while that of an acetal is specific acid catalysis. 

Ketones or aldehydes can undergo acetal exchange with orthoesters. The mechanism starts off as if the orthoester is going to hydrolyse but the alcohol released adds to the ketone and acetal formation begins. The water produced is taken out of the equilibrium by hydrolysis of the orthoester. 

Finally, the [3,3]-sigma tropic rearrangement can be carried out by heat as part of the same step or as a separate step depending on the compounds. This is a very flexible reaction sequence and can be used for aldehydes (as shown above), ketones, esters, or amides. In each case acetal-like compounds are used—acetals themselves for aldehydes and ketones orthoesters and orthoamides for the other two (though the orthoamides are often called amide acetals ). 

The product is an orthoester and is achiral too. This chemistry should remind you of the formation of acetals as described in Chapter 14. 

Displacements from acetals, aminals, orthoesters and related compounds... 

The review will be limited to atom- and bond-bridged bicyclic monomers. The important work of Bailey on the polymerization of spiro bicyclo orthoesters and spiro bicyclic orthocarbonates has been adequately described elsewhere 0 1 60 3. The outstanding and systematic body of work by Schu-erch2 3> and others on the ring opening polymerization of bicyclic acetals derived from carbohydrate precursors will also not be covered here. 

Moreover, the kinetic study of bicyclic acetals, bicyclic orthoesters, and other bicydic monomers has not yet been done. 

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

Reaction of 1,2,4-triazol-4-ylamidines (473) with diethyl carbonate in the presence of sodium ethoxyethoxide led (70JPR669) to intermediate 474 which, upon cyclization, gave the l,2,4-triazolo[3,4-/]l,2,4-triazino-8-ones (475). Kurasawa and his group (85JHC1715) reported that the reaction of 3-(a-hydroxyimino-4-amino-5-methyl-4//-l,2,4-triazol-3-ylmethyl)2-oxo-l,2-dihydroquinoxaline (476) with orthoesters and iron powder in acetic acid gave l,2,4-triazolo[3,4-/]l,2,4-triazines 480 and its 7,8-dihydro isomers 479. 

Scheme 51 presents an entirely different mode of catalyzed [4 + 2] cycloadditions. Thus irimediylsilyl triflate or triflic acid apparently transform vinyl orthoesters and acrolein acetals to powerful transient allyl cation dienophiles (214) and (219), respectively. The ionic Diels-Alder reactions (213) (216)... 

The success of the Claisen-Cope rearrangement need not be limited to the production of aldehydes via enol ethers. Allylic alcohol (58) is successively transposed into a mixture of allylic isomers (59 Scheme 4), and is subjected to an orthoester Claisen rearrangement at 150 "C to provide ester (61). The moderate temperature of the Claisen step permits the isolation of an intermediate (c/. Scheme 3) prior to the final Cope rearrangement (195 C) to. y-unsaturated esters (60). The esters (60) are a 55 45 mixture of ( )- and (Z)-double bond isomers owing to the near equal steric bulk of the methyl and acetic acid residues in the transition state for the Cope rearrangement. ... 

This chapter focuses the attention on the reactions of nonstabilized carbanionic compounds such as alkyl, vinyl, aryl, alkynyl metals, etc., and the chemistry of the stabilized system, i.e. allylic, propargylic or oxaallylic carbanions is presented in Volume 2 of this series. Electrophiles with C=X bonite which are discussed include aldehydes, ketones, epoxides, aziridines, acetals, orthoesters and imines, all of which turn into highly reactive electrophiles in the presence of Lewis acids. 

Recent reports from Takazawa ° provide the background for the reaction of enamines with aldehydes and acetals as well as with orthoesters in the presence of Lewis acids (equations 22 and 23 ). For these reactions it was found that the enamine from morpholine provided the highest yield as did the use of boron trifloride etherate as a Lewis acid (in stoichiometric amounts). 

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