For orthoesters

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). 

Deprotections. ethers and Boc-prote with a hydroxylic soh Pinacol rearrang effective inducer for orthoesters. 

The loss of an alkoxy group, after protonation, is the starting point of hydrolysis. An orthoester can provide for this loss to take place with the assistance from one or two stereoelectronic effects, the latter being obviously favored over the former. The conformer 92d does not allow any stereoelectronic effects. This conformer may therefore be treated as the slow reacting or even as the neutral conformer. This prediction has been verified experimentally by studying the hydrolysis of 93, a rigid 92d conformer, which was found to be stable to the normally employed mild acidic conditions for orthoester hydrolysis [2-5]. Therefore, the conformer 92d is also eliminated from further discussion. 

It must be added that the hyperconjugative nature of the O—C—O anomeric interactions has recently been supported by X-ray data for orthoesters containing C(OC)3 (214) and C(OC)4 (155) groups [see, however, below for compounds containing a QSC) group]. 

It is a useful reagent for orthoester homologation via dialkoxy-carbenium ions and for oxazole formation by reaction of keto-carbenes (via diazo esters/Cu(OTf)2) with nitriles (eq 10). With unsaturated nitriles, the nitrile group is selectively attacked. Kinetic and ESR evidence shows that Cu Cu reduction is the key step. ... 

The structure of an orthoester reminds us of that of acetals and ketals, compounds that are easily cleaved by dilute acids. The mechanism of hydrolysis for orthoester 4 should be similar to that of the acetals and ketals, starting with the protonation of one of the oxygen atoms and followed by the formation of a carbo-cation greatly stabilized by resonance. The overall process is a SnI mechanism that ends up by addition of water. Two different species 8 and 10 can be formed... 

Alkyl halides and sulfonates are the most frequently used alkylating acceptor synthons. The carbonyl group is used as the classical a -synthon. O-Silylated hemithioacetals (T.H. Chan, 1976) and fomic acid orthoesters are examples for less common a -synthons. In most synthetic reactions carbon atoms with a partial positive charge (= positively polarized carbon) are involved. More reactive, "free carbocations as occurring in Friedel-Crafts type alkylations and acylations are of comparably limited synthetic value, because they tend to react non-selectively. 

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). 

As a class of compounds, nitriles have broad commercial utility that includes their use as solvents, feedstocks, pharmaceuticals, catalysts, and pesticides. The versatile reactivity of organonitnles arises both from the reactivity of the C=N bond, and from the abiHty of the cyano substituent to activate adjacent bonds, especially C—H bonds. Nitriles can be used to prepare amines, amides, amidines, carboxyHc acids and esters, aldehydes, ketones, large-ring cycHc ketones, imines, heterocycles, orthoesters, and other compounds. Some of the more common transformations involve hydrolysis or alcoholysis to produce amides, acids and esters, and hydrogenation to produce amines, which are intermediates for the production of polyurethanes and polyamides. An extensive review on hydrogenation of nitriles has been recendy pubHshed (10). 

Poly(orthoesters) represent the first class of bioerodible polymers designed specifically for dmg deUvery appHcations (52). In vivo degradation of the polyorthoester shown, known as the Al amer degradation, yields 1,4-cydohexanedimethanol and 4-hydroxybutyric acid as hydrolysis products (53). 

Orthoesters. The value of cycHc orthoesters as intermediates for selective acylation of carbohydrates has been demonstrated (73). Treatment of sucrose with trimethylorthoacetate and DMF in the presence of toluene-/)-sulfonic acid followed by acid hydrolysis gave the 6-0-acetylsucrose as the major and the 4-0-acetylsucrose [63648-80-6] as the minor component. The latter compound underwent acetyl migration from C-4 to C-6 when treated with an organic base, such as / fZ-butylamine, in DMF to give sucrose 6-acetate in >90% yield (74). When the kinetic reagent 2,2-dimethoxyethene was used,... 

In order to become useful dmg delivery devices, biodegradable polymers must be formable into desired shapes of appropriate size, have adequate dimensional stability and appropriate strength-loss characteristics, be completely biodegradable, and be sterilizahle (70). The polymers most often studied for biodegradable dmg delivery applications are carboxylic acid derivatives such as polyamides poly(a-hydroxy acids) such as poly(lactic acid) [26100-51-6] and poly(glycolic acid) [26124-68-5], cross-linked polyesters poly(orthoesters) poly anhydrides and poly(alkyl 2-cyanoacrylates). The relative stabiUty of hydrolytically labile linkages ia these polymers (70) is as follows ... 

Selective removal of the hydroxyl protecting groups included in this review is generally difficult to achieve and of little practical importance. Selective hydrolysis of cyclic orthoesters to give monoesters merits attention for its practical interest. 

Three possible mechanisms for the Serini reaction were originally suggested. These proceed via (a) a A -enol acetate, (b) a A -epoxide, or (c) a cyclic orthoester ... 

Ketene di(2-melhoxyethyl) acetal has been obtained by the present method with the use of diethylene glycol dimethyl ether as solvent.3 Other methods for the preparation of ketene acetals include the dehydrohalogenation of a halo acetal with potassium t-butoxide 4 and the reaction of an a-bromo orthoester with metallic sodium.5... 

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. 

Both the exchange and elimination are catalyzed by the addition of a small amount of a weak acid, such as propanoic acid. These reactions are usually conducted at the reflux temperature of the orthoester, which is about 110°C for the trimethyl ester and 140° C for the triethyl ester. Microwave heating has been used and is reported to greatly accelerate orthoester-Claisen rearrangements.232... 

Scheme 6.15 gives some representative examples of the orthoester Claisen rearrangement. Entry 1 is an example of the standard conditions for the orthoester Claisen rearrangement using triethyl orthoacetate as the reactant. The allylic alcohol is heated in an excess of the orthoester (5.75 equivalents) with 5 mol % of propanoic acid. Ethanol is distilled from the reaction mixture. The E-double bond arises from the chair TS. 

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