Hydrolysis orthoester

The driving force for a hydrolysis orthoester —> normal ester + alcohol is greater than the driving force for a hydrolysis 0,0-acetal —> carbonyl compound + alcohol. This is because the newly formed C=0 double bond receives approximately 14 kcal/mol resonance stabilization in the ester (Table 6.1)—that is, starting from an orthoester—but not in the carbonyl compound. 

Orthoester is the triether groups linked a carbon atom. Contrary to the ester that subject to acid-base catalyzed hydrolysis, orthoester is hydrolyzed faster under... 

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,... 

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. 

Orthoesters are stable to base, although nucleophilic attack may occur under drastic conditions. Orthoformates are split by acids to free diols, whereas controlled acid hydrolysis leads to monoformates. " Higher orthoesters are usually split by mineral or organic acids to give monoesters. 

The latter method is improved by use of the 2,2-dimethyl derivative.273 The rearrangement is faster and the stability of the orthoester to hydrolysis is better. Isotopic labeling showed that the rearrangement occurs by ionization at the tertiary position. 

Reactions are also known which are catalysed not only by H30 , but by other acids in the system as well e.g. in the hydrolysis of orthoesters such as MeC(OEt)3 in the presence of an acid, HA, where it is found that ... 

Li S, Dory P. Hydrolysis of cyclic orthoesters experimental observations and theoretical rationalization. Tetrahedron 1996 52 14841. 

This is known as general acid catalysis, general because the catalysis is by proton donors in general, and not by H3O alone. General acid catalysis often only becomes important at hi er pHs, e.g. pH 7 when [H3O ] 10 , while [HA] may be 1-2, molar general acid catalysis will still occur at lower pHs, but may then be masked by the greater contribution by H3O . The above orthoester hydrolysis is believed to proceed (only HA is shown here but HjO will do the same thing). 

The formation of orthoester may be explained tiy the preferential addition of tlie ketene acetal to the most reactive alcohol function (primary hydroxyl g,roup) giving thc f non - i so 1 a t ed) acyclic orthoester whicti is attacked by the neighbouring OH-4 with subsequent elimination of methanol. The partial hydrolysis of the diacetate is assumed to proceed through protonation of the methoxyl group (7), via the dioxocarbenium ion 8 and the orthoacid 9. collapse of 9 by either [lath b or path a accor-ding to the mechanism generally proposed (see, for instance, ref. 29 and refs. cited therein) affords the compounds 5 or respectively. 

In order to obtain information concerning the hydrolysis of a S,6-0-orthoester such as 31, it was thus necessary to prevent the participation of OH-3. Starting (Figure 9) from compound J4 (obtained from 1,2 B,6-di-0-isopropylidene-a-D-glucofuranose throLigh acetylation and selective hydrolysis of the S,6-0-isopropylidene protec-... 

The problem of selective hydrolysis of the acetonlde was studied next. The most practical method consisted of a treatment with acetic acid In aqueous tetrahydrofuran at 65°C which gave a mixture of dlol 103 (major) and trlol 104 (minor) In 77 and 15% yields respectively. Trlol 104 could be converted to 103 by a sequence Involving formation of a 2 3 -orthoester, conversion to the corresponding dl-BOM derivative, then mild hydrolysis. 

Chloro orthoesters 218 or 219 were lithiated using a catalytic amount of DTBB (5%) as the electron carrier and in the presence of the corresponding electrophile, so after controlled hydrolysis with phosphate buffer and final deprotection with methanol and a catalytic amount of PTSA, functionalized esters 220 were obtained (Scheme 75) . 

The synthesis of 2-alkoxymethylpteridines (antiallergic compounds) has also been achieved by the Taylor synthesis <1996EJM273> (Scheme 31). The 3-aminopyrazine-2-carboxamide 163 reacted with orthoesters to give 2-alkoxymethylpteridine derivative 164. Alternatively, 164 was synthesized by condensing 3-aminopyrazine-2-car-bonitrile 165 with the acetoxyamidine 166 followed by the base hydrolysis (Table 9). 

Alternatively, methoxymethyl-substituted dihydrooxazoles are obtained from imino esters or orthoesters by condensation with the methoxyaminopropanol 10, itself obtained from hydrolysis of corresponding 4,5-dihydro-4-methoxymethyl-5-phenyloxazoles without racem-ization (see Section 1.1.1.4.3.)2 20. This method is preferred in the case of 2-benzyl-4,5-dihydro-4-methoxymethyl-5-phcnyloxazole2 and 4,5-dihydro-2-(m-hydroxyalkyl)-4-methoxymethyl-5-phenyloxazoles20. 

Kinetics of the Hydrolysis of Orthoesters A General Acid-Catalyzed Reaction 57... 

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