Orthoesters, nucleophilic attack

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 discovery of conditions under which glycosyl 1,2-orthoesters will ring open by nucleophilic attack at C-1 has led to the development of a l,2-glycoside synthesis devoid of many of the shortcomings of the... 

Employing the lactone 279, the trimethylsilyl cation generates a positive charge at the anomeric carbon position of 280. The corresponding triflate anion recombines with one of the silyl ethers in 281 and yields the alk oxide 282 and a molecule of catalyst. After nucleophilic attack, 283 is formed, and by a subsequent intramolecular reaction, the orthoester 284 is obtained simultaneously releasing a molecule of hexamethyldisil-oxane. 

Enol ether 13 is prepared from butanal 12 by acetalization with alcohol PMBOH 35. The resulting acetal 40 is subjected to elimination with phosphinic acid 36. Acetalization proceeds via nucleophilic attack of the alcohol on the protonated aldehyde 37, dehydratization of the hemiacetal 38 and further nucleophilic attack on the carbenium ion 39. Since all steps are reversible, the created water has to be removed to achieve quantitative turnover. This is carried out by the use of water binding agents or solvents (dry Na2S04, CaCl2, orthoesters) or azeotropic distillation. 

FIG. 6.—Nucleophilic attack on the carbonyl group of a tranr-oriented 2-acetate can occur either via formation of a cyclic orthoester, which by undergoing a second attack affords a product having the same configuration as the starting material (reactions 1 and 2), or by nucleophilic attack on the anomeric carbon to afford a product having the inverted configuration (reaction S). 

On the basis of this mechanism it can safely be predicted that neutral orthoesters will not suffer alkaline hydrolysis, since they do not contain the necessary carbonyl group. Indeed, the stability of the orthoesters in basic solutions is one of the characteristic properties of these substances. However, it is conceivable that under drastic conditions such as high temperature, fairly high hydroxyl ion concentration, or a long period of time, a nucleophilic attack on one of the R s by hydroxyl ion will result in a typical three-center displacement reaction ... 

An efficient method for the synthesis of 2-substituted benzoxazin-4-ones was performed by the condensation of anthranilic acid (436) with various orthoesters by classical heating for 1 2h to give 75 91% yields. But under MWI in an open vessel, a rapid formation of benzoxazin-4-ones 439 in high yields (76-94%) took place within 1-5 min (Scheme 86). The reaction may proceed through the imidic ester intermediate 437, which upon nucleophilic attack by the carboxyl oxygen produced the cycKzed intermediate 438 that then eliminated a molecule of alcohol to give 439 (97JCR(S)286). 

The double bond in chlorotrifluoroethylene is polarized by back-donation of electrons of fluorine in such a way that the negative charge is on the carbon linked to chlorine and fluorine. Consequently, the difluorome-thylene end of the double bond is more electrophilic and is attacked by the ethoxide anion. Subsequent ejection of fluoride anion gives an unsaturated intermediate, l-chloro-l,2-difluoro-2-ethoxyethylene, compound V. This compound reacts with another ethoxide anion in a similar way and yields l-chloro-2,2-diethoxy-1-fluoroethylene. Nucleophilic addition of a third molecule of ethanol gives the final product, the orthoester of chlorofluoroacetic acid, compound W [75]. 

In the NMR experiments carried out by Wenthe and Cordes [187] with methyl orthobenzoate and methyl orthocarbonate in CD3OD—D20 solutions, the rate coefficients for the disappearance of orthoester and those for the formation of CH3OD and of carboxylic ester have been found identical within experimental error (Table 15). This indicates that there is no exchange of methoxy groups prior to hydrolysis. The same result has been obtained from product analysis studies of the carboxylic esters formed. Consequently, the rate-determining step must be carbonium ion formation or a previous step. The findings do not support an A2 mechanism, for the following reason. As the nucleophilic reactivities of water and methanol are similar, the A2 reaction with attack of water... 

---