Acetals as carbonyl-protecting groups

The use of acetals as carbonyl-protecting groups is illustrated by the synthesis of 5-hydroxy-5-phenylpentanal from benzaldehyde and 4-bromobutanal ... 

Hemithioacetals may be transformed in two ways with Raney Ni. The sulfur group may be removed with the oxygen group intact as in eq. 13.78 or desurfiirized to recover the parent carbonyl compounds. In the ethylenehemithio acetal of a ketone, since the oxo group can be recovered by treatment with Raney Ni, this reaction makes it possible to use the hemithio acetal as a protective group for the carbonyl group (eq. 13.79). 

The overall equilibrium constant for formation of the dimethyl acetal of acetaldehyde is 1.58 The comparable value for the addition of water is about Because the position of the equilibrium does not strongly favor product, the synthesis of acetals is carried out in such a way as to drive the reaction to completion. One approach is to use a dehydrating reagent or azeotropic distillation so that the water that is formed is irreversibly removed from the system. Because of the unfavorable equilibrium constant and the relative facility of the hydrolysis, acetals are rapidly converted back to aldehydes and ketones in acidic aqueous solution. The facile hydrolysis makes acetals useful carbonyl protecting groups (see Part B, Section 3.5.3). 

Addition of Alcohols to Form Acetals (Section 16.7B) Formation of acetals is catalyzed by acid. Acetals are stable to water and aqueous base but are hydrolyzed in aqueous acid. Acetals are valuable as carbonyl-protecting groups. The mechanism for conversion of a hemiacetal to an acetal involves protonation of the OH group of the hemiacetal... 

The Lewis acid-catalyzed Fries rearrangement is performed under strong acidic conditions and therefore reqnires protection of sensitive functional groups. Conversely, the PFR can be achieved nnder milder conditions (organic solvents, nentral media, room temperature, etc.) and is therefore free from this type of problems. Moreover, polyacylation of aromatics is usually difficult to achieve. In the PFR, this problem can be solved by using acetals [144—146] or enol esters [147] as carbonyl protecting groups. Addition of anhydrous K CO is convenient to avoid deprotection [148]. 

The methods which are available for the protection of the aromatic carbonyl group are similar to those for the aliphatic and alicyclic analogues (Section 5.8.8, p. 623). It should be noted however, that when a cyclic acetal is used as the protecting group, a Birch reduction (Section 7.5) on the protected compound usually results in hydrogenolysis of the protecting acetal. 

Ethylene glycol, HOCH2CH2OH Reacts with ketones or aldehydes in the presence of an acid catalyst to yield acetals that serve as useful carbonyl protecting groups (Section 19.10). 

This three-step procedure is illustrated in Figure 25.10. In this way, the amide serves as a protecting group for the NH2 group, in much the same way that fcrf-butyldimethylsilyl ethers and acetals are used to protect alcohols and carbonyls, respectively (Sections 20.12 and 21.15). 

The carbonyl protecting group in 22 is known as a dioxolane, a cyclic acetal. These acetals are more stable towards hydrolysis than acyclic ones, and therefore require treatment with pyridinium / -toluene-sulfonate (PPTS) under reflux. In general, acetals can only be cleaved using acidic conditions and are stable under basic conditions. 

Via 0,0-Acetals Acyclic and cyclic acetals are the most important carbonyl protecting groups of aldehydes and ketones, and also serve as efficient chiral auxiliaries for the synthesis of enantiomerically pure compounds. ... 

Since an acetal is produced by the reaction of a carbonyl with a diol, an acetal can serve as a protective group for either functional group. Deprotection is accomplished as usual by treatment with acid and water hydrolysis of the acetal regenerates both the carbonyl and the diol. Both 1,2- and 1,3-Diols can be protected by reaction with acetone and acid. The resulting cyclic acetal (called an acetonide) is widely used in carbohydrate chemistry to selectively mask pairs of hydroxyl groups in sugars. 

To avoid this undesired reaction, the carbonyl group is first converted into an acetal, which serves as a protecting group. The desired reaction is then performed, and finally, the protecting group (the acetal group) is removed with aqueous acid to give the product ... 

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