Acid-Catalyzed Acetal Formation

These are initial rates of acetohydroxamic acid formation from acetic acid, catalyzed by nickel chloride. 

Show all the steps in the acid-catalyzed formation of a cyclic acetal from ethylene glycol and an aldehyde or ketone. 

The THP group can be removed by dilute aqueous acid. The chemistry involved in both the introduction and deprotection stages is the reversible acid-catalyzed formation and hydrolysis of an acetal (see Part A, Section 7.1). 

As expected, some sequences also occur where a domino anionic/pericyclic process is followed by another bond-forming reaction. An example of this is an anionic/per-icyclic/anionic sequence such as the domino iminium ion formation/aza-Cope/ imino aldol (Mannich) process, which has often been used in organic synthesis, especially to construct the pyrrolidine framework. The group of Brummond [450] has recently used this approach to synthesize the core structure 2-885 of the immunosuppressant FR 901483 (2-886) [451] (Scheme 2.197). The process is most likely initiated by the acid-catalyzed formation of the iminium ion 2-882. There follows an aza-Cope rearrangement to produce 2-883, which cyclizes under formation of the aldehyde 2-884. As this compound is rather unstable, it was transformed into the stable acetal 2-885. The proposed intermediate 2-880 is quite unusual as it does not obey Bredf s rule. Recently, this approach was used successfully for a formal total synthesis of FR 901483 2-886 [452]. 

The scope of the acid-catalyzed formation of C-glycosyl compounds has been greatly expanded with the finding that enol ethers and ketene acetals can be used as the carbon source in electrophilic substitution reactions at the anomeric center.126 Treatment of 198 with the trimethylsilyl enol ether derived from cyclohexanone, in the presence of stannic chloride, led to 2-(2,3,5-tri-0-benzoyl-/J-D-ribofuranosyl)cyelohexanone (206), presumably by way of the inter-... 

This protective group is introduced by an acid-catalyzed addition of the alcohol to the vinyl ether moiety in dihydropyran. />-Toluenesulfonic acid or its pyridinium salt is used most frequently as the catalyst,3 although other catalysts are advantageous in special cases. The THP group can be removed by dilute aqueous acid. The chemistry involved in both the introduction and deprotection stages is the reversible acid-catalyzed formation and hydrolysis of an acetal (see Part A, Section 8.1). 

Clemmensen-type reduction.1 Aromatic ketones can be reduced to the corresponding methylene compounds with ammonium formate on transfer hydrogenation in acetic acid catalyzed by 10% Pd/C. The reduction is usually complete in 10-30 minutes at 110°. Halo and nitro substituents can be reduced under these conditions, and a,p-unsaturated carbonyl groups are reduced to saturated carbonyl groups. 

When the 2-aldehyde of imidazole (209) is treated with ethanol some decarbonylation takes place by way of a nucleophilic attack of the alcohol on the carbonyl carbon (Scheme 111). The products isolated are imidazole and ethyl formate. One would normally expect that acetal formation would result under these conditions, but it appears that in the acid-catalyzed formation of acetals from (209) the yield of acetal depends on the amount of catalyst. When the ratio of imidazole is >1, then the diethyl acetal is produced in high yield. When this ratio falls to less than unity there is some decarbonylation, and in the absence of acid only decarbonylation occurs. Electron-withdrawing groups in the heterocyclic nucleus (or quaternization) assist this reaction which does not appear to occur with 4- or 5-aldehyde functions (80AHC(27)241). 

The decarbonylation of imidazole-2-aldehyde in ethanol involves nucleophilic attack by the alcohol on the carbonyl carbon (see Scheme 42) to give the imidazole and ethyl formate." It was found that in the acid-catalyzed formation of acetals of imidazole-2-al-dehydes the yield of acetal depended on the amount of catalyst. When the H imidazole ratio is >1, good yields of the diethylacetal are obtained, but when the ratio is < 1 decarbonylation occurs to some extent. When only ethanol is used (no acid) only decarbonylation takes place. Electron-withdrawing groups on imidazole assist the reaction, as does quaternization, and it does not occur with 4- and S-aldehydes." ... 

Rearrangement of sulfonium ylides constructed on a chiral oxathianone template provides an effective asymmetric entry to optically active 4-pentenoic acids118. The requisite ylides 17 are obtained by intramolecular alkylation of diazoketones 16, which are in turn prepared from the valine derived hydroxy thiol 15. Ylide formation can be accomplished directly by treatment of diazoketones 16 with rhodium(II) acetate or by a two-step sequence involving acid-catalyzed formation of the sulfonium salt and subsequent treatment with base at low temperature, a procedure which affords superior yields and diastereoselectivity. 

For many further syntheses, it is necessary to block the hydroxy functions of tartaric acid. This can be done by acid-catalyzed formation of cyclic acetals or ketals (1,3-dioxolanes) with carbonyl compounds, e.g., 43. Acetone, acetophenone, benzaldehyde, pivalaldchydc, and other simple carbonyls have been used for this purpose28 31,42-43. The protected esters of tartaric acid, used as starting materials for many purposes (Sections 2.3.2. and 2.5.3.), can be prepared in a one-pot procedure. 

Clayton and Eastham found that in 1,2-dichloroethane at 20°C, the rate of boron trifluoride-acetic acid-catalyzed isomerization of 1-butene to cis- and trans-l-huients is proportional to the concentration of both free boron trifluoride and of boron trifluoride-acetic acid complex. The kinetic results are evidence for pre-equilibrium formation of an adduct between the butene and the boron trifluoride-acetic acid complex. 

A reduction in the yield of such principal products as 93 may occur during the hydrolysis step through the acid-catalyzed formation of acetals between the alditol moiety and the glycolaldehyde released, a side-reaction that appears to be more severe with a-glycans. " However, this complication is avoidable by methylating the polyol before partial hydrolysis, because it blocks the hydroxyl groups that, otherwise, would be engaged in acetal formation. 

Propose a detailed mechanism for the specific acid-catalyzed formation of butyl acetate when butoxyacetylene is heated in water, and explain why this compound is more reactive toward hydration in water than is butylacetylene. 

The mechanism for acetal formation involves acid-catalyzed formation of the hemiacetal, then an acid-catalyzed elimination of water, followed by a second addition of the alcohol and loss of a proton. 

Acetals, Imines, and Enamines Common Mechanistic Themes in Their Acid-catalyzed Formation from Aldehydes and Ketones... 

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