Diethyl acetal, hydrolysis

Our first goal was to develop a scaleable route to the single enantiomer propargylic alcohol. The racemic alcohol was readily produced on a multi-kilogram scale by alkylation of the phenol with inexpensive bromoacetaldehyde diethyl acetal, hydrolysis to the aldehyde, and addition of the acetylenic Grignard reagent. With this material at hand we developed an efficient bioresolution process that esterified the alcohol in the presence of Chirazyme L9 (Scheme 30.7).26 At this point... 

The capsule 397 is reported in [73] to be a reasonably strong Bronsted acid with high affinity toward tertiary amines, their salts, and other guests shown in Scheme 3.74. This allowed performing highly substrate-selective Witting reaction and substrate-selective diethyl acetal hydrolysis within its cavity. 

Isoxazole was first synthesized by Claisen in 1903 from propargylaldehyde diethyl acetal and hydroxylamine (03CB3664). It has also been obtained by addition of fulminic acid to acetylene in methanol-dilute sulfuric acid solution, by acidic hydrolysis of 5-acetoxyisoxazo-line, by reaction of /S-chloroacrolein or/3-alkoxyacrolein with hydroxylamine hydrochloride... 

Arrange the carbonyl compounds in each group in order of decreasing rate of hydrolysis of their respective diethyl acetals or ketals. Explain your reasoning. 

Problem 17.8 asked you to write details of the mechanism describing formation of benzaldehyde diethyl acetal from benzaldehyde and ethanol. Write a stepwise mechanism for the acid hydrolysis of this acetal. 

Treatment of 2- 5//-dibenz[i>,/]azepin-5-yl acetaldehyde (16), prepared in 68% yield by /V-alkylation of 5/7-dibenz[A,/]azepine with bromoacetaldehyde diethyl acetal followed by acid hydrolysis, with methyl hydroxylamine yields the isolable nitrone 17, which in refluxing toluene undergoes intramolecular 1,3-dipolar cycloaddition at the CIO —Cl 1 alkene bond to give 2,3,3a, 12b-tetrahydro-2-methyl-3,8-methano-8//-dibenz[i>,/]isoxazolo[4,5-r/]azepine (18).235... 

The carbonyl group can be deprotected by acid-catalyzed hydrolysis by the general mechanism for acetal hydrolysis (see Part A, Section 7.1). A number of Lewis acids have also been used to remove acetal protective groups. Hydrolysis is promoted by LiBF4 in acetonitrile.249 Bismuth triflate promotes hydrolysis of dimethoxy, diethoxy, and dioxolane acetals.250 The dimethyl and diethyl acetals are cleaved by 0.1-1.0 mol % of catalyst in aqueous THF at room temperature, whereas dioxolanes require reflux. Bismuth nitrate also catalyzes acetal hydrolysis.251... 

A completely different approach to lithium homoenolate synthons uses a carbon-oxygen bond cleavage. Lithiation of acrolein diethyl acetal 180 with lithium and a catalytic amount of DTBB (2.5%) in the presence of different carbonyl compounds in THF at 0°C gave, after final hydrolysis, the corresponding y-products 181 in different diastereomeric ratios (Z/ 3/1 to 20/1) (Scheme 63) . 

Triethyl orthoformate is often used in reactions with enolates and carbanions to form diethyl acetals that on treatment with dilute acid give the corresponding formyl derivatives. However, when indole is heated at 160 C with triethyl orthoformate the locus of reaction is at N-1 rather than at C-3, and 1-(diethoxymethyl)indole is formed (Scheme 7.6). The A -substituent is easily removed by acidic hydrolysis to reform indole. 

Oxazine ring in 212 was formed by spontaneous lactonization in the hydrolysis of 3-aza-5-hydroxy ester 265 (Equation 22) <2005SL693>. The same method was used in the synthesis of 219 <1993LA477>. Oxazine 267 was formed in the hydrolysis of a 3-aza-5-hydroxyaldehyde diethyl acetal 266 <1981JHC825> (Equation 23). 

A tetrahydropyrido[3,4-/)]pyrazine nucleus was constructed from 2,3-dimethylpyrazine 687 by chlorination with A-chlorosuccinimide (NCS) to give 2,3-bis(chloromethyl)pyrazine 688, followed by cyclization with diethyl acet-amidomalonate to pyridopyrazine 689. Hydrolysis and decarboxylation of 689 in hydrochloric acid, then esterification by action of thionyl chloride in methanol gave methyl 5,6,7,8-tetrahydropyrido[3,4-. ]pyrazine-7-carboxylate hydrochloride 690 (Scheme 32) <2003BMC433>. 

Stereospecific syntheses of the 1,1-diethyl acetals 45 and 47 were performed by Makin and coworkers.29 trans-5,5-Diethoxy-2-penten-l-ol (44) was cis-hydroxylated with potassium permanganate, to yield the diethyl acetal (45) of 2-deoxy-DL-threo-pentose. Epoxidation of 44 and alkaline hydrolysis of the epoxide 46 gave the diethyl acetal (47) of 2-deoxy-DL-en/thro-pentose. 

Aliphatic nitro compounds are versatile building blocks and intermediates in organic synthesis,14 15 cf. the overview given in the Organic Syntheses preparation of nitroacetaldehyde diethyl acetal.16 For example, Henry and Michael additions, respectively, lead to 1,2- and 1,4-difunctionalized derivatives.14 18 1,3-Difunctional compounds, such as amino alcohols or aldols are accessible from primary nitroalkanes by dehydration/1,3-dipolar nitrile oxide cycloaddition with olefins (Mukaiyama reaction),19 followed by ring cleavage of intermediate isoxazolines by reduction or reduction/hydrolysis.20 21... 

To a soln of cyclic template c[-Amhn-Lys-Gly-Lys-Pro-Gly-Lys-Gly-Lys-] -4 HC1 (see Section 13.1.1.1.2) (10 mg, 9 pmol) in DMF (2mL) (at 0°C), DIPEA (7 pL, 39.5 pmol) and (Et0)2CHC02Su (19 mg, 39.5 pmol) were added slowly and the mixture stirred at rt for 3 h. The solvent was removed and the residue redissolved in EtOAc (10 mL). The organic phase was washed with 10% citric acid (3 x), H20 (1 x), and dried (Na2S04). EtOAc was removed and the residue dried in high vacuo yield 7.7mg (56%). The residue was treated with H20/1.2M HC1 (1 1) in order to hydrolyze the tetrakis(diethyl acetal). After 1 h stirring at rt, the solvent was removed in high vacuo. This procedure was repeated three times as the completion of hydrolysis was monitored by analytical HPLC. The residue was purified by HPLC and lyophilized yield 3 mg (66%). 

Alternatively, when 21 was treated with benzaldehyde diethyl acetal-hydrochloric acid, ethyl 3,5 4,6-di-0-benzylidene-L-gulonate (76) was formed in >90% yield. Diacetal 76 was efficiently oxidized to 77 (>90% yield) with dimethyl sulfoxide-trifluoroacetic anhydride, or by way of the nitrate of 76 and triethylamine. Hydrolysis of 77 then afforded ethyl L-xy(o-2-hexulosonate in 86% yield.383... 

Compound 164 was readily synthesized in two steps starting from 2-fluoro-5-nitrobenzaldehyde diethyl acetal 162 by nucleophilic substitution. Acidic hydrolysis of the diethylacetal function of 163 restored the aldehyde group, followed by spontaneous cyclization yielding oxazepine 164 (Scheme 25) <2004TA2555>. 

One can also acetalize carbonyl compounds completely without using the alcohol in excess. This is the case when one prepares dimethyl or diethyl acetals from carbonyl compounds with the help of the ortho formic acid esters trimethyl ortho formate HC(OCH3)3 or triethyl ortho formate HC(OC2H5)3, respectively. In order to understand these reactions, one must first clearly understand the mechanism for the hydrolysis of an orthoester to a normal ester (Figure 9.13). ft corresponds nearly step by step to the mechanism of hydrolysis of 0,0-acetals, which was detailed in Figure 9.12. The fact that the individual steps are analogous becomes very clear (see Figure 9.13) when one takes successive looks at... 

Fio. 7. Logarithms of second-order rate constants (in units of min"i) for the hydrolysis of a series of para-substituted benzaldehyde diethyl acetals in aqueous solution (lower line) and in the presence of sodium dodecyl sulfate (upper line) plotted against the Hammett substituent constants (Dimlap et cU., 1969). 

A synthesis of the fragrant terpenoid Sinensal [Scheme 2.51] is noteworthy for two reasons.1()6 First, the method used to prepare the diethyl acetal is a rare example of an acetal synthesis which takes place under basic conditions secondly, the hydrolysis of the acetal product was only achieved after considerable effort by reaction with aqueous oxalic add adsorbed on silica gel.109... 

Z)-condenses with aldehydes in a (Z)-stereoselective Wittig reaction to afford diethyl acetals of (Z)-a,jS-unsaturated aldehydes in 57-86% yield. Hydrolysis of the acetals with p-TsOH as catalyst in acetone-water or with moist silica gel (2 days at 23°) affords the corresponding (Z)-unsaturated aldehydes in 47-98% yield. The product usually contains 4-14% of the (E)-isomer. These results contrast with those of Wittig reactions of formylmethylenetriphenylphosphorane and l,3-dioxolan-2-ylmethylenetriphenyl-phosphorane (5, 269), which afford (E)-unsaturated aldehydes. 

Chromium enolate chemistry exhibits diverse thermochemical facets. For example, contrast the energetics of enolate addition reactions to benzaldehyde and to benzaldehyde JT-bonded to Cr(CO)3 and of the enolate addition reactions to acetophenone and to acetophenone 71-bonded to Cr(CO)3. Thermochemical analysis is still unreported, although the reactions are synthetically usefuP . It is clear that the organic ligands are electronically coupled to the metallic center—PhCHO Cr(CO)3 is red, PhCH(OEt)2 Cr(CO)3 is yellow but benzaldehyde and its diethyl acetal are both colorless. It is well established that acetophenone, and presumably other acylated benzenes such as benzaldehyde, binds Cr(CO)3 rather more weakly than does toluene, and presumably other alkylated benzenes such as the aforementioned benzaldehyde acetal. The enthalpy of hydrolysis of the metallated acetal remains unknown other than it is therefore smaller than that of the unmetallated species . ... 

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