Benzylidene acetal

An improved method for the preparation of methyl 4,6-0-benzylidene a- and /3-D-glucopyranoside that can be accomplished within a day utilizes a preformed benzaldehyde-zinc chloride complex. 

The crystal structures of the thermodynamically less stable (/ )-diastereoisomers of methyl 4,6-O-benzylidene-2,3-di-O-methyl-0(-D-gluco- and -jS-D-galacto-pyrano-sides have been reported. In each the 2-phenyl-l,3-dioxane ring adopts the expected (Eliel, Pure Appl. Chem., 1971, 25, 509) axial phenyl chair.The 

Conventional methods have been used to prepare the three series of ketals 

Liptak, F. Pekar, J. Janossy, I. Jodil, P, Fiigedi, J. Harangi, P. Nan4si, and J. Szejtli, Acta Chem. Acad. Set Hung., 1979, 99, 201. 

A review of the chemistry of formamide acetals with inter alia some carbohydrate and nucleoside examples has appeared. 

A reinvestigation of the main product from reaction of D-ribono-lactone with benzaldehyde dimethyl acetal has shown that it is the 2,3-0-benzylidene derivative of the 1,4-lactone and not the 2,4- -benzylidene analogue of the 1,5-lactone as previously suggested. 

4 6-diol with e, l-dichlorotoluene in the presence of potassium butoxide and shown to have chair configurations in each case. 

2-0-benzylidene- -L-rhamnoside (7) has been synthesized by treatment of 2,3 4-tri-0-benzoyl-o, -L-rhamnopyranosyl bromide with sodium 

Application of vicinal C- H J values to derivatives of 3 4-0-benzylidene-galactose, 2,3-0-benzylidene-mannose, and 2,3-0-benzyl-idene-gulose, each as separate R and S epimers at the benzylidene carbon, has provided data on the conformations adopted. Where data were also available from jC-ray diffraction, the conformations were found to be the same in solution as in the solid state. 

The acetal diastereomers were separated as their acetates by column chromatography. It was noted that 90% trifluoroacetic acid completely hydrolyzed the benzylidene derivatives in 2h at room temperature, whereas the ethylidene compounds were unaffected under these conditions the latter required boiling with aqueous acetic acid for 6h. The two anomers of methyl 4. 6- -benzylldene- 

D-galacto- and -gluco-pyranosides have been prepared in 96 - 99% 

Trans-acetalisations are often performed in DMF at elevated temperatures under reduced pressure or a stream of nitrogen. These conditions result in removal of the methanol that is formed in the reaction and, as a. result, the benzylidenation is driven to completion. It has been reported that the use of chloroform as a solvent gives higher yields and, in this case, pyridinium p-toluene sulfonate (PPTS) may be used as a catalyst. 

Benzylidene acetals can be removed by mild aqueous acid hydrolysis (80% AcOH or TFA/DCM/H2O) or by catalytic hydrogenolysis over Pd(OH)2 or Pd-C.30 

Mechanism of regioselective reductive cleavage of benzylidene acetals 

For a five-membered dioxolane ring, the regioselectivity depends on the stereochemistry of the benzylidene acetalic carbon atom. For example, treatment of the methyl endo 2,3-0-benzylidene protected rhamnoside with LiAlILi-AlClj gave a 2-0-benzyl derivative, but the same reaction with the 2-exo isomer yielded mainly the 3-0-benzyl derivative.32 

Benzylidene acetals can be oxidatively cleaved by jV-bromosuccinimide (NBS) to give 6-bromo-4-benzoyl-hexopyranosides (see Chapter 3). This reaction has also been performed on 1,2-0-benzylidene derivatives and it appears that the cleavage reactions result in the formation of a derivative that has an axial benzoyl ester.33 

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Cinnamic acid is usually prepared by Perkin s reaction, benzaldehyde being heated with sodium acetate in the presence of acetic anhydride. It is probable that the benzaldehyde and the acetic anhydride combine under the catalytic action of the sodium acetate, and the product then readily loses water to give mono-benzylidene acetic anhydride (. ). The latter, when subsequently... 

LiBF4, CH3CN, 70°, 3-8 h, 81-90% yield. This system of reagents also cleaves benzylidene acetals. Conventional reagents failed to cleave these glycosides. It is interesting to note that the /3-anomers are cleaved more rapidly than the a-anomers and that the furanoside derivatives are not cleaved. 

A benzylidene acetal is a commonly used protective group for 1,2- and 1,3-diols. In the case of a 1,2,3-triol the 1,3-acetal is the preferred product. It has the advantage that it can be removed under neutral conditions by hydrogenolysis or by acid hydrolysis. Benzyl groups and isolated olefins have been hydrogenated in the presence of 1,3-benzylidene acetals. Benzylidene acetals of 1,2-diols are more susceptible to hydrogenolysis than are those of 1,3-diols. In fact, the former can be removed in the presence of the latter. A polymer-bound benzylidene acetal has also been prepared." ... 

Pd-C, hydrazine, MeOH. In this case a 1,2-benzylidene acetal was cleaved in the presence of a 1,3-benzylidene acetal. 

Benzylidene acetals have the useful property that one of the two C—O bonds can be selectively cleaved. The direction of cleavage is dependent on steric and electronic factors as well as on the nature of the cleavage reagent. 

The acetal can also be cleaved with DDQ (CH2C12, H2O, 66% yield) to afford the monobenzoate. Treatment of a 3,4-dimethoxybenzyl ether containing a free hydroxyl with DDQ (benzene, 3 A molecular sieves, rt) affords the 3,4-dimethoxy-benzylidene acetal. ... 

I2, MeOH, reflux, 2 h, 79% HCIO4, H2O, 25°, 16 h, 87% yield. These conditions also cleave acetonides and benzylidene acetals. ... 

Dimethyldioxirane, acetone, 48 h, rt, 85-93% yield. p-Bromo-, p-cyano- and 2-naphthylmethyl ethers, and benzylidene acetals can also be deprotected. 

Reductive cleavage of the acrolein acetal proceeds similarly to that of the benzylidene acetals. ... 

In this type of cleavage reaction, it appears that the axial benzoate is the preferred product. If water is excluded from the reaction, a bromo benzoate is obtained.The highly oxidizing medium of 2,2 -bipyridinium chlorochromate and MCPBA in CH2CI2 at rt for 36 h effects a similar conversion of benzylidene acetals to hydroxy benzoates in 25-72% yield. ... 

Me2BBr, TEA, BH3-THF, —78° warm to —20° over 1 h, 70-97% yield. These conditions cleave the benzylidene acetal, to leave the least hindered alcohol as a free hydroxyl. If diborane is omitted from the reaction mixture and the reaction is quenched with PhSH and TEA, the benzylidene group is cleaved to give an (9,5 -acetal [ROCH(SPh)Ph]. Acetonides are cleaved similarly." ... 

BH3 SMe2, CH2CI2, 0°, 1 h, then BF3, 5 min. Simple benzylidene acetals are cleaved efficiently without hydroboration of alkenes that may be present, and acetonides are converted to the hydroxy isopropyl ethers. 

Acetonide Derivative 11. Benzylidene Acetal 13. p-Methoxybenzylidene Acetal 18. Methoxymethylene Acetal 20. Dimethoxymethylenedioxy Derivative... 

The Preparation of Bromodeoxy Sugars from O-Benzylidene Acetals... 

Subsequent to the announcement (47) of this reaction, a similar transformation of 4,6-O-benzylidene acetals was reported (35) in which a free radical initiator was used. Under these conditions a blocked derivative such as 93 (R = Bz) was transformed in 76% yield into the corresponding 94. Selective formation of the 6-bromo derivative was observed as in the initial studies (47). 

The synthesis of the right-wing sector, compound 4, commences with the prochiral diol 26 (see Scheme 4). The latter substance is known and can be conveniently prepared in two steps from diethyl malonate via C-allylation, followed by reduction of the two ethoxy-carbonyl functions. Exposure of 26 to benzaldehyde and a catalytic amount of camphorsulfonic acid (CSA) under dehydrating conditions accomplishes the simultaneous protection of both hydroxyl groups in the form of a benzylidene acetal (see intermediate 32, Scheme 4). Interestingly, when benzylidene acetal 32 is treated with lithium aluminum hydride and aluminum trichloride (1 4) in ether at 25 °C, a Lewis acid induced reduction takes place to give... 

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