Alcohols, reaction with dihydropyran

Acetalation with Enol Ethers Under Kinetically Controlled Conditions. The first mention of the use of an enol ether to protect the hydroxyl group of an alcohol was developed by Paul [46], who introduced the reaction with dihydropyran to give tetrahydro-pyranyl ethers, which is still used 60 years later. In spite of some noticeable developments, such as the preparation of 2 3 -0-aIkylidene derivatives of nucleosides [33] the synthesis of 4,6-O-ethylidene-a-D-glucopyranoside with use of methylvinylether [47] the intra-... 

One method that has found widespread use for the protection of an alcohol is reaction with dihydropyran to form a tetrahydropyranyl ether. Once the desired reaction has been accomplished, the protecting group can be removed by treatment with aqueous acid or acid and ethanol. The formation of a tetrahydropyranyl ether and its cleavage are illustrated in the following equation ... 

We protect one hydroxyl terminus of the commercially available 1,8-octane diol 1 by reaction with dihydropyran to give the monoalcohol, 8-tetrahydropyranyloxyoctanol 2. The protected alcohol 2 is oxidized to the aldehyde with pyridinium chlorochromate to give 8-tetrahydropyranyl-oxyoctanal 3. 1-Heptyne 4 is coupled with propargyl bromide 5 in a copper catalyzed reaction to produce the diacetylenic 1,4-decadiyne 6. 

Tetrahydropyranyl ethers. Protection of alcohols by reaction with dihydropyran is promoted by LiBp4 in MeCN. 

For those substrates more susceptible to nucleophilic attack (e.g., polyhalo alkenes and alkenes of the type C=C—Z), it is better to carry out the reaction in basic solution, where the attacking species is RO . The reactions with C=C—Z are of the Michael type, and OR goes to the side away from the Z. Since triple bonds are more susceptible to nucleophilic attack than double bonds, it might be expected that bases would catalyze addition to triple bonds particularly well. This is the case, and enol ethers and acetals can be produced by this reaction. Because enol ethers are more susceptible than triple bonds to electrophilic attack, the addition of alcohols to enol ethers can also be catalyzed by acids. " One utilization of this reaction involves the compound dihydropyran... 

Aside from alcohols, other oxygen nucleophiles have also participated in hydroalkoxylation reactions with alkynes. The most common of these are 1,3-dicarbonyl compounds, whose enol oxygens are readily available to add to alkynes. Cyclization reactions of this type have been carried out under Pd(0) catalysis with various aryl or vinyl iodides or triflates, often in the presence of CO, affording the corresponding furan derivatives (Equation (95)).337-340 A similar approach employing cyclic 1,3-diketones has also been reported to prepare THFs and dihydropyrans under Pd, Pt, or W catalysis.341 Simple l-alkyn-5-ones have also been isomerized to furans under the influence of Hg(OTf)2.342... 

In an attempt to further elucidate the mechanism of this process, these workers monitored the reaction between propiophenone enolsilane and fumaroylimide by in situ infrared (IR) spectroscopy, Scheme 25 (240). In the absence of alcoholic additives, the accumulation of an intermediate is observed prior to appearance of product. When i-PrOH is introduced, immediate decomposition of the intermediate occurs with concomitant formation of product. Evans suggests that the intermediate observed in this reaction is dihydropyran (374). Indeed, this reaction may be viewed as a hetero-Diels-Alder cycloaddition followed by alcohol induced decomposition to the desired Michael adduct. That 374 may be acting as a competent inhibitor was suggested by an observed rate reduction when this reaction was conducted in the presence of IV-methyloxazolidinone. 

The reaction of dihydropyran with water in the presence of a trace of mineral acid gives an equilibrium mixture of 2-hydroxytetrahydropyran and 5-hydroxypentanal. However, the products from the addition of alcohols to dihydropyrans are stable under basic conditions and can be isolated after destruction of the acid catalyst (47JA2246). A wide range of substituted tetrahydropyrans has been made in this way and the diastereoisomers separated by gas chromatography (68JOC3754). 

Tetrahydropyranylation The reaction of an alcohol (even tertiary) with dihydropyran is catalyzed efficiently by [(CH3)3Si0]2S02. The resulting ether is isolated in 90-100% yield by addition of pyridine and concentration of the solvent. The sulfate also catalyzes alcoholysis of the derivative at 25° (10-90 minutes). It is also useful in some transesterifications. 

Treatment of keto alcohols 877 with (triphenylphosphonylidene)ethanone forms the intermediate ylide 878, which cyclizes via an intramolecular Wittig reaction to afford 5,6-dihydropyran-2-ones 879 (Scheme 243, Table 38). A slight improvement in yield can be observed by using keto alcohols masked as their 1,3-acetals <1998T2161>. 

Tetrahydropyranylation of tert-alcohols.2 The reaction of ten-alcohols with dihydropyran in CH2C12 at 0° catalyzed by this reagent provides tetrahydropyranyl ethers in 78-96% yield. 

Treatment of the monochloro diethylene glycol 9 with dihydropyran yields the protected alcohol 10. Reaction of 2,2, 2"-triaminotriethylamine (tren) 11 with toluenesulfonyl chloride gives the tritoluenesulfonyl derivative 12. The pyranyl ether 10 may be condensed with the tris(sodium) salt of 12 leading to 13. Removal of the tetrahydropyranyl group is achieved in high yield under... 

In many instances the reaction of an alcohol with dihydropyran (or ethyl vinyl ether or 2-methoxypropene) does not go to completion despite the addition of a large excess of the enol ether as much as 20% of the starting material will be present at equilibrium. The equilibrium, once reached, can be shifted toward product by adding excess finely powdered anhydrous potassium carbonate and stirring the reaction mixture at room temperature. As the acid concentration gradually diminishes, the reaction goes to completion. 

Acid Catalyst. Camphorsulfonic acid (CS A) has been used extensively in synthetic organic chemistry as an acid catalyst. It has particularly been used in protecting group chemistry. For example, hydroxyl groups can be protected as tetrahydropyranyl (THP) ethers using dihydropyran and a catalytic amount of CSA (eq 1). Both 1,2- and 1,3-diols can be selectively protected by reaction with orthoesters in the presence of camphorsulfonic acid to form the corresponding cyclic orthoester (eq 2) This method of protection is particularly useful in that reduction of the orthoester with Diisobutylaluminum Hydride forms the monoacetal, which allows for preferential protection of a secondary alcohol in the presence of a primary alcohol. Ketones have also been protected using catalytic CSA (eq 3). ... 

Treatment of an alcohol with dihydropyran yields an acetal called a tetrahyd pyranyl ether, a reaction that can be used as a method of protecting alcohols S tion 17.9). Show the mechanism of the reaction. 

The already described alcohol (23), prepared from Wieland-Miescher ketone (1) was made to react with dihydropyran to obtain (170) which on subjection to hydroboration-oxidation yielded the alcohol (171). Its mefliyl derivative (172) was converted on oxidation to the ketone (173). The formyl derivative of (173) was subjected to annelation reaction following the procedure of Howell and Taylor [74]. The resulting adduct... 

The metal-catalyzed transvinylation of vinylacetates or vinyl ethers with alcohols is initiated by an oxy-metallation reaction. With PdCl2(PhCN)2 as the catalyst and at low temperature, transvinylation takes place exclusively (Scheme 5a). At higher temperatures, acetal formation is observed after an induction period, in addition to precipitation of palladium (Scheme 5b). It is probable that the acetaliza-tion step is catalyzed exclusively by traces of Brpnsted acid (HCl), rather than via proto-de-metallation of a Pd(II) alkyl species [21, 22]. Consequently, a recent report on the protection of primary alcohols as tetrahydropyranyl- (THP-)ethers by addition to 2,3-dihydropyrane in the presence of PdCl2(MeCN)2 as catalyst... 

A major disadvantage of the tetrahydropyranyl ether as a protecting group is that an asymmetric center is produced at C-2 of the tetrahydropyran ring on reaction with the alcohol. This asymmetry presents no difficulties if the alcohol is achiral, since a racemic mixture results. If the alcohol has an asymmetric center anywhere in the molecule, however, condensation with dihydropyran can afford a mixture of diastereomeric tetrahydropyranyl ethers, which may complicate purification and characterization. One way of surmounting this problem is to use methyl 2-propenyl ether, rather than dihydropyran. No asymmetric center is introduced, and the acetal offers the further advantage of being hydrolyzed under milder conditions than those required for tetrahydropyranyl ethers. Ethyl vinyl ether is also useful as a hydroxyl-... 

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