Ethers, tetrahydropyranyl alcohol protection

Tetrahydropyranyl (TUP) and tetrahydrofuranyl ethers are important protecting groups for alcohols and phenols in organic synthesis, but they can also be converted to other useful functional groups [8, 118]. For example, allylation of a TUP ether should yield a highly functionalized molecule (Scheme 15). 

Dicarboxypyridinium chlorochromate (2,6-DCPCC)392 possesses an acidic character that allows the in situ deprotection and oxidation of alcohols, protected as tetrahydropyranyl and trimethylsilyl ethers. 2,2 -Bipyridinium chlorochromate (BPCC)393 contains a ligand that complexes efficiently with the reduced chromium species, generated during the oxidation of alcohols, allowing for a substantial simplification of the work-ups. For this reason, it enjoys a popularity among chlorochromates surpassed by only PCC. 

Problem 3.7. Dihydropyran (DHP) reacts with alcohols under acid catalysis to give tetrahydropyranyl (THP) ethers. The alcohols can be released again by treating the THP ether with MeOH and catalytic acid. Thus, the THP group acts as a protecting group for alcohols. Draw mechanisms for the formation and cleavage of the THP ether. 

Tetrahydrofuranyl (THF) ethers are reported to be useful alternatives to tetrahydropyranyl (THP) ethers for the protection of alcohols (and thiols). THF ethers are easily formed, and are more sensitive to acidic hydrolysis than are THP ethers. We are warned that hydroboration-oxidation or peracid oxidation of simple unsaturated compounds containing a hydroxy-group protected as its THP ether has led to violent detonations. The danger comes from the ready formation of peroxides from THP ethers, and presumably also from THF ethers these peroxides, though very sensitive, are not easily removed by ordinary chemical methods. 

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-... 

In the presence of polymer-supported (PS) SO3H resins, Abulyl ethers and tetrahydropyranyl ethers of alcohols and phenols are formed. Elimination by-products that are formed during the protection of secondary and tertiary alcohols (eq 2) can be avoided using PS-SO3H. Additionally, selective tetrahydropyran protection of primary and secondary symmetrical diols can be undertaken to yield monoprotected products. In the presence of water, Dowex 50W and Amberlite IR-120 give higher yields of monoethers than Amberlyst 15. 

Tetrahydropyranylation of Alcohols. Protection of alcohol functionality as the THP ether is an often-utilized tool in organic synthesis. It must be noted that the reaction of a chiral alcohol with dihydropyran introduces an additional asymmetric center and hence a diastereomeric mixture is obtained (eq 1). This can lead to difficulties with purification, assignment of spectral features, etc., but does not prevent successful implementation. ... 

Six protective groups for alcohols, which may be removed successively and selectively, have been listed by E.J. Corey (1972B). A hypothetical hexahydroxy compound with hydroxy groups 1 to 6 protected as (1) acetate, (2) 2,2,2-trichloroethyl carbonate, (3) benzyl ether, (4) dimethyl-t-butylsilyl ether, (5) 2-tetrahydropyranyl ether, and (6) methyl ether may be unmasked in that order by the reagents (1) KjCO, or NH, in CHjOH, (2) Zn in CHjOH or AcOH, (3) over Pd, (4) F", (5) wet acetic acid, and (6) BBrj. The groups may also be exposed to the same reagents in the order A 5, 2, 1, 3, 6. The (4-methoxyphenyl)methyl group (=MPM = p-methoxybenzyl, PMB) can be oxidized to a benzaldehyde derivative and thereby be removed at room temperature under neutral conditions (Y- Oikawa, 1982 R. Johansson, 1984 T. Fukuyama, 1985). 

The 21-hydroxyl group in the corticosteroid series can be protected as the base stable triphenylmethyl ether and tetrahydropyranyl ether. " " Mixed acetals from 21-alcohols are extremely acid sensitive compounds. ... 

In 1975, van der Baan and Bickelhaupt reported the synthesis of imide 37 from pyridone 34 as an approach to the hetisine alkaloids, using an intramolecular alkylation as the key step (Scheme 1.3) [23]. Beginning with pyridone 34, alkylation with sodium hydride/allyl bromide followed by a thermal [3,3] Claisen rearrangement gave alkene 35. Next, formation of the bromohydrin with A -bi omosuccinimide and subsequent protection of the resulting alcohol as the tetrahydropyranyl (THP) ether produced bromide 36, which was then cyclized in an intramolecular fashion to give tricylic 37. 

Several authors reported the use of ionic liquids containing protonic acid in catalysis (118-120). For example, strong Bronsted acidity in ionic liquids has been reported to successfully catalyze tetrahydropyranylation of alcohols (120). Tetra-hydropyranylation is one of the most widely used processes for the protection of alcohols and phenols in multi-step syntheses. Although the control experiments with the ionic liquids showed negligible activity in the absence of the added acids, high yields of product were obtained with the ionic liquid catalysts TPPTS or TPP.HBr-[BMIM]PF6. By rapid extraction of the product from the acidic ionic liquid phase by diethyl ether, the reaction medium was successfully reused for 22 cycles without an appreciable activity loss. A gradual loss of the catalyst and a reduced volume of the ionic liquid were noted, however, as a consequence of transfer to the extraction solvent. 

In 2007, another departure from carbonyl-type activation was marked by Kotke and Schreiner in the organocatalytic tetrahydropyran and 2-methoxypropene protection of alcohols, phenols, and other ROH substrates [118, 145], These derivatives offered a further synthetically useful acid-free contribution to protective group chemistry [146]. The 9-catalyzed tetrahydropyranylation with 3,4-dihydro-2H-pyran (DHP) as reactant and solvent was described to be applicable to a broad spectrum of hydroxy functionalities and furnished the corresponding tetrahydro-pyranyl-substituted ethers, that is, mixed acetals, at mild conditions and with good to excellent yields. Primary and secondary alcohols can be THP-protected to afford 1-8 at room temperature and at loadings ranging from 0.001 to 1.0mol% thiourea... 

Dihydropyran is of value as a protecting group for alcohols and phenols, and to a lesser extent amines, carboxylic acids and thiols (B-67MI22403, B-81MI22404). The resulting tetrahydropyranyl ethers (736) are stable to base, but are readily cleaved under acidic conditions (Scheme 284). 

As an alternative to protection as ethers, alcohols can also be protected as acetals, the most common being tetrahydropyranyl ethers (THP-OR) and 1-ethoxyethyl ethers (EE-OR) (Table 7.7). Support-bound secondary aliphatic alcohols have been... 

Under acidic conditions, dihydropyran will undergo additions with alcohols at room temperature to form 2-tetrahydropyranyl ethers (equation 247).398 This reaction constitutes an important method for the protection of primary and secondary alcohols.400... 

A 1,2-hydride shift has been invoked399 to account for the formation of p-methoxyphenylbutyraldehyde derivatives (337) during the treatment of />methoxy-benzyl-protected allylic alcohols (336) with zeolites. A similar C-glycosidation procedure involving Lewis acid-catalysed anomeric oxygen to carbon rearrangement of tetrahydropyranyl ether derivatives has been reported400 (see Scheme 82). It has been... 

Nafion-H has been shown to be effective in a variety of protection-deprotection reactions including (9-trialkylsilylation of alcohols, phenols, and carboxylic acids, as well as the preparation and methanolysis of tetrahydropyranyl (THP) ethers.672 However, when compared, for example, with HBF4-silica or Nafion nanocomposites,... 

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