Tetrahydropyranyl, as protecting group

There are comparatively few reports in the literature relating to the use of acetal systems other than tetrahydropyranyl as protecting groups for isolated hydroxyl functions. However, acetals derived from acetaldehyde have been used several times... 

A similar reaction occurs when enol ethers react with alcohols in acid solution and in the absence of water, but now we are starting in the middle of the acetal hydrolysis mechanism and going the other way, in the direction of the acetal A useful example is the formation of THP (= TetraHydroPyranyl) derivatives of alcohols from the enol ether dihydropyran. You will see THP derivatives of alcohols being used as protecting groups in Chapter 24. 

Heterocyclic intermediates are being used more and more in synthesis as protecting groups, readily generated and, when their job is done, readily removed. We have seen two examples of this the temporary incorporation of the carboxyl group into a 2-oxazoline ring (Sec. 26.6), and the temporary formation of tetrahydropyranyl (THP) esters, resistant toward alkali but extremely easily cleaved by acid (Problem 16, p. 692). 

These ethers (and methoxymethyl) have not found extensive use in phenol chemistry as protecting groups possibly because their lability towards aqueous acid is so much greater than that of the conventional alkyl or benzyl group. One distinction which may be of advantage is that they are formed in the absence of base. Thus they are generated by addition of the phenol to an olefin, isobutylene or dihydropyran, under acid catalysis [12, 18]. The tetrahydropyranyl ether of 2-methyl-4-acetoxy-a-naphthol is thus formed at room temperature in ethyl acetate saturated with hydrogen chloride [18]. 

Alternate protective groups and parent polymers have been utilized in the design of chemically amplified resists. Generally, thermally stable, add labfle substituents are desirable as protective groups for aqueous base soluble parent polymers. Some typical examples that have been employed indude rerf-butyl (46, 47), tetrahydropyranyl (48-52), and a,a-dimethylbenzyl (49, 53, 54). In situations where adequate moisture is expected to be present in the film, hydrotyzable groups such as trimethylsilyl have also been utilized (55). As mentioned above. 

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). 

As chemists proceeded to synthesize more complicated stmctures, they developed more satisfactory protective groups and more effective methods for the formation and cleavage of protected compounds. At first a tetrahydropyranyl acetal was prepared, by an acid-catalyzed reaction with dihydropyran, to protect a hydroxyl group. The acetal is readily cleaved by mild acid hydrolysis, but formation of this acetal introduces a new stereogenic center. Formation of the 4-methoxytetrahy-dropyranyl ketal eliminates this problem. 

The principal variations on the normal crown synthesis methods were applied in preparing mixed crowns such as those shown in Eq. (3.55) and in forming isomers of the dibinaphthyl-22-crown-6 systems. The latter has been discussed in Sect. 3.5 (see Eq. 3.21) . The binaphthyl unit was prepared to receive a non-naphthyl unit as shown in Eq. (3.57). Binaphthol was allowed to react with the tetrahydropyranyl ether or 2-chloroethoxyethanol. Cleavage of the THP protecting group followed by tosyla-tion of the free hydroxyl afforded a two-armed binaphthyl unit which could serve as an electrophile in the cyclization with catechol. Obviously, the reaction could be accomplished in the opposite direction, beginning with catechol". ... 

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... 

Unsaturated tetrahydropyran derivatives have received only cursory attention in the literature as heterocyclic monomers. 2,3-Dihydropyran and several of its substituted derivatives apparently undergo cationic polymerization in a manner typical of vinyl ethers (72MI11103), while tetrahydropyranyl esters of methacrylic acid (123) are fairly typical free radically polymerizable monomers (Scheme 35) (74MI11105). The THP group was used in this study as a protecting group for the acid functionality, and it was found that deprotection of polymers (124) could be accomplished under extremely mild conditions. 

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