2/7-Pyran, 3,4-dihydro- protection with

Although many organic chemists still use 3,4-dihydro-2H-pyran [214,215] for the protection of OH groups, protection with ethyl vinyl ether has distinct advantages. Ethyl vinyl ether [216] is much cheaper than the cyclic ether, but chemists working in a university will perhaps find the advantage of the easier protection and deprotection more important Furthermore, H NMR-spectroscopic analysis of the adducts from ethyl vinyl ether in many cases will be easier. 

Regio- and enantioselective differentiation of symmetrical polyols has been accomplished with dispoke derivatives [Scheme 3.106]. Reaction of S,S)-6,6 -bis(2-methyl-3,4-dihydro-2//-pyran) (105.1) with 1,5-disilylated xylitol 106.2 in boiling chloroform containing a catalytic amount of camphorsulfonic acid gave the protected polyol 1063 as the only isolated product. The reaction was completely diastereoselective and the product formed was the most thermodynamically stable in which the two side chain methyl groups and the two hydro-xylated side chains on the dioxane ring were equatorially oriented, with the spirocentres benefiting from maximum anomeric stabilisation. 

Pyrano[3,2 ]indolizines such as 120 can be prepared from the reaction of N-( 1 -benzotriazolylmethyl)indolines with 3,4-dihydro-2//-pyran under acidic or Lewis-acidic conditions (Equation 26) <2001T4933>, and a simpler analogue 122 is the end product of an annulation process starting from the enamine 121 and ethyl acrylate <1996H(43)1391> (Scheme 34). Pyrano[4,3-/]indolizinetriones, for example, 124, result from the hydrolysis of protected 2,3-dihydro-l//-indolizincdioncs 123 (Equation 27) <2000H(53)771>. 

Merrifield resin (1 % crosslinked) was employed as the solid support. The problem of oligomerization was prevented by protection of the hydroxyl of 38 as a THP ether by treatment with 3,4-dihydro-2H-pyran (DHP) in the presence of pyridinium /7-toluenesulfonate (PPTS) to give 46. Immobilized 46 was successfully coupled with 24 to give disaccharide 47. The THP group of 47 was easily removed by treatment with acetic acid/water to yield 45. 

Protection of alcohols with 3,4-dihydro-2//-pyran can be carried out by EGA... 

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... 

When reacted with an alcohol in the presence of a catalytic amount of a strong acid, 3,4-dihydro-2/f-pyran yields a base-stable 2-alkoxytetrahydropyran (a cyclic acetal) (Scheme 4.13). The reaction is reversed if the acetal is treated with aqueous acid (see Section 3.3.4, page 54), so that this provides a simple way of protecting alcohols in syntheses where a strong base might otherwise deprotonate them. The conformational preferences of 2-alkoxytetrahydopyrans, mediated by the anomeric effect, were commented upon earlier (Section 1.5.3). 

South described the protection of 4,5-dichloropyridazin-3(2//)-one as a 2-tetrahydropyranyl derivative. The pyr-idazinone is treated with 3,4-dihydro-2/7-pyran in the presence of /)-toluenesulfonic acid or pyridinium -toluene-sulfonate in refluxing tetrahydrofuran <1995JHC1473>. The deprotection is discussed in Section 8.01.8.1. 

The step 2 product (14.9 mmol) and pyridinium p-toluenesulfonate (0.477 mmol) were treated in 150 ml chloroform with 3,4-dihydro-2H-pyran (110 mmol) and the protected isolated. 

The reaction between vinyl ethers and unsaturated carbonyl compounds, which provides a powerful synthetic route to dihydropyrans, has been adapted to the synthesis of pyran-2-ones (72CC863). 2-Chloro-1,1 -dimethoxyethylene, which is a protected form of chloroketene, undergoes cycloaddition with a number of enones to give the cis or trans isomers of 3-chloro-3,4-dihydro-2,2-dimethoxypyrans (338) and (339) or a mixture of both. Although... 

In a manifestation of the reaction shown above, quinoline rings have also been formed by the cycloaddition of /V-arylketenimines 543 with 3,4-dihydro-2//-pyran 455 under high-pressure conditions (Scheme 100) <2001H(55)1971>. The reaction is proposed to proceed via the initial formation of 544 by attack of the enol ether on the protonated ketenimine subsequent electrophilic aromatic substitution gives 545. Protonation of the enamine to give 546 is followed by elimination to produce 547. Protection of the alcohol with 455 gives 548. 

Besides the methods described above for the side-chain anchoring of Ser and Thr, the 3,4-dihydro-2//-pyran-2-functionalized-resin and handle 331 23,124] Table 3) allows the preparation of peptide alcohols by treatment with TEA in the presence of scavengers. Furthermore, the alkylation of Fmoc amino alcohols with a diphenyldiazomethane polymeric resin 34 gives rise to a benzhydryl ether, which can be cleaved with TFA/CH2CI2 (2 98) to give protected peptide alcohols. 

Acid-catalyzed addition of aliphatic, aromatic or heteroaromatic cyanohydrins to ethyl vinyl ether, n-butyl vinyl ether or dihydro-4//-pyran provides base stable, protected cyanohydrin derivatives. Phase transfer catalyzed alkylation of aliphatic cyanohydrins with allylic bromides gave a-substituted a-allyl-oxyacetonitrile. Carbonyl compounds react wiA cyanide under phase transfer catalysis to give cyanohydrin anions, which are trapped by an acyl chloride or ethyl chloroformate to give acyl- or alkoxycarbonyl-protected cyanohydrins respectively. The reduction of the carbonyl group of an acyl cyanide by NaBH4 under phase transfer conditions followed by esterification serves as an alternative route to aldehyde-derived cyanohydrin esters. ... 

Dihydro-2/f-pyran and 2,3-dihydrofuran behave as enol ethers, the former being widely used to protect alcohols, with which it reacts readily under acidic catalysis, producing acetals that are stable to even strongly basic conditions, but easily hydrolysed back to the alcohol under mildly acidic aqueous conditions. Each can also serve as equivalents of 5-(4-)-hydroxy-aldehydes (see below). 

The glycals react with water, alcohols, phenols, carboxylic acids, and certain bases, in the presence of an acidic catalyst, in the same way as does 2,3-dihydro-4/f-pyran (which gives, for example, 2-hydroxy-, 2-alkoxy-, and 2-aryloxy-tetrahydropyrans in high yield ). (Tetrahydro-pyranyl ethers are useful for protecting alcoholic groupings during reactions in basic media, and are readily hydrolyzed with acid,) The first step of these additions would be expected to be protonation at C-2, followed by attack of the nucleophilic reagent on the resonance-stabilized, C-1 carbonium ion. 

Alcohols, as well as phenols, add to 3,4-dihydro-2//-pyran under acid catalysis giving 2-alkyl(aryl)-oxytetrahydropyrans 3 [16a]. These cyclic acetals are stable to base but prone to hydrolysis even with dilute acids. Thus, OH functions can be blocked reversibly (THP protecting group in organic synthesis) ... 

Reaction of methyl a-D-galactopyranoside 102.1 with 6,6 -bis(3,4-dihydro-2//-pyran) (bis-DHP, 1023) in refluxing chloroform (thermodynamic conditions) gives the dispoke (dispiroketal) derivative 102.2 in 64% yield. - The preference for rram-diequatonal protection is a consequence of steric interactions and multiple stabilising anomeric effects of the two acetal functions in the dispoke derivative. The pure bis-DHP reagent 1023 is a low melting solid (mp 49-50 C) that is stable at -10 °C in the absence of acid and moisture. It is prepared in 55% yield by the oxidative dimerisation of 6-lithio-3,4-dihydro-2//-pyr-an. As can be seen from Scheme 3.103, the preference for frum-diequatorial protection is excellent in the fiico, manno, and fyxo series but it is poor in the case of the arabino and rhamno series. 

Kumar and coworkers have reported preparation of 2, 3 -epimino analogues of the antibiotics neamine, ribostamine, and kanamycin B by reaction of suitably protected vicinal benzyloxycarbonylamino tosylates with NaH in N,N-dimethylformamide, followed by deprotection. lodo-carbamates 119 and 120 were obtained by addition of iodine isocyanate to 2-methoxy-4,6-dimethyl-3, 6-dihydro-2/f-pyrane 118 (a mixture of cis and trans isomers), followed by treatment with MeOH. Treatment of compound 119 and 120 with potassium hydroxide in refluxing methanol afforded epimines 121 and 122. 

Pyrazole could also be protected as its corresponding tetrahydropyranyl (THP) derivative by treating pyrazole with 3,4-dihydro-2//-pyran (DHP) with the aid of a catalytic amount of TFA. " C5-Lithiation of THP-pyrazole could also be achieved using n-BuLi. Pyrazole-5-boronic acid was prepared in this fashion. 

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