Protecting groups, primary hydroxyl

The crotonate esters, prepared to protect a primary hydroxyl group in nucleosides, are cleaved by hydrazi ne (MeOH, Pyr, 2 h). The methoxycrotonate is 100-fold more reactive to hydrazinolysis and 2-fold less reactive to alkaline hydrolysis than the corresponding acetate. ... 

The triphenylmethyl (trityl) group remains the most frequently used for the temporary protection of primary hydroxyl groups (for review see Refs. [2, 3, 254]) which can be conveniently regenerated from the corresponding ethers by mild acid treatment or by hydrogenolysis. Moreover, good crystallizing properties of trityl ethers, easy... 

NT0-Bis(terf-butyldimethylsilyl)acetaniide silylates tertiary and hindered secondary alcohols in the presence of a catalytic amount of TBAF or another source of fluoride anion [Scheme 4.67].113 Protection of primary hydroxyl groups in the presence of secondary ones and secondary in the presence of tertiary is possible but the monoprotection of 1,2-diols fails due to the migration of the silyl group caused by the presence of basic fluoride anion. 

Selective protection of primary alcohols. Selective protection of primary hydroxyl groups of carbohydrates is possible by reaction of this chlorosilane and polyvinylpyridine in CH2CI, or THF in the presence of HMPT. Amberlite A-26 in the F form is recommended for desilylation. 

Imidazole carboxylic esters of secondary or tertiary alcohols, such as 1053 and 1054,, form carbonates exclusively with primary alcohols (Scheme 253). Thus, 1054 is a useful reagent for the BOC-protection of primary hydroxyl groups < 19990L933>. In some cases, 1054 offers better selectivity than pivaloyl chloride in the protection of carbohydrates <1998S1787>. Similarly, l-(methyldithiocarbonyl)imidazole 1055 and its methyl triflate salt convert alcohols to ri -methyldithiocarbonates <1997SL1279> and amines to 6 -methyldithiocarbamates or thioureas <2000T629>. 

SCHEME 3.10 Examples of selective protection of primary hydroxyl groups. 

The TIPS group [334] is one of the most sterically hindered silyl protecting groups, being removed only slowly under standard acid- or base-catalyzed hydrolysis conditions. The large steric bulk ensures high selectivity in the protection of primary hydroxyl groups over sec-... 

Hydroxyl protection. The primary hydroxyl group of sugars is selectively acylated... 

No acetolyses appear to have been performed on methylene acetals of aldoses or aldosides. The use of the trifluoroacetic anhydride-acetic acid sequence would be one way of protecting a primary hydroxyl group and freeing a particular secondary one. 

Protection of primary hydroxyl groups. Sodium alkoxides (from sodium hydride) react with iodomethyl methyl sulfide at 0° in DME to form methyl-thiomethyl ethers (MTM ethers) in yields usually >86%. These ethers are stable to bases and nucleophiles (NaH, RLi, NaOR) and fairly stable to acid. Thus acetonide and THP protecting groups can be cleaved more easUy by acid than the MTM ether function. 

Protection of primary hydroxyl groups. The 5 -hydroxyl groups of nucleosides can be protected as the a-naphthyldiphenylmethyl ether. The group is selectively cleaved reductively in the presence of a p-methoxytrityl protecting group by sodium anthracenide in THE (HMPT). Sodium naphthalenide is less selective. The a-naphthyldiphenylmethyl group is relatively stable toward the benzophenone radical anion, which readily cleaves /3,/3,/3-trichloroethyl groups. 

Polymeric reagent. A polymeric form (1) of trityl chloride can be prepared from a styrene-divinylbenzene polymer( as formulated. The reagent has been used to protect the primary hydroxyl groups of glucopyranosides. Use of the... 

Heating a tertiary alcohol with l-(trimethylsilyl)iniidazole (abbreviated TMSIM. by-product imidazole) at 100 °C accomplishes O-trimethylsilylation even in the presence of a trisubstituled oxirane [Scheme 4.10].Tetrabutylammonium fluoride (TBAP) catalyses the 0-silylation of alcohols with various silazanes, including l-(trimethylsilyI)imidazole, so that silylation takes place at room temperature in DMF [Scheme 4.11]. In the absence of TBAF, no silylation occurs. The use of more hindered silazanes such as the bissilyl derivative of 5,5-dimethyIhy-dantoin allows regioselective TMS or TBS protection of primary hydroxyl groups in the presence of secondary and tertiary ones. Hydrosilanes and disilanes can be used instead of silazanes in TBAF-caialysed protection of primary and secondary alcohols. ... 

Overman and Paone used the 2-(trimethylsilyl)ethyl ether to protect a primary hydroxyl during a synthesis of the C2 Symmetric bis-pyrrolidinoindoline alkaloid Ditryptophenaline [Scheme 4.301], The Fmoc groups did not survive deprotection with TBAF or trifluoroborane, but they were preserved when the depro-... 

Later, it was found that the imidazole-iV-carboxylate esters (35 and 36) formed by the reaction of 1 and either secondary or tertiary alcohols react selectively with primary hydroxyls in polyols containing mixtures of primary, secondary, and tertiary hydroxyls, without the need for protecting group chemistry (eq 29). With this method, selective f-Boc protection of primary hydroxyl groups could be easily achieved through a single step. 

TBDMSCl has been used to selectively protect the primary hydroxyl group of 1,2- and 1,3-diols under mild conditions, via dibutylstannylene acetal intermediates. For example, treatment of the dibutylstannylene acetal of l-phenylethane-l,2-diol with TBDMSCl in chloroform affords the primary ether in excellent yield (eq 27). This selectivity for the primary hydroxyl group is different from acylation or alkylation of dibutylstannylene acetal... 

Some of the original work in the carbohydrate area in particular reveals extensive protection of carbonyl and hydroxyl groups. For example, a cyclic diacetonide of glucose was selectively cleaved to the monoacetonide. A summary describes the selective protection of primary and secondary hydroxyl groups in a synthesis of gentiobiose, carried out in the 1870s, as triphenylmethyl ethers. 

The tritylone ether is used to protect primary hydroxyl groups in the presence of secondary hydroxyl groups. It is prepared by the reaction of an alcohol with 9-phenyl-9-hydroxyanthrone under acid catalysis (cat. TsOH, benzene, reflux, 55-95% yield).It can be cleaved under the harsh conditions of the WolfT-Kishner reduction (H2NNH2, NaOH, 200°, 88% yield), " and by electrolytic reduction (-1.4 V, LiBr, MeOH, 80-85% yield). It is stable to 10% HCl, 55 h. ... 

PhN=C=0, Pyr, 20°, 2-3 h, 100% yield. This method was used to protect selectively the primary hydroxyl group in several pyranosides. ... 

The reactivity of various steroid alcohols decreases in the order primary > secondary (equatorial) > secondary (axial) > tertiary. The only systematic investigation relating to the selective protection of steroidal hydroxyl functions has been carried out with the cathylate (ethyl carbonate) group. Since only equatorial hydroxyl groups form cathylates this ester has been used as a diagnostic tool to elucidate the configuration of secondary alcohols. 

As previously discussed, ethyl chlorocarbonate reacts rapidly and selectively with an equatorial 3-hydroxyl group to give the corresponding cathylate. Trityl ethers, usually employed as a selective protecting group for primary hydroxyls, can be prepared from A -3j3-ols by heating with triphenylmethyl chloride in pyridine, and from 5a-3 -alcohols by more prolonged heat-... 

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