Protecting groups for alcohols and phenols

Thermolytic Cleavage of Allvlic and Benzvlic Ethers and Polvethers. The thermal lability of the types of ethers which are of interest in the context of this study was discovered during a thorough study of the application of certain benzylic carbonates as labile protecting groups for alcohols and phenols [IS]. It was observed that, under acid catalysis, the bis-methylcarbonate derivative of l-(4-hydroxyphenyl)ethanol (4, in Equation 1) was transformed into the benzylic ether (5) which then underwent clean acid-catalyzed thermolysis to the corresponding styrene (6) in very high yield [14]. 

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). 

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). 

Literak, J., Wirz, J. and Klan, P. (2005) 2,5-Dimethylphenacyl carbonates A photoremovable protecting group for alcohols and phenols. Photochemical el... 

In this section, the formation and cleavage of eight protecting groups for alcohols and phenols are presented acetate acetonides for diols benzyl ether para-methoxybenzyl (PMB) ether methyl ether methoxymethylene (MOM) ether ferf-butyldiphenylsilyl (TBDPS) silyl ether and tetrahydropyran (THP). 

Protection of Alcohols. In addition to being used as a halide equivalent, methanesulfonates have also been used as protecting groups for alcohols and phenols. The use of methanesulfonate as a protecting group for alcohols is mainly limited to carbohydrate synthesis due to the lability of the methanesulfonate group toward nucleophilic attack. The sulfonate ester is stable to acidic conditions and can be cleaved by Sodium Amalgam. ... 

Valuable protecting groups for alcohols, phenols, amines, and carboxylic acids, and an introduction/protection reagent for thiols, all dependent upon the lability of this group to Zn/AcOH reductive elimination, have been developed. They are summarized in Table 2. 

Benzyl ethers are formed by treatment of an alcohol or a phenol with benzyl chloride in the presence of a base such as triethylamine or pyridine. The particular value of benzylic ethers is that they can serve as protecting groups for the —OH groups of alcohols and phenols. 

Sulphonic esters have been obtained from the sulphonyl chlorides in high yields under mild conditions for a range of alcohols and phenols [e.g. 18, 19]. Of particular value is the protection of glycosides possessing a free hydroxyl group and hydroxy-steroids, which are tosylated readily under phase-transfer conditions [20-22]. Alkyl sulphinites have been obtained in a similar manner [23]. Alternatively, preformed tetra-rt-butylammonium sulphonates or their alkali metal salts have also been alkylated with haloalkanes or alkyl fluorosulphonates [24,25]. In contrast with more classical procedures, tosylation of alcohols, which are susceptible to E/Z-isomerism, e.g. Z-alk-2-en-l-ols, occurs with retention of their stereochemistry under phase-transfer catalysis [26]. 

The parent 2(3/i/)-oxazolone moiety functions as a bifunctional leaving group when carboxyl groups are activated for acylations and condensations, similar to other five- and six-membered heterocycles such as imidazole, triazole, and 2-pyridinethiol. The excellent leaving ability of a 2(3//)-oxazolone moiety has led to the development of versatile reagents. Thus, 3-acyl- and 3-alkoxycarbonyl-2(3//)-oxazolones serve as ready-to-use -type agents for the regioselective and chemoselective N-protection of amino alcohols, amino phenols and polyamines. 

A mild procedure for the appendage of MOM groups to acid-sensitive substrates is illustrated by the protection of the allylic alcohol in Avermectin derivative 259.1 using [(methoxymethyl)thio]-2-pyridine (259 2) sitver(I) Inflate and sodium acetate in THF at room temperature [Scheme 4.259],479 Primary secondary and tertiary alcohols and phenols are methoxymethylated in good yield though phenols are slower to react. Reagent 259.2 (bp 66 °C/0.088 kPa) is easily prepared in 75% yield by the reaction of pyridine-2-thiol with dimethoxy-methane activated by trifluoroborane etherate. 

Esters of aromatic acids and alcohols are usually on reduction cleaved to aryl car-boxylate and alkyl radical, which may be reduced to the anion and protonated to the hydrocarbon [43,44]. The influence of EGB should be considered when an acid is used as protecting group. Acyl derivatives of phenols as a rule cleaves between the carbonyl group and oxygen to phenolate and acyl radical, and may thus be used for protection of a phenol. The fate of the acyl radical is not clear a dimerization to a diketone has been suggested [45,46]. Such a ketone would be more easily reduced than the ester and possibly attacked by the EGB [47]. The radical anion of some easily reducible esters (e.g., esters of 4-nitrobenzoic acid) cleaves very slowly, but the dianion usually cleaves fast [46]. 

Triisopropylsilyl chloride (TIPS-Cl) is an excellent reagent for the selective protection of a primary OH in the presence of a secondary OH group. ° A simple and efficient method for silylation of alcohols and phenols is using TIPS-Cl and imidazole under microwave irradiation. The TIPS group is stable under a wide range of reaction conditions, such as acid and basic hydrolysis, and toward powerful nucleophiles. 

Tetrahydropyranyl (THP) ethers are frequently used as a protecting group for the hydroxyl group. Their formation and cleavage from alcohols and phenols have been successfully catalyzed by Bi(N03)3 5H20 [92] and Bi(0Tf)3 %H20 [93]. The conversion of THP ethers to acetate and formate esters has been reported to be efficiently catalyzed by Bi(0Tf)3 xH20 [94]. 

Another new reagent for the protection of alcohols and phenols is 2-trimethyl-silylethoxymethyl chloride (67), said to be readily available. The derived SEM ethers (Scheme 30) are stable to acidic conditions that remove 2-tetrahy-dropyranyl, 2-tetrahydrofurfuryl, and trialkylsilyl groups, but can be cleaved by fluoride ion. Phenylthiomethyl ethers may be used in the protection of phenols. They have been reported as more resistant to hydrolysis than aliphatic or aromatic methylthiomethyl ethers, and are removed with mercuric chloride. 

Chloromethyl-4-nitrophenol has been described as a protecting group for alkyl or aryl phosphates [10]. Upon treatment with pyridine, the group is activated to form a phos-phorylating agent, and dialkyl or alkyl aryl phosphate esters may be obtained on reaction with the appropriate alcohol or phenol (Fig. 6.4). 

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