Protection of alcohol

It often happens, particularly during the preparation of complex molecules, that one functional group in a molecule interferes with an intended reaction on another functional group elsewhere in the same molecule. For example, a Grignard reagent can t be prepared from a halo alcohol because the C-Mg bond is not compatible with the presence of an acidic -OH group in the same molecule. 

One of the more common methods of alcohol protection is by reaction with a chlorotrialkylsilane, Cl-SiRa, to yield a trialkylsilyl ether, R -O-SiRa. Chlorotrimethylsilane is often used, and the reaction is carried out in the presence of a base, such as triethylamine, to help form the alkoxide anion from the alcohol and to remove the HCl by-product from the reaction. 

The ether-forming step is an SN2-like reaction of the alkoxide ion on the silicon atom, with concurrent loss of the leaving chloride anion. Unlike most Sn2 reactions, though, this reaction takes place at a tertiaiy center—a trialkyl-substituted silicon atom. The reaction occurs because silicon, a third-row atom, is larger than carbon and forms longer bonds. The three methyl substituents attached to silicon thus offer less steric hindrance to reaction than they do in the analogous tert-hutyl chloride. 

CHAPTER 13 ALCOHOLS, PHENOLS, AND THIOLS ETHERS AND SULEIDES 

FIGURE 13.7 UseofaTMS-protected alcohol during a Grignard reaction. 

Problem 17.1S TMS ethers can be removed by treatment with fluoride ion as well as by add-catalyzed hydrolysis. Propose a mechanism for the reaction of eyclohexyl TMS ether with LiF. Fluorotrimethylsilane is a product. 

Like most other ethers, which we ll study in the ne.xt chapter, TMS ethers are relatively unreactive. I hey have no acidic hydrogens and don t react with 

TMS ethers can be removed bv treatment with fluoride ion as well as bv acitl- 

HOCH2CH2CH2Br + (CH3)3SiCI Step 2a Form Grignard reagent  

Protect alcohol H CH2CH2CH2Br + iCH3 aSiCl Form Grignard reagent  

The ether-forming step is an SN2-like reaction of the alkoxide ion on the silicon atom, with concurrent loss of the leaving chloride anion. Unlike most 

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HCCH2CH2CHzBr -l- (CH3 3SiCI -H - (CH3)3SiCCH2CH2CH2Br Step 2a Form Grignard reagent  

Another common method for alcohol protection is reaction with RjSiCl to give a silyl ether. Reaction conditions usually involve RjSiCl, with 4-dimethylaminopyridine (DMAP) as the base. Both the ease of preparation of the silyl ether and the stability of the protected species depend on the nature of the R groups. Trimethylsilyl ethers (ROTMS) are very labile and readily removed with water and dilute acid. The triethylsilyl group (ROTES) is a little more robust but may be removed with fluoride ion (the use of fluoride to cleave silyl groups reflects the strength of the Si-F bond). r-BuMejSiCl (TBDMSCl) reacts selectively with 

To achieve this transformation via a Grignard reaction, the following Grignard reagent would be required  

As we saw in the previous section, it is not possible to form this Grignard reagent, because of incompatibility with the hydroxyl group. To circumvent this problem, we employ a three-step process. 

Form the Grignard reagent and perform the desired Grignard reaction. 

Deprotect, by converting the protecting group back into a hydroxyl group. 

Form Grignard reagent and perform Grignard reaction 

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The most stable protected alcohol derivatives are the methyl ethers. These are often employed in carbohydrate chemistry and can be made with dimethyl sulfate in the presence of aqueous sodium or barium hydroxides in DMF or DMSO. Simple ethers may be cleaved by treatment with BCI3 or BBr, but generally methyl ethers are too stable to be used for routine protection of alcohols. They are more useful as volatile derivatives in gas-chromatographic and mass-spectrometric analyses. So the most labile (trimethylsilyl ether) and the most stable (methyl ether) alcohol derivatives are useful in analysis, but in synthesis they can be used only in exceptional cases. In synthesis, easily accessible intermediates of medium stability are most helpful. 

Allylamines are difficult to cleave with Pd catalysts. Therefore, amines are protected as carbamates, but not as allylamines. Also, allyl ethers used for the protection of alcohols cannot be cleaved smoothly, hence alcohols are protected as carbonates. In other words, amines and alcohols are protected by an allyloxycarbonyl (AOC or Alloc) group. 

Silylation of alcohols, amines and carboxylic acids with hydrosilanes is catalyzed by Pd catalysts[l 19], Based on this reaction, silyl protection of alcohols, amines, and carboxylic acids can be carried out with /-butyldimethylsilane using Pd on carbon as a catalyst. This method is simpler and more convenient than the silylation with /-butyldimethylsilyl chloride, which is used commonly for the protection. Protection of P-hydroxymethyl-(3-lactam (125) is an example 120]. 

See also C. B. Reese, Protection of Alcoholic Hydroxyl Groups and Glycol Systems, in Protective Groups in Organic Chemistry, J. F. W. McOmie, Ed., Plenum, New York and London, 1973, pp. 95-143 H. M. Flowers, Protection of the Hydroxyl Group, in The Chemistry of the Hydroxyl Group, S. Patai, Ed., Wiley-Interscience,... 

The use of allyl ethers for the protection of alcohols is common in carbohydrate literature because allyl ethers are generally compatible with the various methods... 

Two new sections on the protection of phosphates and the alkyne-CH are included. All other sections of the book have been expanded, some more than others. The section on the protection of alcohols has increased substantially, reflecting the trend of the nineties to synthesize acetate- and propionate-derived natural products. An effort was made to include many more enzymatic methods of protection and deprotection. Most of these are associated with the protection of alcohols as esters and the protection of carboxylic acids. Here we have not attempted to be exhaustive, but hopefully, a sufficient number of cases are provided that illustrate the true power of this technology, so that the reader will examine some of the excellent monographs and review articles cited in the references. The Reactivity Charts in Chapter 10 are identical to those in the first edition. The chart number appears beside the name of each protective group when it is first introduced. No attempt was made to update these Charts, not only because of the sheer magnitude of the task, but because it is nearly impossible in... 

Additional examples of ether cleavages may be found in Section 45A (Protection of Alcohols and Thiols). 

Further examples of the reaction ROH -> RC02R are included in Section 107 (Esters from Acid Derivatives) and in Section 45 A (Protection of Alcohols and Phenols). 

Kulikov, A. Arumugam, S. Popik, V. V. Photolabile protection of alcohols, phenols, and carboxylic acids with 3-hydroxy-2-naphthalenemethanol. J. Org. Chem. 2008. 73, 7611-7615. 

The use of trichloroimidates for the preparation of ethers is an effective method for O-alkylation of alcohols [27]. This method has found widespread use in the protection of alcohols as benzyl ethers since the corresponding trichlorobenzylimi-date is inexpensive and commercially available. The mechanism involves activation of the imidate with a catalytic amount of a strong acid (typically TfOH) which leads to ionization of the electrophile and the formation of carbocation which is rapidly trapped by an alcohol. For the preparation of sec-sec ethers, this protocol has been limited to glycosidation reactions, due to the SN1 nature of the reaction which often leads to diastereomeric mixtures of products [26],... 

Protection of alcohols. /-Butyldiphenylsilyl ethers (6, 51) are useful for pro-tecton of alcohols, but are more resistant to acid hydrolysis and fluorolysis than /-butoxydiphenylsilyl ethers. In contrast, /-butoxydiphenylsilyl ethers are relatively acid-stable but are readily cleaved by fluoride ion in CFLCU. The ethers are stable to most alkyllithiums and to Swern or PCC oxidation. 

Protection of alcohols. Even somewhat hindered secondary alcohols or tertiary alcohols are converted into (p-methoxybenzyloxy)methyl (PMBM) ethers by reaction with 1 and diisopropylethylamine in CH2C12 for 3-30 hours. Deprotection can be effected by oxidation with DDQ (65-95% yield), a method previously recommended for deprotection of p-methoxybenzyl ethers (11, 166-167). 

Silyl protecting groups are the gold standard for the protection of alcohols.234 Novel photochemically removable protection groups for alcohols have been developed by Brook et a/.23S and Pirrung et al,236 For instance, cyclo-pentanol can be reacted with tris(trimethylsilyl)chlorosilane 53 in the presence of a mild base to yield the protected silyl ether 54. The protection group can be removed conveniently upon UV irradiation or by the use of Bu4NF (Scheme 12). 

Protection of Alcohols. Trimethylsilyl ethers, readily prepared from alcohols by treatment with a variety of silylating agents have found considerable use for the protection of alcohols. They are thermally stable and reasonably stable to many organometallic reagents and they are easily cleaved by hydrolysis in acid or base or by treatment with fluoride ion. t, Butyl dimethylsilyl ethers have considerably greater hydrolytic stability and are easier to work with than trimethylsilyl ethers. They are prepared from alcohols by treatment with t. butyl dimethylsilyl chloride. 

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

Acetals and ketals are very important protecting groups in solution-phase synthesis, but only a few constructs have been used as linkers in solid-phase synthesis (Tab. 3.3). The THP-linker (22) (tetrahydropyran) was introduced by Ellman [54] in order to provide a linker allowing the protection of alcohols, phenols and nitrogen functionalities in the presence of pyridinium toluene sulfonate, and the resulting structures are stable towards strong bases and nucleophiles. Other acetal-linkers have also been used for the attachment of alcohols [55, 56]. Formation of diastereomers caused by the chirality of these linkers is certainly a drawback. Other ketal tinkers tike... 

The protection of alcohols by conversion into light-sensitive ethers is most attractive. Initially, the preparation of 2-nitrobenzyl (nBn) ethers presented a problem, although their potential usefulness as protecting groups, stable under a variety of reaction conditions, that nevertheless are readily photolyzed at >320 nm (see Scheme 2) was recognized immediately. 

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... 

Organic radical chemistry in synthesis has truly blossomed in the past two decades, and more dramatic advances are expected given the vast scope of synthesis. Radical methodology is attractive because typical conditions for carbon-radical generation and functionalization do not require protection of alcohol and carbonyl functionality... 

The tritylone group (22), which has been used199 for the protection of alcohols, resembles the trityl group, but it is more stable to acid. It... 

The related reaction foro-nttrobenzyl esters results in hydrolysis of the ester, and this has been developed for use in the protection of alcohols, carboxylic acids and amines. For example, the C-1 hydroxyl group in carbohydrates can be protected as its o-njtrobenzyl ester, and the ester group removed under the very mild conditions of irradiation in neutral solution (5.51). Similarly, the carboxylic acid... 

Usually, 3- and 4-substituted thianes are prepared from the 3- and 4-oxothians by the common techniques applicable to alicyclic chemistry. Reduction affords alcohols which may be etherified or halogenated, while oximation and reduction produces the amino derivatives, which are also accessible via the halo compounds. 2-Alkoxy and 2-alkylthio compounds are made by acid catalyzed addition of alcohols and thiols to 3,4-dihydro-2H-thiopyran (75MI22502) in a reaction analogous to the use of dihydropyran for protection of alcohols as THP ethers. 

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