Linkers for Alcohols and Phenols

Alcohols and phenols can be attached to support-bound alcohol linkers as carbonates [467,665,666], although few examples of this have been reported. For the preparation of carbonates, the support-bound alcohol needs to be converted into a reactive carbonic acid derivative by reaction with phosgene or a synthetic equivalent thereof, e.g. disuccinimidyl carbonate [665], carbonyl diimidazole [157], or 4-nitrophenyl chloro-formate [467] (see Section 14.7). The best results are usually obtained with support-bound chloroformates. The resulting intermediate is then treated with an alcohol and a base (DIPEA, DMAP, or DBU), which furnishes the unsymmetrical carbonate. Carbonates are generally more resistant towards nucleophilic cleavage than esters, but are less stable than carbamates. Aryl carbonates are easily cleaved by nucleophiles and are therefore of limited utility as linkers for phenols. 

Examples of the cleavage of support-bound carbonates are given in Table 3.36. Depending on the structure of the carbonate, acidolytic, base-induced, nucleophilic, or photolytic cleavage can be used to release the alcohol. Acidolysis of the benzylic C-O bond of resin-bound benzyl carbonates leads to the release of an unstable carbonic acid ester, which undergoes decarboxylation to yield the alcohol. 

Few examples have been described of nucleophilic cleavage of carbonate- or carbamate-linked alcohols from insoluble supports. A serine-based linker for phenols releases the phenol upon fluoride-induced intramolecular nucleophilic cleavage of an aryl carbamate (Entry 2, Table 3.36). A linker for oligonucleotides has been described, in which the carbohydrate is bound as a carbonate to resin-bound 2-(2-nitrophen-yl)ethanol, and which is cleaved by base-induced 3-elimination (Entry 3, Table 3.36). Trichloroethyl carbonates, which are susceptible to cleavage by reducing agents such as zinc or phosphines, have been successfully used to link aliphatic alcohols to silica gel (Entry 4, Table 3.36). These carbonates can also be cleaved by acidolysis (Table 3.22). 

Entry 7 in Table 3.36 is a rare example of the use of a phosphodiester as a linker for alcohols. This linker, when used in combination with an enzyme-compatible support, can be selectively cleaved with a phosphodiesterase. To obtain the free alcohol, the released phosphate must be subjected to an additional enzymatic dephosphorylation. 

Polystyrene-derived phenylboronic acids have been used for the attachment of diols (carbohydrates) as boronic esters [667]. Cleavage was effected by treatment with acetone/water or THF/water. This high lability towards water and alcohols severely limits the range of reactions that can be performed without premature cleavage of this linker. Arylboronic acids esterified with resin-bound diols can be oxidatively cleaved to yield phenols (Entry 8, Table 3.36). Alcohols have also been prepared by nucleophilic allylation of aldehydes with polystyrene-bound, enantiomerically enriched allyl-silanes [668], as well as by Pummerer reaction followed by reduction of resin-bound sulfoxides [669]. 

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Dihydropyran (DHP) linker 45 is a common handle that couples an alcohol to a solid support with subsequent release upon mild TFA conditions (Fig. 12) [54]. An alternative approach is to prepare an active carbonate linker. TV,TV -Disuccinimidyl carbonate (DSC), a valuable reagent for converting hydroxymethyl-based supports to their corresponding carbonates, was reacted with 4-hydroxymethylpolystyrene 46 and 4-nitrobenzamido (Nbb) 47 resins to anchor alcohols and phenols (Scheme 17) [55]. The final products were released from the solid support by HF and photolysis, respectively. 

Various linker strategies for the attachment of alcohols and phenols have been devised and the most recent examples are listed in Table 1.7.6. 

Only a few examples have been reported of the etherification of alcohols with resin-bound diarylmethyl alcohols (Entry 5, Table 3.30 Entry 5, Table 3.31 [564]). Diarylmethyl ethers do not seem to offer advantages over the more readily accessible trityl ethers, which are widely used as linkers for both phenols and aliphatic alcohols. Attachment of alcohols to trityl linkers is usually effected by treating trityl chloride resin or 2-chlorotrityl chloride resin with the alcohol in the presence of a base (phenols pyridine/THF, 50 °C [565] or DIPEA/DCM [566] aliphatic alcohols pyridine, 20-70 °C, 3 h-5 d [567-572] or collidine, Bu4NI, DCM, 20 °C, 65 h [81]). Aliphatic or aromatic alcohols can be attached as ethers to the same type of light-sensitive linker as used for carboxylic acids (Section 3.1.3). 

Amino Rosins. Melamine (l,3,5-triazine-2,4,6-triamine) [108-78-1] is reacted with formaldehyde [50-00-0] and alcohols to make melamine-formaldehyde (MF) resins, the most widely used cross-linkers for baked coatings. The ethers groups are activated toward nucleophilic substitution by the neighboring N. Hydroxyl, carboxylic acid, urethane, and phenols with an unsubstituted ortho position react (see Amino Resins). 

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... 

Immobilized, highly reactive phenyl esters can be prepared by acylating resin-bound 4-acyl-2-nitrophenol (Entry 4, Table 3.13 [285-288]) or 4-(aminocarbonyl)-2,3,5,6-tetrafluorophenol (Entries 7 and 8, Table 3.13). These esters are similar to oxime esters (see Section 3.3.3.3), and even react with weak nucleophiles such as anilines or alcohols. This type of linker is not, therefore, well suited for long synthetic sequences on insoluble supports, but only for the preparation of simple acid derivatives. Because cleavage yields the unchanged phenol, these resins can be reused several times, which renders this strategy of preparing acid derivatives quite cost-effective. 

Two new silyl linkers (61 and 62, Fig. 5) have been synthesized starting from Merrifield resin, 3-methyl-l,3-butanediol, and diphenyldichlorosilane or dimefhyl-dichlorosilane [64]. Linker 61 was used for the attachment of primary and secondary alcohols as well as for phenols, whereas tinker 62 was designed for the binding of tertiary alcohols. 

The hydroxyl version of the Rink amide linker, known as the Rink acid resin (25), was developed as a tool for the preparation of protected peptide fragments [13]. The peptide-linker ester bond is labile to extremely weak acids, such as HOBt or acetic acid, allowing peptides bearing t-butyl-based side-chain protection to be cleaved intact. Conversion of the hydroxyl group into chloride [66] or trifluoroacetyl [67] provides linkers that have been used for immobilization of various nucleophiles, including alcohols, N-protected hydroxylamines, phenols, purines, amines, anilines and thiols [66-68], The stability of the cation derived from this tinker is such that even thiols and amines can be cleaved from this tinker with TFA (Figure 14.12). 

Cross-Linker. It is well known that polyfunctional benzylic alcohols act as good crosslinkers for poly(4-hydroxystyrene) (11). This acid-catalyzed cross-linking reaction was studied in detail, and the reaction was proposed to proceed via a direct C-alkylation as well as an initial O-alkylation, followed by a subsequent acid-catalyzed rearrangement to the final alkylated product. Furthermore, both a thermal cross-linking and an acid-catalyzed cross-linking process were proposed for this alkylation (72). Thus we decided to use 4,4 -methylenebis[2,6-bis(hydroxymethyl)phenol] (MBHP) and 2,6-bis(hydroxy-methyl)phenol (BHP) in conjunction with 1 and 2, respectively, on the basis of its avail-... 

Blocked isocyanates permit making coatings that are stable at ambient temperature when baked, the monofunctional blocking agent is volatilized and the coreactant is cross-linked. An extensive review of blocked isocyanates, their reactions, and uses is available (127). The blocking agents most widely used are phenols, oximes, alcohols, e-caprolactam (hexahydro-2ff-azepin-2-one) [105-60-2], 3,5-dimethylpyrazole, 1,2,4-triazole, and diethyl malonate (propanedioic acid diethyl ester) [105-53-3]. A variety of catalysts are used DBTDL is most widely used but many other catalysts have also been used. Bismuth tris(2-ethyl hexanoate) has been particularly recommended (128). In electrodeposition primers, DBTDL has insufficient hydrolytic stability, and tributyltin oxide is an example of an alternate catalyst (129). Cyclic amidines, such as l,5-diazabicyclo[4.3.0]non-5-ene, are reported to be superior catalysts for use with uretdione cross-linkers in powder coatings (130). 

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