Benzylic halide resins

Three different strategies are generally used for the attachment of carboxylic acids to resins as benzyl esters (a) acylation of resin-bound benzyl alcohols [38-40], (b) O-alkylation of carboxylates by resin-bound benzylic halides [4143], or (c) O-alkylation of carboxylic acids under Mitsunobu conditions [44,45] (Figure 3.3). These reactions are treated in detail in Section 13.4. 

As illustrated by the examples in Table 3.9, resin-bound 4-alkoxybenzylamides often require higher concentrations of TFA and longer reaction times than carboxylic acids esterified to Wang resin. For this reason, the more acid-sensitive di- or (trialkoxy-benzyl)amines [208] are generally preferred as backbone amide linkers. The required resin-bound, secondary benzylamines can readily be prepared by reductive amination of resin-bound benzaldehydes (Section 10.1.4 and Figure 3.17 [209]) or by A-alkyla-tion of primary amines with resin-bound benzyl halides or sulfonates (Section 10.1.1.1). Sufficiently acidic amides can also be A-alkylated by resin-bound benzyl alcohols under Mitsunobu conditions (see, e.g., [210] attachment to Sasrin of Fmoc cycloserine, an O-alkyl hydroxamic acid). 

Illustrative examples of cleavage reactions of /V-arylbenzylaminc derivatives are listed in Table 3.25. Aromatic amines can be immobilized as /V-bcnzylanilincs by reductive amination of resin-bound aldehydes or by nucleophilic substitution of resin-bound benzyl halides (Chapter 10). The attachment of the amino group of 5-aminoin-doles to 2-chlorotrityl chloride resin has been reported [486]. Anilines have also been linked to resin-bound dihydropyran as aminals [487]. 

Phenols can be etherified with resin-bound benzyl alcohols by the Mitsunobu reaction [554,555], or, alternatively, by nucleophilic substitution of resin-bound benzyl halides or sulfonates [556,557], Both reactions proceed smoothly under mild conditions. Aliphatic alcohols have been etherified with Wang resin by conversion of the latter into a trichloroacetimidate (C13CCN/DCM/DBU (15 100 1), 0°C, 40 min), fol-... 

Merrifield resin [33-37] and other support-bound benzyl halides [38] have also been used to alkylate amines (Entries 5-10, Table 10.2). Similarly, resin-bound allyl bromides react cleanly with aliphatic or aromatic amines (Entry 16, Table 10.2). Entry 15 in Table 10.2 is a rare example of the N-alkylation of an amine under the conditions... 

Arylmethyl(homobenzyl)ethylsulfonium salts are appropriate substrates for Suzuki-type coupling reactions. In this reaction, performed on a polymer-bound sulfonium tetrafluoroborate, the benzyl fragment on the sulfur atom was transferred to the boronic acid residue. The sulfonium salt was prepared from an al-kylthiol resin by alkylation with a substituted benzyl halide to give thioether 98 and subsequent alkylation with triethyloxonium tetrafluoroborate. Reaction with a boronic acid derivative yielded diaryl methanes 99 [94] (Scheme 6.1.22). 

Several conclusions have to be drawn. The first is related to the obvious gap between the empiricism and even archaism of most of industrial cationic polymerization processes and the level of fundamental science devoted for decades to these reactions. Previous chapters in this volume clearly illustrate the situation. This feature was pointed out in the early book of Kennedy and Marechal [1], and the explanation based on the very favorable price/performances characteristics of the products is still realistic. Nevertheless it is noteworthy that recent improvements or new processes based on more scientific approaches led to a better control of the polymerization, of polymer structure, and to high-performance commercial products which will increasingly occupy the market. This is the case for the recently marketed reactive BF3-based polybutenes with high content of exomethylenic chain ends, for the strongly developing pure monomer hydrocarbon resins ( + 8% in 1994), or for the new benzyl halide-based halobutyl rubber, and it is revealing that these products represent the three families of cationically prepared industrial polymers... 

Selenides (selenoethers)and tellurides can be prepared via RSe and RTe species, and selenium and borohydride exchange resin followed by the halide give the selenoether. The La/l2-catalyzed reaction of diphenyl diselenide with primary alkyl iodides gave arylalkyl selenides, and Inl has been used with benzyl halides. Diaryl selenides (Ar—Se—AF) have been prepared by couphng aryl iodides with tin reagents (ArSeSnR3) with a palladium(O) catalyst. ... 

A similar process has been used to prepare benzyl ethers of phenols, a strongly basic exchanger being washed with a solution of the phenol in water and in dilute alkali and then with alcohol. The modified resin is then stirred with a solution of a benzyl halide until reaction is complete. 

A benzyl halide solid support If (Table 1) has been reported [77] that affords anchoring groups which are less labile than trityl anchors Ib-le but more labile than anchors to chloromethyl-PS (la). Resin If has been used to prepare amides and sulfonamides by reaction with an amine followed by acylation or sulfonylation, respectively, and cleavage using 95% TFA. When the same reaction sequence was conducted on an analogous resin Ig prepared from Tentagel AC (acid-cleavable linker), the products could be cleaved under milder conditions (5% TFA) because of the greater stability... 

X- = NCO From Amberlyst A-26 (Cl ) by treatment with aq. KOCN Symmetrical MN -dialkyl ureas from primary and secondary as well as from benzylic and allylic halides if the reaction was performed with wet resin in apolar solvents, N-Substituted ethyl urethanes were obtained from alkyl and benzyl halides if the reaction was carried out in EtOH. 

Pellicularized resins, i.e., glass beads coated with co(polystyrene-DVB), and functionalized (benzyl halides) glass or silica beads. The swelling of the support is independent of the solvent, and eliminates failure sequences, but the resin capacity is low... 

The authors chose polystyrene/divinylbenzene sodium sulfinate resin as the solid support, as it easily grants access to the vinyl sulfone needed for the cycloaddition reaction. The sulfone was generated via a microwave-assisted reaction with a suitable benzyl halide bearing an electron-withdrawing group (Scheme 8.12). 

Preparation.—A quaternary ammonium anion-exchange resin, in its carbonate form, is the reagent in a new and convenient procedure for the hydrolysis of primary, allyl, and benzyl halides to the corresponding alcohols. A shortened (two-stage) sequence for the conversion of primary alkylamines to alcohols mediated by pyrilium salts (c/. 2,113 4,138) is outlined in Scheme l treatment of the intermediate pyridinium salt (1) with sodium 2-hydroxymethylbenzoate (or thiobenzoate) leads directly to isolation of the alcohol, rather than the esters obtained when sodium acetate or sodium trifluoroacetate are employed. 

A thiazolium amino acid (Taz) has been developed which can be utilized to mimic TDP-dependent enzyme function [52]. In this strategy, illustrated in Fig. 15, the commercially available amino acid 4-thiazolylalanine is incorporated into peptides by solid phase peptide synthesis. Prior to deprotection of the amino acid side chains and cleavage of the peptide from the resin, the thiazole amino acid is alkylated with an alkyl halide to generate the corresponding thiazolium amino acid having various N3-substituents (BzTaz = 3-benzyl-Taz, NBTaz = 3-nitrobenzyl-Taz). 

Because of the special structural requirements of the resin-bound substrate, this type of cleavage reaction lacks general applicability. Some of the few examples that have been reported are listed in Table 3.19. Lactones have also been obtained by acid-catalyzed lactonization of resin-bound 4-hydroxy or 3-oxiranyl carboxylic acids [399]. Treatment of polystyrene-bound cyclic acetals with Jones reagent also leads to the release of lactones into solution (Entry 5, Table 3.19). Resin-bound benzylic aryl or alkyl carbonates have been converted into esters by treatment with acyl halides and Lewis acids (Entry 6, Table 3.19). Similarly, alcohols bound to insoluble supports as benzyl ethers can be cleaved from the support and simultaneously converted into esters by treatment with acyl halides [400]. Esters have also been prepared by treatment of carboxylic acids with an excess of polystyrene-bound triazenes here, diazo-nium salts are released into solution, which serve to O-alkylate the acid (Entry 7, Table 3.19). This strategy can also be used to prepare sulfonates [401]. 

Table 6.2. Conversion of resin-bound benzylic and allylic alcohols into halides.

The Mitsunobu reaction is usually only suitable for the alkylation of negatively charged nucleophiles rather than for the alkylation of amines, and only a few examples of such reactions (mainly intramolecular N-alkylations or N-benzylations) have been reported (Entry 15, Table 10.2). Halides, however, are very efficiently alkylated under Mitsunobu conditions, and it has been found that the treatment of resin-bound ammonium iodides with benzylic alcohols, a phosphine, and an azodicarboxylate leads to clean benzylation of the amine (Entry 9, Table 10.3). Unfortunately, alkylations with aliphatic alcohols do not proceed under these conditions. The latter can, however, also be used to alkylate resin-bound aliphatic amines when (cyanomethyl)-phosphonium iodides [R3P-CH2CN+][r] are used as coupling reagents [62]. These reagents convert aliphatic alcohols into alkyl iodides, which then alkylate the amine (Entry 10, Table 10.3). 

Indium-mediated Barbier-type coupling between carbonyl compounds and allyl halides has been revealed to proceed effectively in diverse reaction media. Even under solvent-free conditions, allylation works well, although no reaction is observed with benzyl bromide and a-halo carbonyl compounds.59 Various aldehydes react with allyl bromide mediated by indium in liquid carbon dioxide to give homoallylic alcohols (Scheme 1). In contrast to the corresponding neat allylation, the liquid C02-mediated reaction can allylate solid aldehydes successfully.60 Indium-mediated allylations of carbonyl compounds with allyl bromide proceed in room temperature ionic liquids. In [bmim][BF4] and [bmim][PF6] (bmin l-butyl-3-methylimidazolium), the desired homoallylic alcohols are formed with good levels of conversion.61 Homoallyllic alcohols are also prepared by the reaction of resin-bound aldehydes (Equation (l)).62... 

Apart from their behaviour as ligands in metal catalyst systems, studies of the reactivity of phosphites towards a wide variety of other substrates have attracted attention. New aspects and applications of the classical Michaelis-Arbuzov reaction and its variants continue to appear. Evidence of the thermal disproportionation of methyltriaryloxyphosphonium halides formed in the reactions of triarylphosphites with alkyl halides, together with the formation of P-O-P intermediates, has been reported. The Michaelis-Arbuzov reaction has been used in the synthesis of phosphonate-based styrene-divinylbenzene resins and polyphosphonated chelation therapy ligands.Treatment of electron-rich benzylic alcohols dissolved in triethylphosphite with one equivalent of iodine affords a low-temperature one-pot route to the related benzylic phosphonates, compounds which are otherwise difficult to prepare. Upper-rim chloromethylated thiacalix[4]arenes have also been shown to undergo phosphonation on treatment with a phosphite ester in chloroform at room temperature. The nickel(II)-catalysed reaction of aryl halides with phosphite esters in high boiling solvents, e.g., diphenyl ether, (the Tavs reaction), has also... 

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