Merrifield resin, and

Acetal handle 78 synthesized from Merrifield resin and 4-hydroxy-benzaldehyde was applied to the solid-phase synthesis of carbohydrates and 1-oxacephams (Scheme 41) [90]. For the latter, a 1,3-diol was initially anchored to the support to form a cyclic acetal. A ring opening reaction with DIBAL generated a resin-bound alcohol which was converted to the corresponding triflate for A-alkylation with 4-vinyl-oxyazetidin-2-one. A Lewis acid catalyzed ring closure released 1-oxa-cephams from the support. 

Devaky and Rajasree have reported the production of a polymer-bound ethylenediamine-borane reagent (63) (Fig. 41) for use as a reducing agent for the reduction of aldehydes.87 The polymeric reagent was derived from a Merrifield resin and a 1,6-hexanediol diacrylate-cross-linked polystyrene resin (HDODA-PS). The borane reagent was incorporated in the polymer support by complexation with sodium borohydride. When this reducing agent was used in the competitive reduction of a 1 1 molar mixture of benzaldehyde and acetophenone, benzaldehyde was found to be selectively reduced to benzyl alcohol. 

Scheme 7.8 Resin functionalization with carboxylic acids using (a) Merrifield resin and (b) chlorinated Wang resin as the polymer support.

Dendritic polymeric supports or hybrids of these with solid-phase resins are among the most promising candidates for new high-loading supports in organic synthesis and catalysis. However, every new polymeric support has to compete with the current bench mark, the so-called Merrifield resin and its derivatives. 

The observed selectivity of the acylation with diphenylketene for the ethyl, isopropyl, and tert-butyl ester products of the monomeric concave pyridine, 9 and 10, was almost the same. Lower selectivities were found when the modified Merrifield resin and poly(vinyl benzylchloride) polymer were used. Dendrimer 10 (MW = 3,863 Da) could be recovered from the reaction mixture in 70—90% yield by nanofiltration over a membrane. 

Synthesis of the polymer-bound allyl sulfoximine 60 was accomplished by the addition-elimination-isomerization route starting from the enantiomerically pure polymer-bound N-methyl-S-phenylsulfoximine 59, which was prepared as previously described from Merrifield resin and sulfoximine 12 with a loading of 84% (Scheme 1.3.23) [42]. The successive treatment of resin 59 with n-BuLi in THF and with isovaleraldehyde furnished the corresponding polymer-bound lithium alcoholate, which upon reaction with ClC02Me and DBU afforded the corresponding polymer-bound vinylic sulfoximine (not shown in Scheme 1.3.23), the isomerization of which with DBU in MeCN afforded sulfoximine 60. 

Polystyrene has been used most often as the support for phase transfer catalysts mainly because of the availability of Merrifield resins and quaternary ammonium ion exchange resins. Although other polymers have attrative features, most future applications of polymer-supported phase transfer catalysts will use polystyrene for several reasons It is readily available, inexpensive, easy to functionalize, chemically inert in all but strongly acidic media, and physically stable enough for most uses. Silica gel and alumina offer most of these same advantages. We expect that large scale applications of triphase catalysis will use polystyrene, silica gel, or alumina. 

Scheme 50 Solid phase synthesis of penicillin using Merrifield resin and Wang resin...

They possess a gel-type structure due to their styrenic macromolecular chains lightly crosslinked by 1 to 2 % of divinylbenzene. Therefore, the Merrifield resin and its derivatives are able to swell significantly only on good solvents of the polystyrene chain. Their efficiency is therefore strongly lowered in more polar solvents such as alcohol or water. 

The thioketal-containing hydroxyl hnker 1.31 (88) was prepared in three steps from Merrifield resin and used to support carboxyhc acids. The stable resin-bound intermediate is activated via desulfurization, with either Hg(C104)2 or HIO4, and the resulting hnker is photolyzed in standard conditions to give the pure, released acid. 

The redox-sensitive linker 1.34 (91), obtained in several steps from Merrifield resin and a lactone precursor, was charged with a N-protected aminoacid, treated with NBS to debenzylate and oxidize the linker to quinone, and submitted to SPS. The quinone linker was reductively activated to dihydroquinone with NaBH4 in THF/MeOH for 30 min at rt, then cleaved by treatment with anhydrous TBAF in THF for 20 h at rt to provide the free acidic peptide via intramolecular cyclization of the linker moiety. 

The selenium linker 1.45 (103), obtained from Merrifield resin and potassium selenocyanate, was treated according to oxyselenylation conditions to give a supported selenolactone. Oxidative deseleny lation (m-CPB A, DCM, rt) produced the unsaturated lactone in good yield and purity. An expansion of this chemistry, including several SP transformations prior to the cleavage, is mentioned in the original paper (103). 

Because of fhe medicinal relevance of stilbenoids, a solid-phase approach using CM has been recently disclosed [228]. Thus, 4-viriyl phenol (115) was attached to a Merrifield resin and subjected to CM wifh various substituted styrenes in benzene at 80 °C for 12 h in fhe presence of Grubbs rufhenium-carbene catalyst (Scheme 27). 

Enantiomerically pure spiro oxindoles (Scheme 35) were prepared by using solid-supported N-cinnamoyl Evans oxazolidinone (164) [265]. Thus, chiral oxazolidi-none prepared from L-tyrosine was attached to a Merrifield resin and then N-acylated with the required unsaturated acyl chloride such as cinnamoyl chloride (not shown). The resin (165) was then suspended in aqueous dioxane and treated with proline and N-phenyl isatin at 80-90 °C overnight to give a highly substituted spiro compound (167). 

These authors investigated the preparation of solid-supported precursors of N-acyliminium ion and, after attempting to translate the Katritzky s procedure [392] onto solid phase, with very poor results mainly due to the technical difficulty in performing azeotropic removal of water from a solid-phase reaction, they switched to N-(a-aLkoxyaIkyl)amide. Thus, 4-hydroxybenzamide (527) was supported on Merrifield resin, and was then, after optimization, treated with 11 different aldehydes in the presence of trimethylorthoformate (TMOF) and TFA in THF at 30 °C for 12 h (511) (Scheme 106). 

Merrifield resin purchased from Pierce Chemical Co. which contains 0.9 meq/g of chloromethyl groups was treated with histamine free base in the presence of triethylamine.(V) The ring substitution ratio was 2.8% by histamine, 4.5% by chloromethyl group. Some Merrifield resin and potassium phthalate in dry DMF was heated at 120 C overnight. When the reaction was completed, the resin was filtered, washed and treated with NH2NH2 H20 followed by 5% NaOH to give an orange-colored resin. No chlorine was detected in the resin. 

The most commonly used polymeric support is a copolymer styrene/divinylbenzene functionalized with various reactive groups such as chloromethyl (Merrifield resin) and various spacers such as ethylene glycol (Wang-type resin). The supports now available vary one from another in many aspects and properties functionalization, cross-linking, porosity, loading, bead size. All these variations generate different swelling behaviours, different hydrophilicity, and different chemical stability. 

Even if Merrifield resins and their derivatives are still the most commonly used resins for the synthesis of small molecules, one of their limitations is the poor swelling in polar protic solvents. For instance, Merrifield resins can not be applied in protic solvents, such as water or alcohols. This problem, however, can be overcome by designing amphiphilic resins made of a 1% crosslinked polystyrene matrix onto which poly(ethylene oxide) chains are grafted (Fig. 3)... 

The first example of supported titanium-catalysed DA reaction was reported by Luis et al. in 1992 (Scheme 7.49). In this work, the authors described the preparation of several polymeric alcohols derived from Merrifield resin and their efficiency as ligand in titanium-catalysed cycloaddition between methacrolein and cyclopentadiene with yields between 83-99% and good exo selectivity. With the aim to evaluate the enantioselectivity of the reaction, catalyst 80 was then prepared almost quantitatively by double esterification of tartaric acid with chloromethylated polystyrene and a 1 1 mixture of titanium tetrachloride/titanium tetraisopropoxide. " Despite the good conversion and selectivity toward the exo-cycloadduct, only 3% enantiomeric excess was recorded, which was attributed to the very high reactivity of the system. Recycling of the catalyst was successfully performed by filtration from the reaction media and washing with dichloromethane, and catalyst 80 was reused seven times without significant loss of catalytic activity. 

The chemical modification of cross-linked polymers has received considerable interest since the discovery of Merrifield resin and its use in peptide synthesis. Cross-linked polystyrene resins have been mainstays in solid-phase synthesis and organic synthesis. Few successful examples of functionalizing cross-linked polystyrene resins have been reported, as the insoluble cross-linked polymers are particularly resistant to reagents. Rieke metals have been found to be an effective tool for the fimctionalization of cross-linked polymers. 

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