Polystyrene acid mediation

One approach to tetrahydropyridinones is the Lewis acid mediated hetero-Diels-Alder reaction of electron-rich dienes with polystyrene-bound imines (Entries 3 and 4, Table 15.23). The Ugi reaction of 5-oxo carboxylic acids and primary amines with support-bound isonitriles has been used to prepare piperidinones on insoluble supports (Entry 5, Table 15.23). Entry 6 in Table 15.23 is an example of the preparation of a 4-piperidinone by amine-induced 3-elimination of a resin-bound sulfinate followed by Michael addition of the amine to the newly generated divinyl ketone. The intramolecular Pauson-Khand reaction of propargyl(3-butenyl)amines, which yields cyclopenta[c]pyridin-6-ones, is depicted in Table 12.4. 

SPEEDING UP THE RATE OF POLYSTYRENE PRODUCTION USING ACID MEDIATION... 

BMWD at the time because of the very slow polymerization rate needed to produce the A/w1.4 x 106 polystyrene. However, in recent years, through implementation of acid mediation technology, Dow successfully commercialized BMWD polystyrene used for Styrofoam production [25]. 

Aiming to prepare a library of derivatives of the medicinally relevant piperidine scaffold, Veerman [393] and co-workers exploited N-acyhminium ion chemistry, starting from a stable aminal precursor. Coupling of six different amino acetals onto sulfonylethoxycarbonyl-modified (SEC-modified) polystyrene resin afforded the potential precursors. However, attempts to transform these into the desired piperidine derivatives via one-pot generation of N-acyliminium ions and functionalization failed, essentially because direct attack of the nucleophile on the acid-mediated oxycarbenium ion took place at a similar rate to that of the intramolecular carbamate-nitrogen attack. 

Polymer supported reagents, catalysts, protecting groups, and mediators can be used in place of the corresponding small molecule materials (Sherrington, 1991 Sundell and Nasman, 1993). The reactive species is tightly bound to a macromolecular support which immobilizes it. This generally makes toxic, noxious, or corrosive materials much safer. The use of polystyrene sulfonic acid catalyst for the manufacture of methyl r-butyl... 

The von Richter cinnoline process was further extended to solid-phase synthesis. The route began from benzylaminomethyl polystyrene and the required diverse o-haloaryl resins represented by 21 were prepared from substituted o-haloanilines. A Pd-mediated cross-coupling reaction with 21 and the alkynes provided the alkynylaryl derivatives represented by alkyne 22. The von Richter cyclization reaction with hydrobromic or hydrochloric acid in acetone/HaO and cleavage from the resin occurred in the same step to furnish the cinnoline derivatives 23 in 47-95% yield and 60-90% purity (no yield reported for each entry). 

The earliest published example of microwave-assisted SPOS involved diisopropyl-carbodiimide (DlC)-mediated solid-phase peptide couplings [24], Numerous Fmoc-protected amino acids and peptide fragments were coupled with glycine-preloaded polystyrene Wang resin (PS-Wang) in DMF, using either the symmetric anhydride or preformed N-hydroxybenzotriazole active esters (HOBt) as precursors (Scheme 12.1). 

The conversion of the polystyrene-supported selenyl bromide 289 into the corresponding acid 290 allowed dicyclohexylcarbodiimide (DCC)-mediated coupling with an amidoxime to give the 1,2,4-oxadiazolyl-substituted selenium resin 291 (Scheme 48). Reaction with lithium diisopropylamide (LDA) and allylation gave the a-sub-stituted selenium resin 292, which was then used as an alkene substrate for 1,3-dipolar cycloaddition with nitrile oxides. Cleavage of heterocycles 293 from the resin was executed in an elegant manner via selenoxide syn-elimination from the resin <2005JC0726>. 

Amidines and sulfonamides have also been used as linkers for primary or secondary aliphatic amines (Entries 4, 5, and 7, Table 3.23). These derivatives are stable under basic and acidic reaction conditions and can only be cleaved by strong nucleophiles. Phenylalanine amides can be hydrolyzed by treatment with certain enzymes (Entry 8, Table 3.23), and can therefore be used for linking amines to supports compatible with enzyme-mediated reactions (CPG, some polyacrylamides, macroporous polystyrene, etc.). 

PEG-grafted polystyrene is also well suited for reactions with highly reactive orga-nometallic reagents, provided that the support has been dried. PEG-containing polymers are generally more difficult to dry than pure polystyrene. Cross-linked PEG is stable towards Lewis acids, and can be used for SnCl4-mediated allylations of aldehydes with allyl silanes [21],... 

Most of these procedures are incompatible with common linkers, and are therefore unsuitable for the transformation of support-bound substrates into carboxylic acids. A more versatile approach for this purpose is the saponification of carboxylic esters. Saponifications with KOH or NaOH usually proceed smoothly on hydrophilic supports, such as Tentagel [19] or polyacrylamides, but not on cross-linked polystyrene. Esters linked to hydrophobic supports are more conveniently saponified with LiOH [45] or KOSiMe3 in THF or dioxane (Table 13.11). Alternatively, palladium(O)-mediated saponification of allyl esters [94] can be used to prepare acids on cross-linked polystyrene (Entries 9 and 10, Table 13.11). Fmoc-protected amines are not deprotected under these conditions [160],... 

The scope and limitations of Pd(0)-mediated coupling reactions between aromatic halides linked to a polystyrene resin and boronic acid derivatives (Suzuki coupling) or arylstannanes (Stille coupling) have been reported. For all the reactions, the conditions were optimized and evaluated with various reagents. In most cases, products were obtained in excellent yields upon cleavage from the solid support (Eq. (63)) [101]. 

In related work, solid-phase-mediated synthesis of isonitriles from formamides was achieved by using polystyrene-bound sulfonyl chloride as a suitable supported reagent [115]. The sulfonyl chloride resin could be quantitatively regenerated by treatment of the sulfonic acid resin formed with phosphorus pentachloride (PCI5) in N,N-dimethy]formamide at room temperature. 

Treatment of MBH addcut 1 with carboxylic adds under Mitsunobu conditions gave almost exclusively the S 2 products 4, rather than S 2 product 5. Weak and bulky carboxylic acids and low temperatiues favor S 2 addition. Although the reaction conditions were effective for alkyl substituted derivatives, the addition of EtsN to the Mitsunobu conditions was necessary to improve the 5n2 S 2 ratios for the vinyl and phenyl derivatives (Scheme 3.3). " More recently, it was found that the nucleophilic substitution reaction mediated by triphenylphosphine linked to non-crosslinked polystyrene 6 led to a significantly more regioselective transformation. Tri-substituted alkenes 4 were obtained almost quantitatively via a highly regioselective 5n2 Mitsunobu reaction (Scheme 3.3). ... 

A heterogeneous source of copper, the well-characterized, strongly basic, copper-exchanged fluorapatite (CuFAP), is formed as the (mainly) Cu(II) species from Caio(P04)6(F)2 upon treatment with Cu(OAc)2. CuFAP mediates displacement of all aryl halides (F, Cl, Br, I) in DMF (X = F, Cl) or DMSO (X = Br, I), as shown below (Eqn. 1-6). Less basic CHAP [from Caio(P04 (OH)2 + Cu(OAc)2], Cu(OAc)2, CuI alone, or Cu powder are inactive. Interestingly, in 3-chloro-4-fluoronitrobenzene, the C-F bond reacts selectively with imidazole in high yield (85%, isolated). Polymer-supported copper (1) and copper (II) on polystyrene have both been shown usefUl for arylations of anilines and heteroaromatics with boronic acids. 

For an asymmetric reaction to be really useful enantiomeric excesses typically above 90% are needed and preferably even higher. The recent use of a chiral proton donor attached to polystyrene achieves this and perhaps equally important offers a methodology far superior to the nonsupported analogue [93]. In this work (D)-mandelic acid has been bound to chloromethylated polystyrene via its carboxylic acid. This species was then employed as a proton donor to the silyl enol ether derived from racemic mandelic acid to reform specifically one optical isomer of man-delic acid. Enantiomeric excesses up to 94% have been achieved. The chiral polymer has been recycled satisfactorily and one could speculate that a continuous process could be established converting racemic acid into one pure enantiomer using the corresponding polymer-bound enantiomer as the mediator. 

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