Polymer-bound thiols

Scavenger resins and polymer-bound reagents are routinely used to prepare medium-sized (500-1000 member) libraries. Polymer-bound isocyanates (9) and aldehydes (10) are used to remove amines from reaction mixtures, while polymer-bound thiols (11) are used to scavenge halides. 

Polymer-bound thiol was reacted with the complex of NCS and dimethylsulfide to afford 1,2-dithionane through spontaneous cyclization of the dimethyl(thio)sulfonium intermediate 224 (Scheme 46) <2000TL9989>. 

A similar approach towards the synthesis of pyrimidines was recently described by Suto et a/.i starting from polymer-bound thiol 351 as decribed in Scheme 4.6.8. 

Disulfide Formation in Polystyrene Networks. Polymer-bound thiols were prepared by copolymerizations of bis -vinylbenzyl)disulfide with other divinyl monomers followed by diborane reduction (Scheme 5) (fiS). The initially formed thiols were juxtaposed for reoxidation to disulfides. Polymer-bound thiols were prepared also by copolymerization of p-vinylbentyl thiolacetate with divinyl monomers followed by hydrolysis (Scheme 6). llie latter thiols were distributed randomly throughout the polymer network. The copolymer reactivity ratios for p-vinylbenzyl thiolacetate and styrene are unknown, but should be similar to those of styrene (Mi) and p-vinyl-bentyl chloride (M2) ri = 0.6, r2 = 1.1 (fifi). Copolymeiizations with equal volumes of monomers and 1/1 acetonitrile/toluene product macroporous 40-48% DVB-cross-linked networks (651. 

Table L Oxidation of Polymer-Bound Thiols to Disulfides ...

Scheme 37 illustrates one example from a 16-member library where fluorous thiol scavenger 46 quickly purified the crude products of amine alkylation reactions. Amine 43 was reacted with a modest excess (2 equiv.) of alkylating 44 to ensure rapid and complete conversion to 45. The excess halide 44 was then scavenged by addition of thiol 46. Quick aqueous workup to remove the salts followed by two-stage fluorous solid-phase extraction to remove the quenched product 47 and the unreacted thiol 46 provided the pure alkylation product 45 in an excellent yield and purity. Rapid quenching is an attractive feature of this procedure, and control experiments showed that only about one-tenth the reaction time was needed for 46 compared with a related polymer-bound thiol. 

A number of polymer-bound thiols have also been found to be highly effective for ruthenium complexation and removal from polymers formed by ROMP processes. One of the best is the triazine derivative 11 (Figure 13.4), although a simple polymer-bound thioalkyl group can be equally effective [28]. Levels as low as 10-ppm ruthenium can readily be reached, provided that a suitably large excess of the bound ligand is used. 

Acid derivatives that can be converted to amides include thiol acids (RCOSH), thiol esters (RCOSR), ° acyloxyboranes [RCOB(OR )2]. silicic esters [(RCOO)4Si], 1,1,1-trihalo ketones (RCOCXa), a-keto nitriles, acyl azides, and non-enolizable ketones (see the Haller-Bauer reaction 12-31). A polymer-bound acyl derivative was converted to an amide using tributylvinyl tin, trifluoroacetic acid, AsPh3, and a palladium catalyst. The source of amine in this reaction was the polymer itself, which was an amide resin. 

Polymer-Bound Triazine Attached via a Thiol Linker (20) (Fig. 4)14... 

Reaction of Resin-Bound Iron Complex (54) with Alkyl Mercaptans, Thiophenols, and Phenols (Fig. 9)31. Sodium thiolates are prepared analogously to the alkoxides from thiol and sodium hydride, except that dry DMF is used as a solvent. The substitution on the polymer-bound arene (54) is performed at 70° in DMF within 16 h. The resin is filtered and washed with DMF (2 x 50 ml), MeOH (2 x 50 ml), H20 (2 x 50 ml), MeOH (2 x 50 ml), and CH2CI2 (3 x 50 ml) and then dried in vacuo at 40° to yield a red resin. 

In an earlier example of the resin-capture-release methodology trifluoracetylation of amines was achieved using polymer-bound benzyl thiol 8. Trifluoroacetic anhydride was employed in the capturing process while addition of amines to the intermediate polymer-bound thiolester released the desired trifluoroacetamide from the resin [21]. 

In an opposite manner to bases such as 1 and 2 in terms of reactivity, polymer-supported tosyl chloride equivalent 14 is able to capture alcohols as polymer-bound sulfonates 15, which are released as secondary amines, sulfides and alkylated imidazoles with primary amines, thiols and imidazoles as nucleophiles in a substitution process (Scheme 6) [24]. This technique has further been extended for the preparation of tertiary amines [25] and esters [26]. Excess of amine was scavenged by polymer-supported isocyanate 16 [27, 28] while excess of carboxylic acid was removed by treatment with aminomethylated polystyrene 17. 

The mechanistic principle of the chain transfer exploiting functionalized transfer agents was used for the synthesis of polymer bound CB AO, attached to the polymer chain via the sulfur atom. Weinstein [73, 74] used phenolic and aminic thiols 79, 81 and disulfides 80, 82 as generators of thiyls during free-radical bulk or emulsion copolymerization of butadiene or isoprene with styrene. Systems formed can be considered as bifunctional physically persistent stabiUzers combining CB and HD fiinctions. 

The byproduct DBF is not an easy compound to handle, as it polymerizes rapidly forming precipitates and gels. Thus adduct formation is a highly favorable side reaction however, the process of adduct formation is an equilibrium reaction between DBF and the deblocking amine, where the product distribution at equilibrium depends on the solvent and identity of the amine.f 1 This fact affects also the use of polymer-bound amines for Fmoc cleavage which would, upon adduct formation, facilitate separation of the DBF for synthesis in solution.t 1 However, with nonquantitative adduct formation, this type of resin scavenger is more or less useless,whereas, as discussed in Section 2.1.1.1.1.3.2, resin-bound thiols are much more efficient scavengers for DBF. 

For example, the cobalt(II) complex for phthalocyanine tetrasodium sulfonate (PcTs) catalyzes the autoxidation of thiols, such as 2-mercaptoethanol (Eq. 1) [4] and 2,6-di(t-butyl)phenol (Eq. 2) [5]. In the first example the substrate and product were water-soluble whereas the second reaction involved an aqueous suspension. In both cases the activity of the Co(PcTs) was enhanced by binding it to an insoluble polymer, e.g., polyvinylamine [4] or a styrene - divinylbenzene copolymer substituted with quaternary ammonium ions [5]. This enhancement of activity was attributed to inhibition of aggregation of the Co(PcTs) which is known to occur in water, by the polymer network. Hence, in the polymeric form more of the Co(PcTs) will exist in an active monomeric form. In Eq. (2) the polymer-bound Co(PcTs) gave the diphenoquinone (1) with 100% selectivity whereas with soluble Co(PcTs) small amounts of the benzoquinone (2) were also formed. Both reactions involve one-electron oxidations by Co(III) followed by dimerization of the intermediate radical (RS or ArO ). 

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