Resin-bound substrates

An inverted system based on the C02-soluble catalyst Pd(OAc)2/PtBu3 has been utilized for Suzuki-coupling of resin-bound substrates [33], The use of scC02 with polymer-supported substrates seems highly attractive owing to the known plasticizing... 

High loading can, however, be an inconvenience if resin-bound substrates are able to react with themselves (e.g. during olefin cross-metathesis or macrocyclizations), or if bi- or polyfunctional, unprotected reagents are to be used in solid-phase synthesis. 

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]. 

The most common resin-bound substrates for Mitsunobu etherification are primary benzylic alcohols, but a few non-benzylic alcohols have also been converted into aryl ethers (Table 7.13). Support-bound secondary alcohols are less suitable alkylating agents because elimination often predominates. 

The concept of site-isolation in cross-linked resin-bound substrates has been a controversial subject137). The state of perfect site isolation in a polymer-bound substrate is an ideal situation in which there is no interaction between the functional groups bound to the polymer chain. There have been many observations supporting site isolation in suitably cross-linked functionalized polystyrenes there have been also a number of reports of intersite interactions in polymer matrices. 

Fridkin et al. made use of the possibility of bringing about an effective site isolation in resin-bound substrates, a situation approaching infinite dilution of reactants, to effect an intramolecular peptide eyclization for the synthesis of cyclic peptides (see sect. 3.4) 109 110). Several other attempts have been made to exploit the phenomenon of diminished site-site interactions in polymeric matrices relative to those in solutions the results are often difficult to interpret or contradictingly interpretted137). The titanocene derivative 19 which is bound to 20% cross-linked polystyrene shows catalytic activity, whereas its solution counter part dimerizes to the catalytically inactive 20 138). 

This resin-bound substrate was then used for the synthesis of 1,4-quinone derivatives (Fig. 6.2). In the first step, the isopropoxy-group was displaced with primary amines (Fig. 

By immobilizing 3-(n-butyl) 4-isopropoxy squarate instead of diisopropyl squarate, naphthalines were accessible. Thermolysis and air oxidation of this resin-bound substrate gave a 1,4-naphthoquinone derivative (Fig. 6.3). If the hydroxy function was acylat-ed first, no air oxidation was possible during thermolysis and 1,4-dihydroxynaphthalines were obtained (Fig. 6.3). Both compounds were cleaved from resin with 20% TFA in CH2C12. 

Tin hydride reagents are versatile tools for the functionalization of alkenes and alkynes. Based on this concept, Nicolaou and coworkers developed a polymer-bound tin hydride (118) that reacts via Pd-catalyzed hydrostannylation (or nucleophilic attack on the tin chloride with a vinyl lithium) with alkynes to give alkenylstannanes [116]. After further transformation to derivatives 119, the resin-bound substrates undergo proteolytic traceless cleavage to yield unsubstituted alkenes 120. Alternatively, the stannane can be employed for intramolecular Shlle coupling to produce macrolactones 121 in the cleavage step (Scheme 16.28). 

From a practical point of view, if running parallel reactions is quite straightforward in SPS, the analysis of resin-bound substrates and resin-bound products is not. For solution-phase synthesis the experimenter has at his disposal a wide panel of routine analytical techniques that give rapid and readable information. In contrast, for solid-phase reactions, analysis is not routine and chemists often do not have the know-how and the experimental background to analyse reactions in solid support. 

FT-IR is a very convenient method for the evaluation of resin-bound intermediates and can give information on the completeness of reactions.3-i69.400.563,564 Resin-bound substrates are also suitable for KBr pellet IR analysis and for photoacoustic IR.365... 

The resin-bound substrates are assumed to be present on the surface of the resin beads as well as in the cavities or pores of the beads (Merrifield and Littau, 1968). The rate of coupling reactions in the solid-phase method is usually slower compared with those in solution. The reaction... 

The T1 linker originally found use as a traceless linker since treatment of T1 resin-bound substrates with TFA was found to release the corresponding aryl diazonium salts. Enders, in his preparation of p-lactams, was then able to show that heating the diazonium salts liberated nitrogen and a hydrogen residue was left at the cleavage site (Table 1.7, Entry 1). In related... 

The use of resin-bound substrates in combinatorial chemistry is often essential to creating diverse chemical libraries. Such polymer-supported reagents are suitable for Heck-type chemistry for example resin-bound iodobenzyl alcohol 88 was found to undergo reaction with a large range of... 

Cyclization can also be performed via nucleophilic attack of nitrogen nucleophiles as shown for the release of cyclic urea derivatives. Dressman et al. examined a methodology to cleave hydantoins 222 via treatment of carbamate linkers with an intramolecular amide functionahty and base [188]. In the case of resin-bound substrate 221 (Scheme 33), the resulting heterocycle is a five-membered ring system but other heterocycles containing a urea-type unit can also be synthesized as published by diverse other groups (c.f. benzimidazolone-synthesis of li et al. [199]). 

Carbonate linkers have been transformed into carbamates and alcohols via cleavage from the solid support. Alcohols 243 can be produced by the addition of TFA/thioanisole to the resin-bound substrates 242 (Scheme 36). They can also be obtained by photolytic cleavage from resins with general linker structure 238 or via cleavage with fluorine reagents from linkers like 239 in Fig. 11 [205,206]. 

Depending on the nature of the resin-bound substrates, cleavage protocols can provide an (additional) alkene functionality 447 or compounds 448 that are substituted by nucleophiles on the sulfone anchoring side. 

Other nucleophiles can be chosen to perform substitutions on sulfonate ester linkers. Roush et al. synthesized alkyliodides 542 via cleavage of oligosaccharides from Merrifield-type resins 541 by addition of Nal to the resin-bound substrates [314]. 

The Kaiser test is an adaption of the ninhydrin test to sohd phase conditions and allows the visual detection of free amines in resin-bound substrates. The possibility of qualitatively or quantitatively tracking the reaction progress of polyamine modification makes it a very helpful tool for sohd phase chemistry. The general solution phase methods (e.g., thin layer chromatography) are not suitable. Here, the Kaiser test was used to additionally... 

In the case of cyclo-release linker units, an intramolecular cyclization of the resin-bound substrate takes... 

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