A silicon linker (68) which allows for the direct loading of the aromatic compound to the solid support has also been developed (Scheme 34).
The system has the advantage that 68 can be stored indefinitely, but can be activated with HC1 to form 69 before use. The utility of the linker was demonstrated in the synthesis of pyri-dine-based tricyclic structures .
A method for the attachment of haloarylsilanes to a polymer support via the intermediate 70 also led to a traceless system (Scheme 35). The polymer-bound arylhalides were used in a
Suzuki reaction with a variety of arylboronic acids, and the final products were cleaved from the support by different electrophiles (including H+) ,
Scheme 35 70
Cleavage is generally performed as protodesilylation.The conditions very much depend on the nature of the aromatic system, as well as on the substitution. Either neatTFA,TFA vapor orTFA/DCM can be used. Electron-poor aromatic systems require treatment with CsF in DMF/water (4:1) at 110° C.
In the traceless system outlined in Scheme 35 an electrophilic cleavage, either iododesily-lation (ICI in DCM) or bromodesilylation (Br2/pyridine in DCM) is required after the Suzuki coupling. These methods of electrophilic cleavage were found to be superior to pro-todesilylation.
A variant of a silyl linker contains a silyloxy linkage rather than a silylalkyl linkage (71). The diisopropylsilyloxy linkage in this type of linker (which is commercially available with different substituents on the phenyl ring) is stable to a wide range of reagents such as strong bases or moderately strong acids, yet it can be cleaved under mild conditions using TBAF in THF. It is important to note that the cleavage conditions may be highly influenced by substitution on the aryl ring ,
For loading onto the resin, (hydroxymethyl)polystyrene (6.00 g, 6 mmol) and imidazole (36 mmol, 2.45 g) were taken up in 40 mL of DMF.The arylchlorosilane (24.1 mmol, 6.92 g) was added to the suspension and the mixture was kept at rt with shaking for 45 h.The resin was filtered and washed with DMF (three times),THF (three times), and DCM (three times), after which the resin was dried. Repetition of the above procedure enhanced the loading. For cleavage after solid-phase synthesis starting from 71, the resin (0.209 g) in 2 mL of DMF was treated with 1 mL ofTBAF inTHF (1 M), and the mixture was heated at 65° C for 1 h with shaking. After cooling to rt, the mixture was diluted with water (10 mL), filtered and washed with Et20 (three times).The organic layer was washed with water (10 mL) and brine (10 mL), dried and evaporated.The residue was taken up in CHCI3 followed by SPE on basic Al203. Evaporation of the solvent yielded the desired product.
18.104.22.168 Traceless Linkers Based on Olefin Metathesis
Recently, it was shown that bis(tricyclohexyl phosphine) benzylidene ruthenium dichloride (72) [75,76] was also able to catalyze olefin metathesis on a solid support .Thus, if the re action were to be performed as ring closure metathesis, this offered another possibility for a traceless release of combinatorial compounds from solid supports. As only the desired products were cleaved off during the reaction, these were obtained in high purity. The method is compatible with a whole variety of different functionalities such as carboxylic acids, car-boxylic acid anhydrides, amides, aldehydes, ketones, alcohols and sulfonamides.
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