1. Comb. Chemistry 2. N2H4/DMF
In addition to the linkers mentioned above, the chlorotrityl linker commonly applied for the binding of carboxylic acids can also be used for the attachment of secondary amines , An example is the binding of piperazine as the amine component in a Mannich reaction on solid support (Scheme 15). Reaction of an aldehyde with the resin-bound amine, followed by addition of acetylide, led to solid phase-bound intermediates of type 31 from which the final compounds 32 were obtained by acid-mediated cleavage.
Commercially available 2-chlorotrityl chloride resin was treated with piperazine and washed with DMF (three times), MeOH (three times),THF (three times), and DCM (three times) and dried.
For the Mannich reaction, a screw-capped fritted glass reaction vessel was charged with the resin (0.3 g, 0.75 mmol g"1), Cu(l)CI (0.45 mmol, 45 mg) and benzaldehyde (1.57 mmol, 0.16 mL). After shaking for 0.5 h, phenylacetylene (1.57 mmol, 0.173 mL) was added to the mixture, and the reaction vessel was heated to 85° C with shaking for 3 h.The resin was filtered hot and washed thoroughly with dioxane (once), DMF (three times), 20 % aqueous HOAc (once), DMF (once), 7 M NH40H (once), DMF (once), MeOH (three times),THF (three times), and DCM (three times).
Cleavage of the desired product from the solid support was accomplished by treatment of the resin withTFA/DCM (1:1) for 5 min. After filtration, it was washed as above. Evaporation of the solvents under nitrogen gave the desired Mannich adduct as an oily bis-TFA salt (98 mg, 86 %).
A secondary amine can be attached to the 2-chlorotrityl resin in the presence of Huenig's base .
The 2-chlorotrityl linker was used recently also for the synthesis of peptidomimetics libraries of type 33 [28,29]. The actual synthesis is outlined in Scheme 16.
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