2. Comb. Chemistry

2. Comb. Chemistry

Procedure: Preparation of resin-bound amine 16

A 1 M t-BuOK/THF (300 mol %) solution was added to a solution of diol 14 (300 mol %) in dryTHF (2.5 mL/mmol), cooled at 0° C.The solution was stirred at 0° C for 45 min and for 3 h at rt. Merrifield resin (100 mol % of chlorine sites, loading: 1.35 mmol g) was added, and the suspension was shaken for 3.5 days at rt. After filtration, the resin-bound tert.-alkyl alcohol 15 was washed with THF (4 times), 1/1 DMF/water (twice), DMF (twice), THF (twice), and DCM (twice) and dried.

DMAP (50 mol %) and CDI (400 mol %) were added to a suspension of resin 15 (100 mol %) in dry DMF (4.5 mL/mmol).The mixture was shaken for 24 h at rt and filtered.The support was washed with DCM (three times), THF (three times), DCM (three times) and dried.

Methyl triflate (170 mol %) was added to a suspension of the resin (100 mol % of car-bonylimidazole sites) in dry 1.2-DCE (16 mL/mmol), cooled at 10° C.The mixture was stirred for 15 min at this temperature and for 5-10 min while being warmed to rt. After addition of Et3N (500 mol %), stirring was continued for an additional 5 min. A secondary amine was added (600 mol %, neat or as a solution in DCM or DMF) and the mixture was shaken for 3.5 h at rt. and filtered. Polymer-bound carbamate was washed with THF (three times), THF/MeOH 1/1 (three times), THF (three times) and DCM (three times) and dried. The product was characterized by IR and CHN analysis.

Procedure: Cleavage of 16 to yield amine 17

Resin 16 was treated with 10 %TFA/DCM (2.5 mL per 100 mg resin) for 4.5 h and filtered. The resin was rinsed with DCM (three times), MeOH (twice) and the filtrates were evapo-

rated and dried to give the amine 17 as aTFA salt. The 1H-NMR spectra of the cleaved amines were identical with those of authentic samples. A Urethane Linker to be Cleaved by Fluoride Ions

This recently reported linker was synthesized starting from commercially available aldehyde-modified support 18 [18]. After reaction with Grignard compound 19, alcohol 20 was obtained which was then transformed with CDI to the activated species ready for the attachment of the amine to yield 21. The desired amine 3 was liberated by fluoride ions (Scheme 7). The linker is versatile in that it can be used not only for the attachment of amines but also for the attachment of carboxylic acids and alcohols.

Primary amines attached to the solid support via an oxime carbamate were used for the preparation of diverse ureas of type 22 according to Scheme 8. In this respect, further diversity could be introduced, leading at the same time to a release from the support [19]. Benzyl-Linked Approaches for Secondary Amines

An elegant approach for the preparation of secondary amines is outlined in Scheme 9. The method is based on the efficient cleavage of N-benzyl-linked tert. amines from solid support by treatment with a-chloroethyl chloroformate/MeOH [20].

Attachment of a secondary amine as starting material to the chlorobenzyl group of Merri-field resin proceeded with high efficiency. After combinatorial synthesis, treatment with a-chloroethyl chloroformate released the intermediate 23, which decomposed in refluxing methanol to yield the secondary amine 3.

Procedure: Cleavage of N-benzyl-linked tert. amines from the support by a-chloroethyl chloroformate/MeOH to yield sec. amines 17

An excess of an amine was first coupled to the Merrifield resin in a suspension of DMF (if the amine was added as hydrochloride, then 20 equiv. of DIPEA were added).The mixture was stirred for 17 h at 50° C.The substitution level was >0.6 mmol/g (>85 %).To a suspension of the resin in 1,2-dichloropropane, 10 equiv. of a-chloroethyl chloroformate was added and the suspension was stirred for 3 h at rt.The resin was filtered off and the filtrate evaporated to dryness.The residue was dissolved in MeOH and the solution refluxed for no2

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